Publications by authors named "Kechen Ban"

25 Publications

  • Page 1 of 1

Genetic Variant of PP2A Subunit Gene Confers an Increased Risk of Primary Liver Cancer in Chinese.

Pharmgenomics Pers Med 2021 1;14:1565-1574. Epub 2021 Dec 1.

Department of Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, People's Republic of China.

Background: Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese.

Methods: In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform.

Results: The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009-1.650), and the number of insert G allele worked in a dose-dependent manner ( = 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264-7.364) than those never drink ( = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype ( = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers ( < 0.001).

Conclusion: These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.
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http://dx.doi.org/10.2147/PGPM.S335555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654694PMC
December 2021

Feasibility of using digital confocal microscopy for cytopathological examination in clinical practice.

Mod Pathol 2021 Oct 9. Epub 2021 Oct 9.

Department of Neurosurgery Research, The University of Texas, MD Anderson Cancer Center Houston, Houston, TX, USA.

Optical imaging modalities are emerging as digital microscopy tools for tissue examination. The investigation of these techniques for potential applications in anatomic pathology practice has focused primarily on surgical pathology and has not included cytopathological specimens. We evaluated the feasibility of using digital confocal microscopy (CM) to examine cytopathological specimens. Smears and cell suspensions collected in RPMI solution were prepared from tissue scrapes obtained from surgical resections of breast, lung, liver, and kidney. Air-dried smears and cell pellets obtained from centrifugation of the cell suspensions were stained with 0.6 mM acridine orange and imaged with a CM platform. After completion of imaging, the smears were stained with Diff-Quik (DQ), and cell pellets were routinely processed, embedded in paraffin wax, cut, and stained with hematoxylin and eosin (H&E). We evaluated the mean time to acquire digital CM images; quality of images based on the extent of tissue recognition (0%, grade 0; 1-19%, grade 1; 20-50%, grade 2; >50%, grade 3); comparison of images with DQ- and H&E-stained specimens; and ability to make specific diagnoses. We imaged 91 smears and 52 cell pellets and acquired digital CM images within 2-3 min, with 92% and 88% of images, respectively, from smears and cell pellets showing grade 3 quality. On the basis of CM images, 8 smears (9%) and 7 cell pellets (14%) were categorized as benign, and 83 (91%) and 45 (88%), respectively, as malignant. Specific diagnoses were made by using digital CM images of smears and cell pellets that matched accurately with corresponding DQ- and H&E-stained preparations. The results of our first feasibility study clearly indicated the utility of CM as a next-generation digital microscopy tool for evaluating cytology specimens. Prospective clinical studies are warranted for validating our findings for potential incorporation into cytopathological clinical practice.
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http://dx.doi.org/10.1038/s41379-021-00925-4DOI Listing
October 2021

Assessment of breast cancer surgical margins with multimodal optical microscopy: A feasibility clinical study.

PLoS One 2021 11;16(2):e0245334. Epub 2021 Feb 11.

Physical Sciences Inc, Andover, MA, United States of America.

Providing surgical margin information during breast cancer surgery is crucial for the success of the procedure. The margin is defined as the distance from the tumor to the cut surface of the resection specimen. The consensus among surgeons and radiation oncologists is that there should be no tumor left within 1 to maximum 2 mm from the surface of the surgical specimen. If a positive margin remains, there is substantial risk for tumor recurrence, which may also result in potentially reduced cosmesis and eventual need for mastectomy. In this paper we report a novel multimodal optical imaging instrument based on combined high-resolution confocal microscopy-optical coherence tomography imaging for assessing the presence of potential positive margins on surgical specimens. Since rapid specimen analysis is critical during surgery, this instrument also includes a fluorescence imaging channel to enable rapid identification of the areas of the specimen that have potential positive margins. This is possible by specimen incubation with a cancer specific agent prior to imaging. In this study we used a quenched contrast agent, which is activated by cancer specific enzymes, such as urokinase plasminogen activators (uPA). Using this agent or a similar one, one may limit the use of high-resolution optical imaging to only fluorescence-highlighted areas for visualizing tissue morphology at the sub-cellular scale and confirming or ruling out cancer presence. Preliminary evaluation of this technology was performed on 20 surgical specimens and testing of the optical imaging findings was performed against histopathology. The combination of the three imaging modes allowed for high correlation between optical image analysis and histological ground-truth. The initial results are encouraging, showing instrument capability to assess margins on clinical specimens with a positive predictive value of 1.0 and a negative predictive value of 0.83.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877783PMC
July 2021

Comparison of Real-Time Fluorescence Confocal Digital Microscopy With Hematoxylin-Eosin-Stained Sections of Core-Needle Biopsy Specimens.

JAMA Netw Open 2020 03 2;3(3):e200476. Epub 2020 Mar 2.

Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Strategies to procure high-quality core-needle biopsy (CNB) specimens are critical for making basic tissue diagnoses and for ancillary testing.

Objectives: To investigate acquisition of fluorescence confocal microscopy (FCM) images of interventional radiology (IR)-guided CNB in real time in the radiology suite and to compare the accuracy of FCM diagnoses with those of hematoxylin-eosin (H&E)-stained CNB sections.

Design, Setting, And Participants: In this diagnostic study, FCM imaging of IR-guided CNBs was performed in the radiology suite at a major cancer center for patients with an imaging abnormality from August 1, 2016, to April 30, 2019. The time taken to acquire FCM images and the quality of FCM images based on percentage of interpretable tissue with optimal resolution was recorded. The FCM images were read by 2 pathologists and categorized as nondiagnostic, benign/atypical, or suspicious/malignant; these diagnoses were compared with those made using H&E-stained tissue sections. Cases with discrepant diagnosis were reassessed by the pathologists together for a consensus diagnosis. Data were analyzed from June 3 to July 19, 2019.

Interventions: Each IR-guided CNB was stained with 0.6mM acridine orange, subjected to FCM imaging, and then processed to generate H&E-stained sections.

Main Outcomes And Measures: Mean time taken for acquisition of FCM images, quality of FCM images based on interpretable percentage of the image, and accuracy of diagnostic categorization based on FCM images compared with H&E-stained sections.

Results: A total of 105 patients (57 male [54.3%]; mean [SD] age, 63 [13] years) underwent IR-guided CNBs in a mean (SD) of 7 (2) minutes each. The FCM images showed at least 20% of the tissue with optimal quality in 101 CNB specimens (96.2%). The FCM images were accurately interpreted by the 2 pathologists in 100 of 105 cases (95.2%) (2 false-positive and 3 false-negative) and 90 of 105 cases (85.7%) (6 false-positive and 9 false-negative). A reassessment of 14 discordant diagnoses resulted in consensus diagnoses that were accurate in 101 of 105 cases (96.2%) (1 false-positive and 3 false-negative).

Conclusions And Relevance: The ease of acquisition of FCM images of acceptable quality and the high accuracy of the diagnoses suggest that FCM may be useful for rapid evaluation of IR-guided CNBs. This approach warrants further investigation.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.0476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059022PMC
March 2020

Confocal Fluorescence Microscopy Platform Suitable for Rapid Evaluation of Small Fragments of Tissue in Surgical Pathology Practice.

Arch Pathol Lab Med 2019 03 30;143(3):305-313. Epub 2018 Oct 30.

From the Departments of Pathology and Laboratory Medicine (Dr Krishnamurthy) and Pathology (Dr Ban), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (Drs Ban, Shaw, and Mills), and the Department of Interventional Radiology (Drs Sheth, Tam, Gupta, and Sabir), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Rapid advances in the fields of biophotonics, computer science, and instrumentation have allowed for high-resolution imaging of biologic tissues.

Objective.—: To evaluate the quality of images from an optimized confocal fluorescence microscopy (CFM) platform for rapid evaluation of small fragments of tissue, compared with hematoxylin-eosin staining.

Design.—: Tissue fragments (up to 1.0 × 0.3 cm) were stained with 0.6 mM acridine orange for 60 seconds and imaged using a CFM platform at 488-nm and 785-nm wavelength. The imaged tissues were then fixed in formalin and processed to generate hematoxylin-eosin-stained tissue sections. The quality of CFM images was scored on a scale of 0 to 3 on the basis of the percentage of the CFM images with recognizable tissue architecture (0, 0%; 1, <20%; 2, 20%-50%; 3, >50%). The diagnoses made using CFM images were compared with those made using histopathologic analysis of the hematoxylin-eosin-stained tissue sections.

Results.—: We imaged 118 tissue fragments obtained from 40 breast, 23 lung, 39 kidney, and 16 liver surgical excision specimens. We acquired CFM images in 2 to 3 minutes; 95.8% (113 of 118) of images showed a quality score of 3, and 4.2% (5 of 118) had a score of 2. We achieved a sensitivity of 95.5%, specificity of 97.3%, positive predictive value of 95.5%, and negative predictive value of 97.3%.

Conclusions.—: Our results demonstrate the suitability of the CFM platform for rapid and accurate evaluation of small tissue fragments in surgical pathology practice.
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http://dx.doi.org/10.5858/arpa.2018-0352-OADOI Listing
March 2019

RET Signaling in Prostate Cancer.

Clin Cancer Res 2017 Aug 10;23(16):4885-4896. Epub 2017 May 10.

Department of Pathology & Immunology, Baylor College of Medicine and Michael E. DeBakey Dept. of Veterans Affairs Medical Center, Houston, Texas.

Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its coreceptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Because both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. Expression of RET, GDNF, and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion, and growth was determined. Cellular signaling downstream of RET was examined by Western blotting. RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation-related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. , knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small-cell carcinomas examined. RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609835PMC
August 2017

Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock.

J Trauma Acute Care Surg 2016 08;81(2):358-65

From the Shock Trauma Center (Z.P., R.A.K.), University of Maryland, Baltimore, Maryland; Department of Pathology and Immunology (K.B.), Baylor College of Medicine; and Department of Surgery (A.L.), University of Texas, Houston, Texas.

Background: Intravenous tranexamic acid (TXA) is an effective adjunct after hemorrhagic shock (HS) because of its antifibrinolytic properties. TXA is also a serine protease inhibitor, and recent laboratory data demonstrated that intraluminal TXA into the small bowel inhibited digestive proteases and protected the gut. A Disintegrin And Metalloproteinase 17 (ADAM-17) and tumor necrosis factor α (TNF-α) are effective sheddases of intestinal syndecan-1, which when shed, exposes the underlying intestinal epithelium to digestive proteases and subsequent systemic insult. We therefore hypothesized that intraluminal TXA as a serine protease inhibitor would reduce intestinal sheddases and syndecan-1 shedding, mitigating gut and distant organ (lung) damage.

Methods: Mice underwent 90 minutes of HS to a mean arterial pressure of 35 ± 5 mm Hg followed by the intraluminal administration of TXA or vehicle. After 3 hours, the small intestine, lung, and blood were collected for analysis.

Results: Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared with HS alone. Gut, lung, and systemic ADAM-17 and TNF-α were significantly increased by HS but lessened by TXA. In addition, gut and lung syndecan-1 immunostaining were preserved and systemic shedding lessened after TXA. TXA reduced ADAM-17 and TNF-α, but not syndecan-1, in TXA-sham animals compared with sham vehicles.

Conclusion: Results of the present study demonstrate a beneficial effect of intraluminal TXA in the gut and lung after experimental HS in part because of the inhibition of the syndecan-1 shedding by ADAM-17 and TNF-α. Further studies are needed to determine if orally administered TXA could provide similar intestinal protection and thus be of potential benefit to patients with survivable hemorrhage at risk for organ injury. This is particularly relevant in patients or soldiers who may not have access to timely medical care.
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http://dx.doi.org/10.1097/TA.0000000000001056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308205PMC
August 2016

Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice.

Shock 2015 Nov;44(5):452-7

*Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas †Shock Trauma Center, University of Maryland, Baltimore, Maryland ‡Blood Systems Research Institute §Department of Surgery, University of California, San Francisco, California ||University of Texas Health Science Center at Houston, Houston, Texas ¶Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, Massachusetts.

We have shown in a rodent model of hemorrhagic shock (HS) that fresh frozen plasma (FFP) reduces lung inflammation and injury that are correlated with restitution of syndecan-1. As the gut is believed to contribute to distant organ injury and inflammation after shock, the current study sought to determine if the protective effects of plasma would extend to the gut and to elucidate the contribution of syndecan-1 to this protective effect. We also examined the potential role of TNFα, and a disintegrin and metalloproteinase (ADAM)-17, both intestinal sheddases of syndecan-1. Wild-type (WT) and syndecan-1 (KO) mice were subjected to HS followed by resuscitation with lactated Ringer's (LR) or FFP and compared with shock alone and shams. Small bowel and blood were obtained after 3  h for analysis of mucosal injury and inflammation and TNFα and ADAM-17 protein expression and activity. After HS, gut injury and inflammation were significantly increased compared with shams. Resuscitation with LR decreased both injury and inflammation that were further lessened by FFP. KO mice displayed worsened gut injury and inflammation after HS compared with WT mice, and LR and FFP equivalently inhibited injury and inflammation. Both systemic and intestinal TNFα and ADAM-17 followed similar trends, with increases after HS, reduction by LR, and a further decrease by FFP in WT but not KO mice. In conclusion, FFP decreased gut injury and inflammation after hemorrhagic shock, an effect that was abrogated in syndecan-1 mice. Plasma also decreased TNFα and ADAM-17, representing a potential mechanistic link to its protection via syndecan-1.
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http://dx.doi.org/10.1097/SHK.0000000000000452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816460PMC
November 2015

Protection by enteral glutamine is mediated by intestinal epithelial cell peroxisome proliferator-activated receptor-γ during intestinal ischemia/reperfusion.

Shock 2015 Apr;43(4):327-33

*Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas; and †Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland.

We have demonstrated that enteral glutamine provides protection to the postischemic gut, and that peroxisome proliferator-activated receptor-γ (PPARγ) plays a role in this protection. Using Cre/lox technology to generate an intestinal epithelial cell (IEC)-specific PPARγ null mouse model, we now investigated the contribution of IEC PPARγ to glutamine's local and distant organ-protective effects. These mice exhibited absence of expression of PPARγ in the intestine but normal PPARγ expression in other tissues. After 1 h of intestinal ischemia under isoflurane anesthesia, wild-type and null mice received enteral glutamine (60 mM) or vehicle followed by 6 h of reperfusion or 7 days in survival experiments and compared with shams. Small intestine, liver, and lungs were analyzed for injury and inflammatory parameters. Glutamine provided significant protection against gut injury and inflammation, with similar protection in the lung and liver. Changes in systemic tumor necrosis factor-α reflected those seen in the injured organs. Importantly, mice lacking IEC PPARγ had worsened injury and inflammation, and glutamine lost its protective effects in the gut and lung. The survival benefit found in glutamine-treated wild-type mice was not observed in null mice. Using an IEC-targeted loss-of-function approach, these studies provide the first in vivo confirmation in native small intestine and lung that PPARγ is responsible for the protective effects of enteral glutamine in reducing intestinal and lung injury and inflammation and improving survival. These data suggest that early enteral glutamine may be a potential therapeutic modality to reduce shock-induced gut dysfunction and subsequent distant organ injury.
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http://dx.doi.org/10.1097/SHK.0000000000000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359662PMC
April 2015

Inhibition of ERK1/2 worsens intestinal ischemia/reperfusion injury.

PLoS One 2013 20;8(9):e76790. Epub 2013 Sep 20.

Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

Background: The role of extracellular signal-regulated protein kinase (ERK) in intestinal ischemia/reperfusion (I/R) injury has not been well investigated. The aim of the current study was to examine the effect of inhibition of the ERK pathway in an in vitro and in vivo model of intestinal I/R injury.

Methods: ERK1/2 activity was inhibited using the specific inhibitor, U0126, in intestinal epithelial cells under hypoxia/reoxygenation conditions and in mice subjected to 1 hour of intestinal ischemia followed by 6 hours reperfusion. In vitro, cell proliferation was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, apoptosis by DNA fragmentation, and migration using an in vitro model of intestinal wound healing. Cells were also transfected with a p70S6K plasmid and the effects of overexpression similarly analyzed. In vivo, the effects of U0126 on intestinal cell proliferation and apoptosis, intestinal permeability, lung and intestinal neutrophil infiltration and injury, and plasma cytokine levels were measured. Survival was also assessed after U0126. Activity of p70S6 kinase (p70S6K) was measured by Western blot.

Results: In vitro, inhibition of ERK1/2 by U0126 significantly decreased cell proliferation and migration but enhanced cell apoptosis. Overexpression of p70S6K promoted cell proliferation and decreased cell apoptosis. In vivo, U0126 significantly increased cell apoptosis and decreased cell proliferation in the intestine, increased intestinal permeability, intestinal and lung neutrophil infiltration, and injury, as well as systemic pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β. Mortality was also significantly increased by U0126. Inhibition of ERK1/2 by U0126 also abolished activity of p70S6K both in vitro and in vivo models.

Conclusion: Pharmacologic inhibition of ERK1/2 by U0126 worsens intestinal IR injury. The detrimental effects are mediated, at least in part, by inhibition of p70S6K, the major effector of mammalian target of rapamycin pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779170PMC
May 2014

Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice.

PLoS One 2012 27;7(7):e41584. Epub 2012 Jul 27.

Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

The mTOR signaling pathway plays a crucial role in the regulation of cell growth, proliferation, survival and in directing immune responses. As the intestinal epithelium displays rapid cell growth and differentiation and is an important immune regulatory organ, we hypothesized that mTOR may play an important role in the protection against intestinal ischemia reperfusion (I/R)-induced injury. To better understand the molecular mechanisms by which the mTOR pathway is altered by intestinal I/R, p70S6K, the major effector of the mTOR pathway, was investigated along with the effects of rapamycin, a specific inhibitor of mTOR and an immunosuppressant agent used clinically in transplant patients. In vitro experiments using an intestinal epithelial cell line and hypoxia/reoxygenation demonstrated that overexpression of p70S6K promoted cell growth and migration, and decreased cell apoptosis. Inhibition of p70S6K by rapamycin reversed these protective effects. In a mouse model of gut I/R, an increase of p70S6K activity was found by 5 min and remained elevated after 6 h of reperfusion. Inhibition of p70S6K by rapamycin worsened gut injury, promoted inflammation, and enhanced intestinal permeability. Importantly, rapamycin treated animals had a significantly increased mortality. These novel results demonstrate a key role of p70S6K in protection against I/R injury in the intestine and suggest a potential danger in using mTOR inhibitors in patients at risk for gut hypoperfusion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407246PMC
March 2013

Syndecan 1 plays a novel role in enteral glutamine's gut-protective effects of the postischemic gut.

Shock 2012 Jul;38(1):57-62

Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Syndecan 1 is the predominant heparan sulfate proteoglycan found on the surface of epithelial cells and, like glutamine, is essential in maintaining the intestinal epithelial barrier. We therefore hypothesized that loss of epithelial syndecan 1 would abrogate the gut-protective effects of enteral glutamine. Both an in vitro and in vivo model of gut ischemia-reperfusion (IR) was utilized. In vitro, intestinal epithelial cells underwent hypoxia-reoxygenation to mimic gut IR with 2 mM (physiologic) or 10 mM glutamine supplementation. Permeability, caspase activity, cell growth, and cell surface and shed syndecan 1 were assessed. In vivo, wild-type and syndecan 1 knockout (KO) mice received ± enteral glutamine followed by gut IR. Intestinal injury was assessed by fluorescent dye clearance and histopathology, permeability as mucosal-to-serosal clearance ex vivo in everted sacs, and inflammation by myeloperoxidase (MPO) activity. In an in vitro model of gut IR, glutamine supplementation reduced epithelial cell permeability and apoptosis and enhanced cell growth. Shed syndecan 1 was reduced by glutamine without an increase in syndecan 1 mRNA. In vivo, intestinal permeability, inflammation, and injury were increased after gut IR in wild-type mice and further increased in syndecan 1 KO mice. Glutamine's attenuation of IR-induced intestinal hyperpermeability, inflammation, and injury was abolished in syndecan 1 KO mice. These results suggest that syndecan 1 plays a novel role in the protective effects of enteral glutamine in the postischemic gut.
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http://dx.doi.org/10.1097/SHK.0b013e31825a188aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391586PMC
July 2012

Inhibition of the NADPH oxidase regulates heme oxygenase 1 expression in chronic myeloid leukemia.

Cancer 2012 Jul 2;118(13):3433-45. Epub 2011 Dec 2.

Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Patients with chronic myelogenous leukemia (CML) in blast crisis have a poor response to tyrosine kinase inhibitors designed to inhibit the breakpoint cluster region-v-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) oncogene. Recent work has demonstrated that heme oxygenase 1 (HO-1) expression is increased in BCR-ABL1-expressing cells and that the inhibition of HO-1 in CML leads to reduced cellular growth, suggesting that HO-1 may be a plausible target for therapy. The objective of the current study was to clarify the mechanism of HO-1 overexpression and the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a contributor to this mechanism in CML.

Methods: HO-1 expression was evaluated in bone marrow specimens from patients with CML in various stages of disease, in a transplantation-based model for CML, and in CML cell lines. Chemical and genetic inhibition of the NADPH oxidase was carried out in CML cells.

Results: Specimens from patients with CML in blast crisis displayed higher levels of HO-1 staining than specimens from patients with CML in chronic or accelerated phase. HO-1 up-regulation in BCR-ABL1-expressing cells was suppressed by diphenyleneiodonium (DPI), a chemical inhibitor of the NADPH oxidase. Targeting the NADPH oxidase through RNA interference (RNAi) to Ras-related C3 botulinum toxin substrate 1 (Rac1), a dominant-negative Rac1 construct or an inhibitor of Rac1 activity also blunted HO-1 protein expression. Moreover, inhibition of the NADPH oxidase by RNAi directed toward the 47-kd cytosolic subunit of Nox (p47phox) similarly abrogated HO-1 levels.

Conclusions: BCR-ABL1 expression up-regulated HO-1, a survival factor for CML cells. This up-regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR-ABL1-expressing cells.
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http://dx.doi.org/10.1002/cncr.26621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297684PMC
July 2012

Arginine decreases peroxisome proliferator-activated receptor-γ activity via c-Jun.

Mol Cell Biochem 2012 Mar 26;362(1-2):7-13. Epub 2011 Oct 26.

Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

We have previously shown in the post ischemic gut that enteral arginine enhanced injury and inflammation via c-Jun/AP-1 and abrogated peroxisome proliferator-activated receptor (PPAR) γ activity. In the current study, we investigated the mechanism by which arginine inhibited PPARγ in vitro in rat small bowel epithelial IEC-6 cells. Arginine repressed PPARγ transcriptional activity in a time and dose-dependent fashion. Furthermore, downregulation of PPARγ by arginine involved phosphorylation of c-Jun that occurred before to changes in PPARγ transcriptional activity. Silencing of c-Jun increased PPARγ beyond that of nonsilenced cells and was not mitigated by arginine. Using a series of blocking studies, we found no relationship between arginine and the ligand-dependent binding site of PPARγ. In conclusion, arginine decreased PPARγ transcriptional activity in small bowel intestinal epithelial cells. These changes are due, in part, to phosphorylation of c-Jun and may explain the deleterious effects of enteral arginine in the post ischemic gut.
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http://dx.doi.org/10.1007/s11010-011-1122-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270150PMC
March 2012

Glutamine activates peroxisome proliferator-activated receptor-γ in intestinal epithelial cells via 15-S-HETE and 13-OXO-ODE: a novel mechanism.

Am J Physiol Gastrointest Liver Physiol 2011 Sep 7;301(3):G547-54. Epub 2011 Jul 7.

Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Glutamine possesses gut-protective effects both clinically and in the laboratory. We have shown in a rodent model of mesenteric ischemia-reperfusion that enteral glutamine increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and was associated with a reduction in mucosal injury and inflammation. The mechanism by which glutamine activates PPAR-γ is unknown, and we hypothesized that it was via a ligand-dependent mechanism. Intestinal epithelial cells, IEC-6, were co-transfected with PPAR-γ response element-luciferase promoter/reporter construct. Cells were pretreated with increasing concentrations of glutamine ± GW9662 (a specific antagonist of PPAR-γ) and analyzed for PPAR-γ response element luciferase activity as an indicator of PPAR-γ activation. PPAR-γ nuclear activity was assessed by electrophoretic mobility shift assay. Cell lysates were subjected to tandem mass spectroscopy for measurement of prostaglandin and lipoxygenase metabolites. A time- and concentration-dependent increase in PPAR-γ transcriptional activity, but not mRNA or protein, was demonstrated. Activity was abrogated by the PPAR-γ inhibitor, GW9662, and changes in activity correlated with PPAR-γ nuclear binding. Glutamine, via degradation to glutamate, activated the metabolic by-products of the lipoxygenase and linoleic acid pathways, 15-S-hydroxyeicosatetraenoic acid and dehydrogenated 13-hydroxyoctaolecadienoic acid, known endogenous PPAR-γ ligands in the small bowel. This novel mechanism may explain the gut-protective effects of enteral glutamine.
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http://dx.doi.org/10.1152/ajpgi.00174.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174542PMC
September 2011

Mammalian target of rapamycin regulates expression of β-catenin in hepatocellular carcinoma.

Hum Pathol 2011 May 15;42(5):659-68. Epub 2011 Jan 15.

Department of Pathology, Guangxi Medical University, Nanning, Guangxi 530021, PR China.

Although evidence has shown that both the mammalian target of rapamycin and β-catenin are involved in hepatocellular carcinoma, little is known about their relationship in pathogenesis of hepatocellular carcinoma. To investigate the expression of phosphorylated mammalian target of rapamycin and β-catenin and their prognostic impacts, as well as their relationship in hepatocellular carcinoma, we analyzed 63 human hepatocellular carcinoma samples by immunohistochemistry. Phosphorylated mammalian target of rapamycin cytoplasmic and β-catenin cytoplasmic/nuclear-positive immunoreactivities were observed in 63.5% (40/63) and 55.6% (35/63) of the hepatocellular carcinoma specimens, respectively. Significant associations were found between cytoplasmic β-catenin and phosphorylated mammalian target of rapamycin expression and tumor size (both P < .01) and metastasis (P < .01 and P < .05, respectively). In addition, β-catenin expression in the cytoplasm was closely associated with the expression of phosphorylated mammalian target of rapamycin. To further explore the relationship between mammalian target of rapamycin and β-catenin, hepatocellular carcinoma HepG2 and Hep3B cells were treated with β-catenin siRNA and mammalian target of rapamycin inhibitor, rapamycin; and the expression of phosphorylated mammalian target of rapamycin and β-catenin in cells was then measured by Western blot. The activity of Wnt/β-catenin signaling pathway was also assessed by luciferase reporter assay. The cell viability and proliferation were evaluated by thiazolyl blue tetrazolium bromide assay and [(3)H]-thymidine incorporation assay. The results showed that the level of β-catenin protein expression was markedly decreased by rapamycin in HepG2 and Hep3B cells. The reduction of β-catenin and mammalian target of rapamycin resulted in inhibition of cell viability proliferation, but the combination of reduction of β-catenin and mammalian target of rapamycin did not show a synergistic effect on the inhibition of cell viability and proliferation in HepG2 and Hep3B cells. In conclusion, the present study showed that, for the first time, mammalian target of rapamycin regulated the expression level of β-catenin in hepatocellular carcinoma. Both mammalian target of rapamycin and β-catenin play important roles in the growth, metastasis, and prognosis of hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.humpath.2010.07.021DOI Listing
May 2011

Enteral arginine modulates inhibition of AP-1/c-Jun by SP600125 in the postischemic gut.

Mol Cell Biochem 2011 Jan 29;347(1-2):191-9. Epub 2010 Oct 29.

Department of Surgery, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 4.284, Houston, TX 77030, USA.

We previously demonstrated that enteral arginine increased c-Jun/activator protein-1 (AP-1) DNA-binding activity and iNOS expression in a rodent model of mesenteric ischemia/reperfusion (I/R). The objective of this study was to specifically investigate the role of AP-1 in arginine's deleterious effect on the postischemic gut. We hypothesized that AP-1 inhibition would mitigate the effects of arginine. Using a rodent model of mesenteric I/R we demonstrated that gut neutrophil infiltration, activity of c-Jun/AP-1, as well as iNOS expression were increased by I/R and further increased by arginine while lessened by inhibition of c-Jun using the pharmacologic c-Jun N-terminal kinase inhibitor, SP600125. Similar results were demonstrated using a cell culture model of oxidant stress in IEC-6 cells. Importantly, effects of SP600125 were comparable to those of c-Jun silencing. Lastly, the specific iNOS inhibitor, 1400W, had no effect on either AP-1 or c-Jun. In conclusion, SP600125 attenuated the activity of c-Jun/AP-1, iNOS expression, and neutrophil infiltration induced by arginine following mesenteric I/R. Our data suggest that AP-1 inhibition mitigates the injurious inflammatory effects of arginine in the postischemic gut. Further investigation into the pathologic role of enteral arginine in the postischemic gut is warranted.
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http://dx.doi.org/10.1007/s11010-010-0628-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077971PMC
January 2011

Glutamine protects against apoptosis via downregulation of Sp3 in intestinal epithelial cells.

Am J Physiol Gastrointest Liver Physiol 2010 Dec 30;299(6):G1344-53. Epub 2010 Sep 30.

Department of Surgery, University of Texas Medical School, Houston, 77030, USA.

Glutamine plays a key role in intestinal growth and maintenance of gut function, and as we have shown protects the postischemic gut (Kozar RA, Scultz SG, Bick RJ, Poindexter BJ, Desoigne R, Weisbrodt NW, Haber MM, Moore FA. Shock 21: 433-437, 2004). However, the precise mechanisms of the gut protective effects of glutamine have not been well elucidated. In the present study, RNA microarray was performed to obtain differentially expressed genes in intestinal epithelial IEC-6 cells following either 2 mM or 10 mM glutamine. The result demonstrated that specificity protein 3 (Sp3) mRNA expression was downregulated 3.1-fold. PCR and Western blot confirmed that Sp3 expression was decreased by glutamine in a time- and dose-dependent fashion. To investigate the role of Sp3, Sp3 gene siRNA silencing was performed and apoptosis was assessed. Silencing of Sp3 demonstrated a significant increase in Bcl-2 and decrease in Bax protein expression, as well as a decrease in caspase-3, -8, and -9 protein expression and activity. The protein expression of apoptosis-related proteins after hypoxia/reoxygenation was similar to that of normoxia and correlated with a decrease in DNA fragmentation. Importantly, the addition of glutamine to Sp3-silenced cells did not further lessen apoptosis, suggesting that Sp3 plays a major role in the inhibitory effect of glutamine on apoptosis. This novel finding may explain in part the gut-protective effects of glutamine.
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http://dx.doi.org/10.1152/ajpgi.00334.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006244PMC
December 2010

Oxidative stress promotes transcriptional up-regulation of Fyn in BCR-ABL1-expressing cells.

J Biol Chem 2009 Mar 8;284(11):7114-25. Epub 2009 Jan 8.

Department of Pediatrics Research, Unit 853, Children's Cancer Hospital at M. D. Anderson, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Signaling initiated by the BCR-ABL1 kinase causes chronic myelogenous leukemia (CML). Recently, we reported that expression of Fyn, a Src kinase, is heightened in CML cells and patient specimens and confers in vitro and in vivo proliferative advantages. Fyn is regulated by redox, and because BCR-ABL1 raises intracellular oxidant levels, which have been implicated in CML progression, we explored the molecular regulation of Fyn. Here we identify the transcription factors that drive redox- and BCR-ABL1-dependent Fyn expression. Promoter deletion analysis in 293T, BaF3, BaF3-p210, and K562 cells identified the region essential for basal transcriptional activity. Mutation of Sp1 and Egr1 binding sites within the essential region diminished Fyn promoter activity and identified Egr1 as conferring redox sensitivity. Gel shift and chromatin immunoprecipitation assays confirmed the binding of Sp1 and Egr1 to the promoter fragments. Importantly, knockdown of Sp1 or Egr1 with small interference RNA or inhibition of Sp1 binding by mithramycin A repressed Fyn protein expression. Our work is the first to define transcription factors that are responsible for endogenous, oxidative stress-dependent and BCR-ABL1-dependent Fyn expression.
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http://dx.doi.org/10.1074/jbc.M804801200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652262PMC
March 2009

Enteral glutamine: a novel mediator of PPARgamma in the postischemic gut.

J Leukoc Biol 2008 Sep 7;84(3):595-9. Epub 2008 Apr 7.

Department of Surgery, University of Texas Health Science Center of Houston, 6431 Fannin, MSB 4.284, Houston, TX 77030, USA.

Early enteral nutrition supplemented with glutamine, arginine, omega-3 fatty acids, and nucleotides has been shown to decrease infection complications in critically injured patients. Concern has been raised, however, that under conditions of hyperinflammation, these diets may be injurious through the induction of inducible NO synthase by enteral arginine. In a rodent model of gut ischemia/reperfusion, inflammation and injury are intensified by enteral arginine and abrogated by glutamine. These findings correlate with the degree of metabolic stress imposed upon the gut by hypoperfusion. Glutamine is metabolized by the gut and therefore, can contribute back energy in the form of ATP, whereas arginine is a nonmetabolizable nutrient, using but not contributing energy. Recent data suggest that one of the molecular mechanisms responsible for the gut-protective effects of enteral glutamine is the activation of peroxisome proliferator-activated receptor gamma. This anti-inflammatory transcription factor belongs to the family of nuclear receptors, plays a key role in adipocyte development and glucose homeostasis, and has been recognized as an endogenous regulator of intestinal inflammation. Preliminary clinical studies support the use of enteral glutamine in patients with gut hypoperfusion.
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http://dx.doi.org/10.1189/jlb.1107764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516899PMC
September 2008

BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia.

Blood 2008 Mar 7;111(5):2904-8. Epub 2008 Jan 7.

Department of Pediatrics Research, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.
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http://dx.doi.org/10.1182/blood-2007-05-091769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254539PMC
March 2008

NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells.

Blood 2007 Jul 13;110(1):267-77. Epub 2007 Mar 13.

Department of Pediatrics Research, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.

The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma; however, in other hematologic malignancies, bortezomib has been less effective as a single agent. Here, we describe effects of NPI-0052, a novel proteasome inhibitor, in leukemia model systems. In cell lines, NPI-0052 inhibits all 3 proteolytic activities associated with the proteasome: chymotrypsin-, trypsin-, and caspase-like. NPI-0052 also induces DNA fragmentation in leukemia lines and in mononuclear cells from a Ph + acute lymphoblastic leukemia (ALL) patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in Fas-associated death domain (FADD)-deficient or caspase-8-deficient counterparts. NPI-0052-induced apoptosis was further probed using caspase-8 inhibitors, which were more protective than caspase-9 inhibitors. N-acetyl cysteine (NAC) also conferred protection against NPI-0052-induced apoptosis, indicating a role for oxidative stress by NPI-0052. In support of the drug's in vitro activities, biweekly treatment with NPI-0052 lessened total white blood cell (WBC) burden over 35 days in leukemic mice. Interestingly, combining NPI-0052 with either MS-275 or valproic acid (VPA) induced greater levels of cell death than the combination of bortezomib with these histone deacetylase inhibitors (HDACi). These effects of NPI-0052, alone and in combination with HDACi, warrant further testing to determine the compound's clinical efficacy in leukemia.
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http://dx.doi.org/10.1182/blood-2006-03-013128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1896116PMC
July 2007

Adaphostin cytoxicity in glioblastoma cells is ROS-dependent and is accompanied by upregulation of heme oxygenase-1.

Cancer Chemother Pharmacol 2007 Mar 19;59(4):527-35. Epub 2006 Aug 19.

Department of Pediatrics Research, Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., 853, Houston, TX 77030, USA.

Purpose: To delineate a role for reactive oxygen species (ROS) induction in adaphostin-induced apoptosis in glioblastoma cells.

Methods: Three glioblastoma cell lines with different sensitivities to adaphostin were characterized for sensitivity to an oxidant, tert-butyl hydroperoxide. The degree and duration of the ROS levels was assessed in the three cell lines after adaphostin exposure. Antioxidant protein levels were evaluated by Western blotting.

Results: Of the three glioblastoma cell lines, the U87 cells were least sensitive to adaphostin. These cells were also least sensitive to tert-butyl hydroperoxide, indicating that sensitivity to a direct oxidant stress mirrors the cells' adaphostin sensitivities. In addition, the antioxidant N-acetylcysteine, (NAC) was protective against adaphostin-induced apoptosis. Direct measurement of intracellular peroxides showed a transient increase in the two less sensitive cell lines (U87 and LN18) which diminishes by 24 h. In contrast, U251 cells, which are most sensitive to adaphostin, display a sustained increase in the ROS levels. After the initial increase in intracellular peroxides, the heat shock protein and antioxidant heme oxygenase-1 (HO-1) was upregulated. Levels of other antioxidant proteins, such as catalase and thioredoxin, however, were not altered by adaphostin in glioblastoma cell lines. NAC attenuated HO-1 upregulation, confirming the time course analysis.

Conclusions: These results suggest a primary role for ROS in adaphostin-induced apoptosis in glioblastoma. Our data indicate that the duration of intracellular ROS levels is a key factor in mediating sensitivity to adaphostin. Furthermore, upregulation of HO-1 is a novel molecular marker of adaphostin's action. The kinetics with which adaphostin upregulates HO-1 correlates with sensitivity to the drug. Taken together, our data indicate that a cell's ability to cope with ROS dictates sensitivity to adaphostin and conceivably other chemotherapies that cause redox perturbations.
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http://dx.doi.org/10.1007/s00280-006-0295-5DOI Listing
March 2007

FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.

Cancer Res 2006 Apr;66(7):3593-602

Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

The transcription factor Forkhead box M1 (FoxM1) is overexpressed in malignant glioma. However, the functional importance of this factor in human glioma is not known. In the present study, we found that FoxM1B was the predominant FoxM1 isoform expressed in human glioma but not in normal brain tissue. The level of FoxM1 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of FoxM1 protein expression in human glioblastoma tissues was inversely correlated with patient survival. Enforced FoxM1B expression caused SW1783 and Hs683 glioma cells, which do not form tumor xenografts, to regain tumorigenicity in nude mouse model systems. Moreover, gliomas that arose from FoxM1B-transfected anaplastic astrocytoma SW1783 cells displayed glioblastoma multiforme phenotypes. Inhibition of FoxM1 expression in glioblastoma U-87MG cells suppressed their anchorage-independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that FoxM1 regulates the expression of Skp2 protein, which is known to promote degradation of the cell cycle regulator p27(Kip1). These results showed that FoxM1 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity. Therefore, FoxM1 might be a new potential target of therapy for human malignant gliomas.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-2912DOI Listing
April 2006

Expression of interleukin-18, interferon-gamma and interleukin-10 in hepatocellular carcinoma.

Immunol Lett 2002 Dec;84(3):163-72

Department of Clinical Laboratory Science, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.

This is the first report on the detection of IL-18, IFN-gamma and IL-10 proteins in hepatocelllular carcinoma. In the apparently normal surrounding tissue, 13 out of 17 paired specimens showed positive immunoreactivity to IL-18 (76.5%) compared with six out of 17 in the tumour portion (35.3% of specimens). Thus, a significantly higher number of IL-18 positive specimens was found in the hepatocytes of apparently normal surrounding tissue compared with the tumour (P=0.018). In contrast, the number of specimens with positive immunoreactivity to the antibody against the Th1 cytokine, IFN-gamma expression in the hepatocytes was lower. Only one specimen from the apparently normal surrounding tissue (one out of 17; 5.9%) and three other specimens from the tumour portion (three out of 17; 17.6%) had positive immunoreactivity. Similarly, the expression of the Th2 cytokine, IL-10 in normal (four out of 17; 23.5%) and tumour portions (five out of 17; 29.4%) was also low. Thus, there did not appear to be predominant Th2 immune response as denoted by IL-10 expression. Using the Spearman correlation rank test, a significant correlation between IL-18 expression in the apparently normal surrounding tissue and high alpha-foetoprotein (AFP) levels of >350 IU/l. No correlation between IL-18 expression in the tumour portion and clinicopathological factors was found. There was also no correlation found between IL-18 and the other cytokines, namely, IFN-gamma and IL-10 expression These new findings provide additional information on the type of cytokines expressed in the tumour microenvironment and give a further insight into the role of cytokines in the pathogenesis of cancer which is critical for the development of effective immunotherapeutic approaches for cancer therapy in the future.
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http://dx.doi.org/10.1016/s0165-2478(02)00176-1DOI Listing
December 2002
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