Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin-Cholesterol Acyltransferase Autoantibody.

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Vitamin B6 deficiency as a cause of polyneuropathy in POEMS syndrome: rapid recovery with supplementation in two cases.

BACKGROUND: The etiology of POEMS syndrome and its associated polyneuropathy have not been fully elucidated. The clinical picture of POEMS-associated polyneuropathy and nutritional polyneuropathy due to vitamin B6 (VB6) deficiency are strikingly similar, both being typically sensorimotor, symmetrical, stocking and glove distribution, and more severe in the lower extremities. CASE PRESENTATION: We report two consecutive POEMS patients with VB6 deficiency who showed unusual rapid and drastic recovery of polyneuropathies within 6-8 weeks after oral VB6 supplementation. Case 1 was supplemented with VB6 from time of autologous stem cell transplantation. Polyneuropathy began to improve within one week, and he became walker-free and could walk unaided with a cane within 6 weeks. Case 2 was supplemented with VB6 from time of stem cell harvest, and he became cane-free and his gait almost normalized within two months. Nerve conduction studies were also confirmatory of neurologic recovery in both cases. CONCLUSIONS: Objective physical improvement of POEMS-associated polyneuropathy has been reported to typically require approximately a year after autologous stem cell transplantation, and together with our observations of VB6 deficiency and supplementations leading to accelerated recoveries of polyneuropathy, VB6 deficiency most probably contributes to POEMS-associated polyneuropathy. VB6 acts as a coenzyme in approximately 150 biochemical reactions. VB6 has been reported to inhibit the hypoxia-inducible factor/vascular endothelial growth factor (VEGF) pathway, and VEGF levels are known to corollate with disease activity of POEMS syndrome. Therefore, VB6 deficiency may contribute not only to POEMS-associated polyneuropathy, but also to the etiology of POEMS syndrome itself.

Vonoprazan-Based Triple-Therapy Could Improve Efficacy of the Tailored Therapy of Helicobacter pylori Infection.

BACKGROUND AND AIMS: The prevalence of clarithromycin resistant bacteria is increasing, and the effectiveness of Helicobacter pylori (H. pylori) triple therapy is gradually decreasing in Japan. Vonoprazan, a potassiumcompetitive acid blocker, has been reported for its effectiveness in eradicating H. pylori. We aimed to evaluate the efficacy of tailored vonoprazan-based triple therapy in patients with H. pylori. This study is the first to compare the efficacy of vonoprazan-based tailored triple therapy to that of vonoprazan-based conventional therapy. METHOD: This retrospective cohort study evaluated the treatment efficacy in 920 patients. Of these, 541 received conventional and 379 received tailored therapy. Successful eradication was confirmed by a negative 13C-urea breath test 6-8 weeks following completion of H. pylori eradication therapy, and the data were evaluated using the Chi-square test, or Fisher's exact test, as appropriate. RESULTS: The eradication rate of tailored therapy was 90% and 96.3% by intent-to-treat analysis and per protocol analysis, respectively, which was significantly higher than the 85% and 90.2% found for conventional therapy (p < 0.05 and p < 0.001, respectively). Amoxicillin- or clarithromycin-resistant bacteria did not affect treatment outcomes. By univariate and multivariate analysis, both amoxicillin- and clarithromycin-resistant bacteria and conventional therapy were detected as risk factors for eradication failure (odds ratio = 6.267, 95% CI [1.056-119.924], p < 0.05, and odd ratio =3.113, 95% confidence interval [1.688-6.160], p < 0.001, by multivariate analysis). CONCLUSION: Vonoprazan-based triple therapy could be a more effective treatment for H. pylori infection than conventional therapy when combined with a therapy regimen tailored according to bacterial antibiotic susceptibility.

Development of Quality Indicators of Stroke Centers and Feasibility of Their Measurement Using a Nationwide Insurance Claims Database in Japan　­ J-ASPECT Study ­

BACKGROUND: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. METHODS AND RESULTS: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. CONCLUSIONS: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population.

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

Effect of free radical scavenger, edaravone, for patients with carbon monoxide poisoning.

OBJECTIVE: Chronic neurological symptoms after carbon monoxide (CO) poisoning are caused by various biological processes in the damaged brain, with free radicals playing roles as mediators in establishing pathological processes leading to chronic neurological symptoms under CO poisoning. This study aimed to clarify the effects of a free radical scavenger, edaravone, in patients with CO poisoning. METHODS: We retrospectively compared two groups comprising patients treated with hyperbaric oxygenation alone (Group A, n=25) or edaravone in addition to hyperbaric oxygenation (Group B, n=25). Edaravone was administrated intravenously at 30 mg every 12h for 7 days. Patient characteristics, general conditions on admission, and frequency of chronic neurological symptoms were compared between groups. Among patients showing chronic neurological symptoms, cognitive function and daily activity were also compared between groups. RESULTS: No significant differences in characteristics or general conditions on admission were identified between groups. In Group B, no patients presented with marked complications caused by edaravone. Although chronic persisting symptoms were less frequent in Group B (n=1, 0.04%) than in Group A (n=5, 20%), this difference was not significant. In the 11 patients showing chronic symptoms, scores for cognitive function and daily activity in the chronic phase were better in Group B than in Group A, but no significant differences were apparent. CONCLUSIONS: The present results suggest that edaravone represents a tolerable and feasible treatment for CO-poisoned patients. Further studies are needed to clarify whether edaravone can favorably influence chronic neurological symptoms caused by CO poisoning.

Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: a randomized controlled trial in polypectomized participants.

To address preventive effects of n-3 PUFAs/LC n-3 PUFAs on CRTs, a randomized controlled trial was conducted. One-hundred four experimental group participants were advised to increase intake of n-3 PUFAs, including fish/shell fish, fish oil supplements and perilla oils, and to decrease consumption of n-6 PUFAs and fats/oils as a whole for 24 months. One-hundred one control group participants were only cautioned to reduce consumption of fats/oils as a whole. Random allocation was satisfactorily attained, and participants sufficiently complied with our regimen. Intakes, plasma concentrations, and compositions of the RBC and sigmoid colon membranes of n-3 PUFAs, LC n-3 PUFAs, EPA and DHA increased, and the ratios of n-6 PUFAs/n-3 PUFAs and AA/LC n-3 PUFAs decreased without any adverse response. Twenty-four months after the intervention, the multivariate-adjusted hazard ratio (95% confidence intervals) was estimated to be 0.805 (0.536-1.209) with a signal towards the reduced CRT incidence.

Solitary amyloidosis of the sigmoid colon featuring submucosal tumor caused hematochezia.

A previously a healthy 64-year-old woman complained of a two-week history of hemorrhaging upon defecation. The laboratory and urinalysis findings were normal, and no serum or urine M components were detectable on protein electrophoresis. An air contrast barium enema revealed an elevated lesion measuring -20 mm in diameter with a smooth surface and a depression in the sigmoid colon. Colonoscopy revealed a red colored and congested tumor. The exposed surface of the submucosal tumor (SMT) center was somewhat yellow in color and covered with fuzz. All other portions of the colon were normal. The endoscopy and double-contrast barium revealed a normal upper gastrointestinal tract and a normal small intestine, respectively. A histopathological evaluation of a biopsy specimen obtained from the SMT suggested amyloid deposition. However, the other biopsy specimens of the esophagus, stomach, duodenal bulb, second portion of the duodenum, terminal ileum and other portions of the colon demonstrated no amyloid deposition. Colonoscopic ultrasonography (US) revealed the hypoechoic, homogeneous SMT to be mainly localized within the submucosa. An endoscopic submucosal resection (EMR) of the solitary amyloidosis was performed and the immunohistopathology revealed the entire SMT to consist of amyloid light chain kappa amyloid deposition. We considered that the US followed by EMR contributed to the precise diagnosis of solitary amyloidosis and the treatment of hematochezia caused by a solitary area of amyloidosis within the sigmoid colon.

Consumption of polyphenol-rich juar tea increases endothelium-bound extracellular superoxide dismutase levels in men with metabolic syndrome: link with LDL oxidizability.

Endothelium-bound extracellular superoxide dismutase (eEC-SOD), a major antioxidative enzyme in the vasculature, is involved in anti-atherogenesis by inhibiting low-density lipoprotein (LDL) oxidation. The objective was to investigate whether the polyphenol-rich juar tea had beneficial effects on LDL oxidation and eEC-SOD levels in patients with metabolic syndrome (MetS). A total of 20 men with MetS participated in a randomized cross-over trial, comparing consumption of five cups/day of juar tea with that of a polyphenol-poor tea, barley tea, for 4 weeks. Although there was no change in LDL oxidizability after consumption of either tea, juar tea significantly increased eEC-SOD levels by 16% (p < 0.05), whereas barley tea significantly decreased levels by 15% (p < 0.05). It is noteworthy that the changes in eEC-SOD were positively associated with those in LDL oxidizability after tea consumption (r(2) = 0.11, p < 0.05). Tea polyphenols may provide anti-atherosclerotic effects by inhibiting LDL oxidation through EC-SOD bound to the endothelium.

Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats.

We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl salt-sensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40°C water (NS+RHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HS+RHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HS+RHT+17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HS+RHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs.

Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor.

The ionotropic glutamate receptor subunit, GluK1 (GluR5), is expressed in many regions of the nervous system related to sensory transmission. Recently, a selective ligand for the GluK1 receptor, MSVIII-19 (8,9-dideoxy-neodysiherbaine), was synthesized as a derivative of dysiherbaine, a toxin isolated from the marine sponge Lendenfeldia chondrodes. MSVIII-19 potently desensitizes GluK1 receptors without channel activation, rendering it useful as a functional antagonist. Given the high selectivity for GluK1 and the proposed role for this glutamate receptor in nociception, we sought to test the analgesic potential of MSVIII-19 in a series of models of inflammatory, neuropathic, and visceral pain in mice. MSVIII-19 delivered intrathecally dose-dependently reduced formalin-induced spontaneous behaviors and reduced thermal hypersensitivity 3 hours after formalin injection and 24 hours after complete Freund's adjuvant-induced inflammation, but had no effect on mechanical sensitivity in the same models. Intrathecal MSVIII-19 significantly reduced both thermal hyperalgesia and mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain, but had no effect in the acetic acid model of visceral pain. Peripheral administration of MSVIII-19 had no analgesic efficacy in any of these models. Finally, intrathecal MSVIII-19 did not alter responses in Tail-flick tests or performance on the accelerating RotaRod. These data suggest that spinal administration of MSVIII-19 reverses hypersensitivity in several models of pain in mice, supporting the clinical potential of GluK1 antagonists for the management of pain.

1H-magnetic resonance spectroscopy indicates damage to cerebral white matter in the subacute phase after CO poisoning.

OBJECTIVE: The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure. METHODS: Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients. RESULTS: MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio. CONCLUSIONS: These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms.

Green tea catechins improve human forearm vascular function and have potent anti-inflammatory and anti-apoptotic effects in smokers.

OBJECTIVE: Several epidemiological investigations have reported that green tea reduces cardiovascular and cerebral vascular risks. Green tea catechins may improve peripheral endothelial dysfunction in smokers. The purpose of this study was to elucidate the beneficial effect of green tea catechins on the repair of endothelial dysfunction in smokers. METHODS: Thirty healthy male smokers divided into three groups ingested a green tea beverage containing 0 mg (control group), 80 mg (middle dose group) or 580 mg (high dose group) of green tea catechins (GTC) daily for two weeks, and endothelial-dependent vasodilatation was investigated by measuring forearm blood flow (FBF) response to reactive hyperemia (RH) by venous occlusion strain-gauge plethysmography. RESULTS: An acute effect was that the FBF response to RH significantly increased 2 hr after GTC intake in the high dose group. However, no increase was observed in the other groups. The chronic administration of GTC for one or two weeks ameliorated the FBF responses to RH in the high dose group. On the other hand, no significant increase was observed in the FBF responses to RH in the other groups. Moreover, the plasma concentration of 8-OHdG, IL-6, TNF-alpha, and soluble Fas decreased significantly for two weeks in the high dose group, however, the level of IL-1 beta remained unchanged over this period. CONCLUSION: Green tea consumption over short and long periods appears to ameliorate endothelial dysfunction by scavenging free radicals with anti-inflammatory and anti-apoptotic properties in healthy male smokers.

Coffee consumption enhances high-density lipoprotein-mediated cholesterol efflux in macrophages.

RATIONALE: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL). OBJECTIVE: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo. METHODS AND RESULTS: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting [(3)H]cholesterol-labeled acetyl low-density lipoprotein-loaded RAW264.7 cells into mice, then monitoring appearance of (3)H tracer in plasma, liver, and feces. Supporting in vitro and ex vivo data, ferulic acid was found to significantly increase the levels of (3)H tracer in feces. CONCLUSIONS: Coffee intake might have an antiatherogenic property by increasing ABCG1 and SR-BI expression and enhancing HDL-mediated cholesterol efflux from the macrophages via its plasma phenolic acids.

Intussusception in a child caused by capillary hemangioma of the colon.

Intussusception is one of the most common abdominal emergencies in children, but identifying the cause is very difficult. Hemangioma is a common tumor of the head and neck area in children, but it rarely arises in the gastrointestinal tract. This report describes a rare occurrence of intussusception caused by capillary hemangioma of the colon that was identified by ultrasonography (US), computed tomography (CT), and colonoscopy. A male child aged 2 years and 10 months developed painful abdominal cramps and hematochezia. Abdominal US and CT revealed both target and pseudo-kidney signs in the colon, indicating colonic intussusception. An initial diagnostic and therapeutic laparotomy did not reveal any abnormalities. Seven days later, severe abdominal pain recurred. A barium enema revealed the shadow of a 25-mm mass at the hepatic flexure of the colon. Colonoscopic findings revealed a submucosal tumor in the descending colon that was moved to the cecum by compressed air introduced through the colonoscope. We considered that the mass in the cecum had caused the intussusception. The tumor was removed at a second laparotomy, and microscopic pathological examination revealed that it was a capillary hemangioma.

Feasibility of self-expandable metallic stent plus chemotherapy for metastatic gastric cancer with pyloric stenosis.

BACKGROUND AND AIM: Self-expandable metallic stent placement is accepted as palliative therapy for advanced gastric cancer with gastric outlet obstruction, but data are lacking for chemotherapy after self-expandable metallic stent insertion. This study retrospectively compared results between surgery plus chemotherapy and stenting plus chemotherapy for metastatic gastric cancer with pyloric stenosis. METHODS: Subjects comprised 26 patients who received chemotherapy after surgery or endoscopic stenting for metastatic gastric cancer with pyloric stenosis between April 2000 and December 2007 in four Japanese hospitals. Patients were categorized into two groups: 15 patients who received chemotherapy after surgery for pyloric stenosis (Surgery group); and 11 patients who received chemotherapy after self-expandable metallic stent placement for pyloric stenosis (Stent group). RESULTS: Median survival time and median time to treatment failure were 284 days and 226 days in the Surgery group and 337 days and 247 days in the Stent group, respectively. No significant differences were noted between survival and time to treatment failure. No significant differences were found in median oral intake rate (Surgery, 93.1%; Stent, 93.2%) or median hospital stay rate (Surgery, 24.6%; Stent, 23.7%) during survival. Response rate was 45.5% in the Surgery group and 50% in the Stent group, with no significant difference. Likewise, no significant differences were noted between groups for frequencies of toxicity or complications. CONCLUSIONS: The present results suggest that chemotherapy after stenting is as effective and safe as chemotherapy after surgery. Stents may replace surgery in combination therapy with chemotherapy for metastatic gastric cancer with gastric outlet obstruction.

Successful treatment for pouchitis with rebamipide refractory to a combination of metronidazole (MNZ) and ciprofloxacin (CFX).

A 35-year-old male who had undergone proctocolectomy and ileo-anal pouch surgery (IPAA) because of ulcerative colitis presented with worsening diarrhea and hematochezia. Pouchitis was diagnosed, and he was prescribed with metronidazole (MNZ) and a betamethasone enema. However, his condition did not remarkably improve despite these strategies. Endoscopy revealed ulceration and inflammation in the ileal pouch together with contact bleeding and mucous discharge. He underwent granulocytapheresis (G-CAP) and was prescribed anal 5-aminosalicylic acid (5-ASA) and oral prednisolone. Oral azathioprine (AZA) and a combination of MNZ and ciprofloxacin (CFX) did not result in any improvement. He was then treated with rebamipide enemas twice daily for 8 weeks without additional drug therapy. Two weeks thereafter, stool frequency started to decrease, fecal hemoglobin became negative, and his symptoms gradually improved. Endoscopic findings after the rebamipide therapy showed that the ulcers in the ileal pouch had mostly healed without obvious inflammation and bleeding. Rebamipide was thus maintained throughout the therapeutic period and for 13 months of follow-up. Rebamipide effectively treated severe pouchitis that was refractory to intensive conventional medication including antibiotics and corticosteroids.

Suppression of proHB-EGF carboxy-terminal fragment nuclear translocation: a new molecular target therapy for gastric cancer.

PURPOSE: Inactivation of epidermal growth factor (EGF) receptor (EGFR) represents a promising strategy for the development of selective therapies against epithelial cancers and has been extensively studied as a molecular target for cancer therapy. However, little attention has been paid to remnant cell-associated domains created by cleavage of EGFR ligands. The present study focused on recent findings that cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF), an EGFR ligand, induces translocation of the carboxyl-terminal fragment (CTF) of HB-EGF from the plasma membrane to the nucleus and regulates cell cycle. EXPERIMENTAL DESIGN: Two gastric cancer cell lines, MKN28 and NUGC4, were used. KB-R7785, an inhibitor of proHB-EGF shedding, was used to suppress HB-EGF-CTF nuclear translocation with cetuximab, which inhibits EGFR phosphorylation. Cell growth was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, apoptosis was evaluated by assay of caspase-3 and caspase-7, and cell cycle was investigated by flow cytometry. RESULTS: Immunofluorescence study confirmed that KB-R7785 inhibited HB-EGF-CTF nuclear translocation under conditions of proHB-EGF shedding induction by 12-O-tetradecanoylphorbol-13-acetate in gastric cancer cells. KB-R7785 inhibited cell growth in a dose-dependent manner and high-dose KB-R7785 induced apoptosis. Moreover, KB-R7785 induced cell cycle arrest and increased sub-G1 DNA content. KB-R7785 suppressed cyclin A and c-Myc expression. All effects of KB-R7785 were reinforced by combination with cetuximab. CONCLUSIONS: These results suggest that both inhibition of EGFR phosphorylation and inhibition of HB-EGF-CTF nuclear translocation play crucial roles in inhibitory regulation of cancer cell growth. Suppression of HB-EGF-CTF nuclear translocation might offer a new strategy for treating gastric cancer.

Rapid and efficient synthesis of dysiherbaine and analogues to explore structure-activity relationships.

A rapid and efficient total synthesis of dysiherbaine (1), a potent and subtype-selective agonist for ionotropic glutamate receptors, has been accomplished. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 9, an advanced intermediate in our previous total synthesis of neodysiherbaine A, as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular S(N)2 cyclization of N-Boc-protected amino alcohol 20. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 36. The synthetic route developed here provided access to several dysiherbaine analogues, including 9-epi-dysiherbaine (38), 9-deoxydysiherbaine (39), 9-methoxydysiherbaine (40), and N-ethyldysiherbaine (41). The preliminary structure-activity relationship studies revealed that the presence and stereochemistry of the C9 hydroxy group in dysiherbaine is important for high-affinity and selective binding to glutamate subtype receptors.