PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.
Blotting, Western ; Cell Line ; Cisplatin ; Down-Regulation ; Drug Resistance ; Gentian Violet ; Humans ; In Vitro Techniques ; Luciferases ; Parents ; Receptor, Epidermal Growth Factor ; Receptor, ErbB-2 ; RNA Interference ; Stomach Neoplasms ; Transfection ; Up-Regulation

Hypotension is one of the potential causes of dizziness. In this review, we summarize the studies published in recent years about the electrophysiological and pharmacological mechanisms of hypotension-induced dizziness and the role of the vestibular system in the control of blood pressure in response to hypotension. It is postulated that ischemic excitation of the peripheral vestibular hair cells as a result of a reduction in blood flow to the inner ear following hypotension leads to excitation of the central vestibular nuclei, which in turn may produce dizziness after hypotension. In addition, excitation of the vestibular nuclei following hypotension elicits the vestibulosympathetic reflex, and the reflex then regulates blood pressure by a dual-control (neurogenic and humoral control) mechanism. In fact, recent studies have shown that peripheral vestibular receptors play a role in the control of blood pressure through neural reflex pathways. This review illustrates the dual-control mechanism of peripheral vestibular receptors in the regulation of blood pressure following hypotension.
Blood Pressure* ; Dizziness ; Ear, Inner ; Epinephrine ; Glutamic Acid ; Hair Cells, Vestibular ; Hypotension* ; Reflex ; Vestibular Nuclei

PURPOSE: We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. MATERIALS AND METHODS: Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. RESULTS: In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1alpha (HIF-1alpha) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1alpha activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. CONCLUSION: Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1alpha-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
Angiogenesis Modulating Agents ; Animals ; Anoxia ; Blotting, Western ; Carcinogenesis ; Cell Culture Techniques ; Cell Line ; Down-Regulation ; Forkhead Transcription Factors ; Heterografts ; Humans ; Lentivirus ; Mice ; Mice, Nude ; Microvessels ; RNA, Small Interfering ; Stomach Neoplasms* ; Tissue Array Analysis ; Transcription Factors* ; Vascular Endothelial Growth Factor A

Input signals originating from baroreceptors and vestibular receptors are integrated in the rostral ventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contribution of baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotension were quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase (pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate release in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP) infusion. The expression of pERK was significantly increased in the RVLM in the control group following SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than seen in the control group. The SAD group showed a relatively higher reduction in pERK expression when compared with the BL group. The level of glutamate release was significantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and this peaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamate release when compared with the BL group. These results suggest that the baroreceptors are more powerful in pERK expression and glutamate release in the RVLM following hypotension than the vestibular receptors, but the vestibular receptors still have an important role in the RVLM.
Animals ; Blood Pressure ; Denervation ; Glutamic Acid ; Hypotension* ; Neurons ; Nitroprusside ; Pressoreceptors* ; Protein Kinases ; Rats*

Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension.
Animals ; Baroreflex* ; Blood Pressure ; Denervation ; Hypotension* ; Hypotension, Orthostatic ; Neurons ; Nitroprusside ; Pressoreceptors ; Protein Kinases ; Rats* ; Reflex* ; Solitary Nucleus*

Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.
Animals ; Arterial Pressure ; Baroreflex ; Blood Pressure ; Denervation ; Hypertension ; Hypotension ; Infusions, Intravenous ; Nitroprusside ; Phenylephrine ; Pressoreceptors ; Rats ; Salicylamides

BACKGROUND: Ischemia-reperfusion injury related to unsuccessful myocardial protection affects postoperative ventricular function and mortality during open-heart surgery. We prospectively compared the effects of administration of histidine-tryptophan-ketoglutarate (HTK) solution and cold blood cardioplegia (CBC) on myocardial protection and clinical outcome in patients undergoing mitral valve surgery. MATERIAL AND METHOD: Seventy patients with mitral regurgitation (MR) undergoing mitral valve surgery were randomly divided into the HTK group (n=31) and the CBC group (n=31); eight patients were excluded. Perioperative hemodynamics, cardiac medications, pacing, postoperative outcomes and complications were recorded during the hospital stay. All patients received follow-up for at least 6 months postoperatively for morbidity and mortality. RESULT: There were no significant differences in the hemodynamics between the groups during the study period, except for the mean pulmonary artery pressure (MPAP), PCWP and CVP that were lower in the HTK group at 15 min after weaning of CBP. There were no differences for inotropic support and pacing during the 12 hrs postoperatively between the groups. CK-MB values on day 1 and day 2 were 77+/-54 and 41+/-23 for the HTK group and 70+/-69 and 44+/-34 for the CBC group, respectively (p=NS). Postoperative clinical outcomes were similar in both groups for at least 6 months during the follow-up period. CONCLUSION: These results suggest that the use of HTK solution is as safe as cold blood cardioplegia in terms of myocardial protection.
Cardioplegic Solutions* ; Follow-Up Studies ; Heart Arrest, Induced ; Hemodynamics ; Humans ; Length of Stay ; Mitral Valve Insufficiency ; Mitral Valve* ; Mortality ; Prospective Studies ; Pulmonary Artery ; Reperfusion Injury ; Ventricular Function ; Weaning

BACKGROUND: Ginseng has been used to manage various types of pain in folk medicine. This study characterized the effect of treatment with intrathecal ginsenosides, the active components of ginseng in a postoperative pain model. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters. An incision was made in the plantar surface of the hindpaw. Withdrawal thresholds following the application of a von Frey filament to the wound site were measured. To determine the role of the opioid or GABA receptors following treatment with the ginsenosides, naloxone, bicuculline (a GABAA receptor antagonist), and saclofen (a GABAB receptor antagonist) were administered intrathecally 10 min before the delivery of the ginsenosides and the changes of the withdrawal thresholds after application of the von Frey filament were observed. RESULTS: Treatment with the intrathecal ginsenosides increased the withdrawal threshold in a dose dependent manner. Pre-treatment with intrathecal naloxone reversed the antinociceptive effect of the ginsenosides. However, pre-treatment with intrathecal bicuculline and saclofen failed to have an effect on the activity of the ginsenosides. CONCLUSIONS: These results suggest that ginsenosides are effective to alleviate the postoperative pain evoked by paw incision. The opioid receptor, but not GABA receptors, may be involved in the antinociceptive action of the ginsenosides at the spinal level.
Analgesia ; Animals ; Bicuculline ; Catheters ; Ginsenosides* ; Humans ; Male ; Medicine, Traditional ; Models, Animal* ; Naloxone ; Pain, Postoperative* ; Panax ; Rats* ; Rats, Sprague-Dawley ; Receptors, GABA ; Receptors, Opioid ; Spinal Cord ; Wounds and Injuries

Condyloma acuminatum (CA) is a common sexually transmitted disease caused by the human papillomavirus. In gastrointestinal practice, we generally encounter this disease in the anal canal but rarely in the rectum during a colonoscopy. There are many therapeutic options for CA including chemical or physical destruction, immunological therapy, or a surgical excision. All these procedures have some degree of limitations such as limited clearance rate, high recurrence rate, long duration of therapy, bleeding, release of potentially infectious aerosols, scarring etc. With argon plasma coagulation (APC), which is more available than lasers in gastrointestinal practice, a high frequency current flows through the argon plasma to the tissue, allowing well-controlled superficial tissue destruction without any direct contact between the probe and the tissue. We present a case of anal CA that was treated successfully with APC during a colonoscopy with no recurrence during the follow up.
Aerosols ; Anal Canal ; Argon Plasma Coagulation* ; Argon* ; Cicatrix ; Colonoscopy ; Follow-Up Studies ; Hemorrhage ; Humans ; Plasma ; Rectum ; Recurrence ; Sexually Transmitted Diseases

BACKGROUND: Thrombocytosis can result in life-threatening thrombotic or hemorrhagic events. Anagrelide acts exclusively on megakaryocytes and has been reported as an useful agent in controlling thromobocytosis associated with chronic myeloproliferative disorders. METHODS: Seven patients with essential thrombocythemia and three with chronic myelogenous leukemia were enrolled and early responses and adverse effects of anagrelide were retrospectively analyzed. The drug was started with a dose of 2 mg/day with increases of 0.5 mg/day every 5~7 days as needed. RESULTS: Anagrelide in starting doses of 2 mg/day reduced the platelet count by 50%, or to less than 600,000/mm3, for at least 28 days in 7 of the 9 (78%) evaluable patients. Adverse effects of the drug were observed in 5 patients and generally well tolerated; headache in 4, gastrointestinal troubles in 2, palpitations and chest tightness in 1, and tinnitus in 1. Changes in hemoglobin or white blood cell counts in peripheral blood were minimal and tolerable. CONCLUSION: The present study shows that anagrelide is a useful platelet-lowering agent in whom hydroxyurea or interferon has failed. Long-term efficacy and adverse effects of the drug remain to be determined.
Headache ; Humans ; Hydroxyurea ; Interferons ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Leukocyte Count ; Megakaryocytes ; Myeloproliferative Disorders ; Platelet Count ; Retrospective Studies ; Thorax ; Thrombocythemia, Essential ; Thrombocytosis* ; Tinnitus