An outbreak of food poisoning due to Escherichia coli serotype O7:H4 carrying astA for enteroaggregative E. coli heat-stable enterotoxin1 (EAST1).

In June 2020, a large-scale food poisoning outbreak involving about 3000 elementary and junior high school students occurred in Yashio, Saitama, Japan. A school lunch was the only food stuff ingested by all of the patients. Escherichia coli serotype O7:H4 carrying the astA gene for enteroaggregative E. coli (EAggEC) heat-stable enterotoxin 1 (EAST1) was detected in faecal specimens from the patients, and sample inspection revealed its presence in a seaweed salad and red seaweed (Gigartina tenella) as one of the raw materials. Analysis of the antibiotic sensitivity of the isolates revealed resistance to ampicillin and cefotaxime. All isolates were confirmed to be of the same origin by pulsed-field gel electrophoresis after digestion with the restriction enzyme XbaI, and single nucleotide polymorphism analysis using whole genome sequencing. To our knowledge, this is the first report of a large-scale food poisoning caused by E. coli O7:H4, which lacks well-characterized virulence genes other than astA.

Cosmetic benefits of a novel biomimetic lamellar formulation containing niacinamide in healthy females with oily, blemish-prone skin in a randomized proof-of-concept study.

OBJECTIVE: A randomized study was designed to evaluate the potential cosmetic benefit of a biomimetic, niacinamide-containing moisturizing cream in oily, blemish-prone skin. METHODS: Healthy adult women with oily, blemish-prone skin were randomized to one of three treatment groups: test, control, or positive control. In the test group, subjects used the test product (containing 4% niacinamide), plus the standard cleanser (Simple® Kind to Skin Moisturizing Facial Wash). In the control group, subjects received no moisturizer but used the standard cleanser. In the positive control group, subjects used Vivatinell Acnecinamide® Gel Cream (containing 4% niacinamide) as a moisturizer and Neutrogena Visibly Clear® Spot Clearing Facial Wash (containing 2% salicylic acid) as a cleanser. The positive control regimen was included to provide a comparison for estimates of effect size. The primary objective was to evaluate skin moisturization as a change from baseline in corneometer values at 8 h for the test regimen vs. the control regimen. Analysis of covariance was applied for the primary efficacy analysis. RESULTS: A total of 132 subjects were randomized with 44 included in each treatment group. A significant difference was observed in the primary endpoint for the test regimen compared with the control regimen (least-squares mean difference [95% CI]: 3.12 [0.68, 5.56], P = 0.0128). A trend was observed in favour of the positive control regimen compared with the control regimen. Secondary measurements of moisturization supported the primary efficacy outcome. Assessment of blemishes showed a significant difference between the test regimen vs. the control regimen for change from baseline in mean total blemish count at Week 8 (least-squares mean difference [95% CI]: -1.80 [-3.41, -0.19], P = 0.0290). No statistical comparisons between the positive control group and the test group were performed. CONCLUSION: This study provides proof-of-concept evidence that a novel lamellar lipid moisturizer containing niacinamide, in combination with a standard cleanser, can help moisturize the skin and provide an overall improvement in the complexion appearance of people with blemish-prone skin. STUDY REGISTRATION: NCT03093181.

OBJECTIF: Une étude randomisée a été conçue pour évaluer le bénéfice cosmétique potentiel d'une crème hydratante biomimétique contenant du niacinamide sur une peau grasse sujette aux imperfections. MÉTHODES: Des femmes adultes en bonne santé, à peau grasse sujette aux imperfections, ont été randomisées dans l'un des trois groupes de traitement : test, témoin ou témoin positif. Dans le groupe test, les sujets ont utilisé le produit testé (contenant 4 % de niacinamide), plus le nettoyant standard (Nettoyant visage Simple® doux pour la peau). Dans le groupe témoin, les sujets n'ont reçu aucune crème hydratante mais ont utilisé le nettoyant standard. Dans le groupe témoin positif, les sujets ont utilisé le gel crème Vivatinell Acnecinamide® (contenant 4 % de niacinamide) comme crème hydratante et le nettoyant visage pour réduire les imperfections Neutrogena Visibly Clear® (contenant 2 % d'acide salicylique) comme nettoyant. Le schéma de traitement du groupe témoin positif était inclus pour fournir une comparaison des estimations de la taille de l'effet. L'objectif principal était d'évaluer l'hydratation de la peau par le changement par rapport à la référence des valeurs du cornéomètre à 8 h pour le schéma de traitement testé par rapport au schéma de traitement témoin. Une analyse de covariance a été appliquée pour l'analyse de l'efficacité primaire. RÉSULTATS: Un total de 132 sujets ont été randomisés, dont 44 inclus dans chaque groupe de traitement. Une différence significative a été observée dans le critère d'évaluation principal en faveur du schéma de traitement testé par rapport au schéma de traitement témoin (différence moyenne des moindres carrés [IC à 95 %] : 3,12 [0,68, 5,56], P = 0,0128). Une tendance a été observée en faveur du schéma de traitement témoin positif par rapport au schéma de traitement témoin. Les mesures secondaires de l'hydratation ont appuyé le résultat principal d'efficacité. L'évaluation des imperfections a montré une différence significative entre le schéma de traitement testé par rapport au schéma de traitement témoin en ce qui concerne le changement par rapport à la référence dans le nombre moyen total d'imperfections à la semaine 8 (différence moyenne des moindres carrés [IC à 95 %] : _1,80 [_3,41, _0,19], P = 0,0290). Aucune comparaison statistique entre le groupe témoin positif et le groupe test n'a été réalisée. CONCLUSION: Cette étude fournit des éléments de preuve de concept qu'une nouvelle crème hydratante lipidique lamellaire à base de niacinamide, en association avec un nettoyant standard, peut permettre d'hydrater la peau et fournir une amélioration globale de l'aspect du teint chez des personnes dont la peau est sujette aux imperfections. Numéro d'enregistrement de l'étude : NCT03093181.

[Important factors surrounding chest surgery for the patients complicated with digestive disease].

OBJECTIVE: Important factors surrounding chest surgery for the patients complicated with digestive disease were discussed according to the experiences of clinical settings. METHODS: Check points regarding each context, preoperative, perioperative, postoperative, and outpatient care were considered independently. RESULTS: If digestive diseases are uncontrolled, the operation should be postponed until they are appropriately cared. Dental problems such as teeth caries or denture insufficiency should be cleared preoperatively. Dysphagia after the head and neck surgery must be evaluated and alternative feeding methods should be established. The patients with digestive tract disorder have malabsorption and are prone to malnutrition. According to the appropriate assessments of digestion and absorption, an enteral nutrition or a total parenteral nutrition should be considered before and after operation, to improve nutrition status. Immunonutrition is particularly beneficial to reduce the postoperative infection or various stresses of invasive operations in the chest surgery. Chronic pancreatitis is characterized by absorption impairment and pancreatic diabetes. They should also be controlled before the operation using digestive enzymes and an exogenous insulin. CONCLUSION: Teeth problems, dysphagia, malabsorption, malnutrition and pancreatic diabetes should be assessed and cared appropriately before and after the chest surgery using compensative therapy.

A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer. METHODS: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m(-2) over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles. RESULTS: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4 versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40-0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51-1.14); P=0.19). CONCLUSION: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.

A history of smoking is inversely correlated with the incidence of gemcitabine-induced neutropenia.

BACKGROUND: Smoking may affect the efficacy of chemotherapy and the incidence of adverse events. We investigated the correlation between smoking history and gemcitabine-induced neutropenia. PATIENTS AND METHODS: Data on smoking history and incidence of grade 3-4 neutropenia were retrospectively gathered for 103 chemo-naive patients treated with gemcitabine monotherapy (59 patients with pancreatic, 41 with hepatobiliary and three with other cancers). RESULTS: There was a significantly higher incidence of grade 3-4 neutropenia among patients without a history of smoking (55.7%) than among those with a history of smoking (including current and ex-smokers; 23.6%) [odds ratio (OR) 0.244, 95% confidence interval (CI) 0.105-0.569; P < 0.001]. After adjustment for age, gender, platelet and baseline neutrophil counts, history of surgery for primary cancer, creatinine concentration, hemoglobin concentration, aspartate aminotransferase concentration, alanine aminotransferase concentration and total bilirubin concentration, logistic regression analysis identified a history of smoking as an independent inverse predictor of gemcitabine-induced neutropenia (OR 0.188, 95% CI 0.057-0.618; P = 0.006). CONCLUSION: Patients without a history of smoking may be at higher risk of developing gemcitabine-induced neutropenia. The mechanism underlying this phenomenon is unclear at this point.

Effect of physical conditions and chemicals on the binding of a mini-CbpA from Clostridium cellulovorans to a semi-crystalline cellulose ligand.

AIMS: To investigate the effect that environmental factors have on Clostridium cellulovorans cellulose binding domain (CBD) binding to a semi-crystalline cellulose ligand, namely Avicel. METHODS AND RESULTS: The behaviour of a 58 kDa mini-CbpA protein containing the CBD from the scaffoldin protein of C. cellulovorans was studied in the presence of various environmental factors, in order to determine whether such factors promote or reduce CBD binding to its ligand, thus potentially affecting its activity on the substrate. The amount of binding was found to be dependent on the Avicel concentration and optimal binding occurred when the ligand concentration was 15 mg ml(-1). Optimal CBD binding occurred at pH 7.0 and at an incubation temperature of 28 degrees C. The effects of dithiothreitol (DTT), 2-mercaptoethanol, acetone, butanol, ethanol and butyric acid were also investigated. CONCLUSIONS: Temperature, pH, DTT, 2-mercaptoethanol and solvents were shown to affect the binding of C. cellulovorans CBD to Avicel. SIGNIFICANCE AND IMPACT OF THE STUDY: Clostridium cellulovorans CBD binding to Avicel is affected by physical conditions and chemicals.

Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Characteristics of cognitive function in patients after traumatic brain injury assessed by visual and auditory event-related potentials.

OBJECTIVE: Using auditory and visual stimuli including facial affective stimuli, we analyzed the P300 components of event-related potentials (ERPs) in patients after traumatic brain injury (TBI) to assess their cognitive characteristics. DESIGN: Twenty TBI patients and 32 age-matched control subjects were recruited. Using conventional oddball paradigms, visual ERPs were recorded using images of crying and smiling babies as visual stimuli. Auditory ERPs were obtained using 2-kHz tones as stimuli without affective stimuli. The peak amplitude and latency for P300, and the latency for N200, were recorded. RESULTS: : In visual ERPs, the P300 amplitudes were significantly smaller in patients than in controls for the crying baby, but the amplitudes were similar between groups for the smiling baby. Controls showed smaller P300 amplitudes for the smiling baby than for the crying baby, but patients showed no difference. In patients, the P300 latency for both smiling and crying babies was longer than in the controls. Patients' auditory ERPs showed smaller P300 amplitudes but similar P300 latencies compared with controls. The N200 latency in patients was significantly longer than in controls only for the crying baby. CONCLUSIONS: Visual ERPs are a potentially useful marker for evaluating cognitive dysfunction in patients after TBI.

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion.

AIMS/HYPOTHESIS: G protein-coupled receptor 40 (GPR40) is abundantly expressed in pancreatic beta cells in rodents, where it facilitates glucose-induced insulin secretion in response to mid- to long-chain fatty acids in vitro. However, GPR40 gene expression in humans has not been fully investigated, and little is known about the physiological and pathophysiological roles of GPR40 in humans. The aim of this study, therefore, was to examine GPR40 expression and its clinical implications in humans. METHODS: GPR40 mRNA expression in the human pancreas, pancreatic islets and islet cell tumours was analysed using TaqMan PCR. RESULTS: GPR40 mRNA was detected in all human pancreases collected intraoperatively. It was enriched approximately 20-fold in isolated islets freshly prepared from the pancreases of the same individuals. The estimated mRNA copy number for the GPR40 gene in pancreatic islets was comparable to those for genes encoding sulfonylurea receptor 1, glucagon-like peptide 1 receptor and somatostatin receptors, all of which are known to be expressed abundantly in the human pancreatic islet. A large amount of GPR40 mRNA was detected in insulinoma tissues, whereas mRNA expression was undetectable in glucagonoma or gastrinoma. The GPR40 mRNA level in the pancreas correlated with the insulinogenic index, which reflects beta cell function (r=0.82, p=0.044), but not with glucose levels during the OGTT, the insulin area under the OGTT curve or the index for the homeostasis model assessment of insulin resistance (HOMA-IR). CONCLUSIONS/INTERPRETATION: The present study provides evidence for GPR40 gene expression in pancreatic beta cells and implicates GPR40 in insulin secretion in humans.

Morphological imaging in the localization of neuroendocrine gastroenteropancreatic tumors found by somatostatin receptor scintigraphy.

PURPOSE: To evaluate the necessity of morphological images (MI) in reading somatostatin receptor scintigraphy (SRS) in patients with suspected neuroendocrine gastroenteropancreatic (GEP) tumors. MATERIAL AND METHODS: A Japanese multicenter clinical trial of SRS was conducted in 40 patients with suspected GEP tumors. Three experienced radiologists interpreted the images in three separate sessions in a blinded manner (1: SRS images alone, 2: MI alone, 3: SRS and MI analyzed simultaneously), and the reading results of each session were compared. In addition, the diagnostic abilities of SRS, MI and SRS alone and simultaneous SRS and MI readings were compared for patients where final diagnosis was obtained. RESULTS: SRS detected more suspected lesions (positive or inconclusive uptake) than morphological images did (51 vs 27 lesions), but included many physiological uptakes detected as positive or inconclusive uptakes. Combined reading of SRS and morphological images helped to correctly recognize these physiological uptakes, and also helped in determining the anatomical localization of the abnormal uptakes. Combined reading of SRS and morphological images gave the highest diagnostic impact. CONCLUSION: The sensitivity of SRS with regard to GEP is high. However the specificity is very low. Morphologic imaging is necessary for the exclusion of physiological uptake and correct anatomic location of an abnormal tracer uptake. The combined reading of SRS and morphologic imaging studies gives the highest diagnostic impact.

Hand-assisted laparoscopic resection of serous cystadenoma of the pancreas.

It is difficult to exclude the possibility of malignancy of pancreatic cystic tumors because a biopsy of the pancreas is hard to obtain. The indication of open surgery for those cystic tumors without evidence of malignancy is controversial. Therefore, laparoscopic or laparoscopically assisted procedure would be an adequate choice of treatment for cystic tumors of the pancreas. Hand-assisted laparoscopic distal pancreatectomy with preservation of the spleen and the splenic artery and vein was performed for two cases of pancreatic cystic tumors. Three ports and one hand port were used. After careful dissection and accurate hemostasis between the pancreas and splenic vessels, laparoscopic distal pancreatectomy was carried out using an endoscopic linear stapler. There were no perioperative complications. The pathological diagnoses were oligocystic serous cystadenoma and solitary cystic serous cystadenoma, respectively. Hand-assisted, spleen-preserving laparoscopic distal pancreatectomy with preservation of the splenic artery and vein is a feasible procedure for the treatment of benign or borderline-malignant cystic lesions of the distal pancreas.

Indirect conductimetric assay of antibacterial activities.

The applicability of indirect conductimetric assays for evaluation of antibacterial activity was examined. The minimal inhibitory concentration (MIC) obtained by the indirect method was consistent with that by the direct conductimetric assay and the turbidity method. The indirect assay allows use of growth media, which cannot be used in the direct conductimetric assay, making it possible to evaluate the antibacterial activity of insoluble or slightly soluble materials with high turbidity, such as antibacterial ceramic powders.

Antiproliferative activity induced by the somatostatin analogue, TT-232, in human pancreatic cancer cells.

Somatostatin analogues have been developed as antiproliferative agents, but their administration as general antitumour agents is limited, mainly because of the wide distribution of somatostatin receptors throughout the human body. TT-232, a new somatostatin structural analogue, was reported to have tumour-selective antiproliferative activity without an antisecretory action. We examined whether TT-232 had antiproliferative activity in human pancreatic cancer cell lines, and compared its antiproliferative activity with that of RC-160 and other TT-232 derivatives. TT-232 inhibited the growth of all of the cell lines used in this study and induced apoptotic cell death. RC-160 showed no such growth inhibition. TT-232 also inhibited tumour formation in a xenograft model. A competitive binding assay was performed using the cell membrane fraction and 111In-DTPA-TT-232 in order to show the existence of a specific binding site on the cells. A specific binding site was detected in MIAPaCa-2 cells. It has been shown that the activation of protein tyrosine phosphatase (PTPase) is one of the main intracellular pathways responsible for somatostatinergic inhibition of cell growth. We found a significant PTPase stimulation after TT-232 administration using an immunoblot analysis assessing the level of protein tyrosine phosphorylation, and also a direct measurement of the PTPase activity. We also demonstrated that PTPase stimulation by TT-232 was involved in its antiproliferative activity as this activity was reversed by the addition of sodium orthovanadate, a PTPase inhibitor. Our results indicate that TT-232 could be a potentially useful therapeutic agent if these data are translated into clinical practice.

Morphine upregulates kappa-opioid receptors of human lymphocytes.

Opioids such as morphine are potent analgesic and addictive compounds. Chronic morphine use also induces immunomodulatory and immunosuppressive effects, as especially evident in HIV-infected patients. Morphine acts on the immune cells primarily through its binding to mu-opioid receptors on the plasma membrane. However, morphine modulation of immune functions still exists in mu-opioid receptor knockout mice, suggesting that in addition to the mu opioid receptors, morphine may also act by mechanisms mediated by either delta or kappa opioid receptors. To determine whether morphine activates kappa opioid receptors (KOR), a quantitative competitive RT-PCR procedure was utilized to quantify the KOR gene expression of morphine-treated cells. A segment of KOR transcript spanning the second extracellular loop, which has the reported dynorphin specificity, and the seventh transmembrane domain of the receptor was amplified from the total RNA of morphine-treated CEM x174 lymphocytes, along with a competitor molecule. The competitor was constructed by deleting a 33-nucleotide fragment from KOR. The results of the competitive RT/PCR indicated that CEM x174 cells expressed KOR mRNA constitutively, in the order of femto-grams. Treatment of 10 microM of morphine resulted in the up-regulation of KOR gene expression 24 hr post-treatment. The observed morphine effect could be reversed by treating the cells with either naloxone (a KOR-partially selective antagonist) or nor-Binaltorphimine (a KOR-selective antagonist).

Expression of METH-1 and METH-2 in pancreatic cancer.

PURPOSE: METH-1/hADAMTS-1 and METH-2/hADAMTS-8 are recently identified genes that inhibit angiogenesis, and the murine homologue, ADAMTS-1, shows metalloproteinase function. Because the significance of METH-1 and METH-2 has not been determined in solid tumors, we examined the mRNA expressions of these molecules in pancreatic cancer and hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: METH-1 and METH-2 mRNA expressions were identified in six pancreatic cancer cell lines and were quantified by TaqMan reverse transcription-PCR in 18 paired samples of pancreatic cancer and surrounding noncancerous pancreas, and in 14 samples of pancreatic cancer. METH-1 mRNA expression was also examined in 16 pairs of HCC and cirrhotic liver. Vascularity was estimated by CD34 staining. The correlation between clinicopathological factors and METH-1 expression was additionally analyzed. RESULTS: Four of six pancreatic cancer cell lines expressed METH-1, and 1/6 expressed METH-2. METH-1 was substantially expressed in both pancreatic cancer and noncancerous pancreas, but METH-2 was not. METH-1 expression in pancreatic cancer tissue was significantly lower than that in noncancerous pancreas (P = 0.002), and a similar result was obtained between HCC and cirrhotic liver (P = 0.003). METH-1 expression did not show a significant correlation with vascularity in pancreatic cancer or in HCC. However, pancreatic cancer with higher expression of METH-1 showed significantly severe lymph node metastasis or retroperitoneal invasion (P = 0.033 and P = 0.018, respectively) and worse prognosis (P = 0.038). CONCLUSIONS: METH-1, which was initially reported to have a potent antiangiogenic effect, does not seem to be a predominant determinant of tumor vascularity in pancreatic cancer. Rather, METH-1 seems to be involved in progression of pancreatic cancer through local invasion and lymph node metastasis.

Characterization of xylanolytic enzymes in Clostridium cellulovorans: expression of xylanase activity dependent on growth substrates.

Xylanase activity of Clostridium cellulovorans, an anaerobic, mesophilic, cellulolytic bacterium, was characterized. Most of the activity was secreted into the growth medium when the bacterium was grown on xylan. Furthermore, when the extracellular material was separated into cellulosomal and noncellulosomal fractions, the activity was present in both fractions. Each of these fractions contained at least two major and three minor xylanase activities. In both fractions, the pattern of xylan hydrolysis products was almost identical based on thin-layer chromatography analysis. The major xylanase activities in both fractions were associated with proteins with molecular weights of about 57,000 and 47,000 according to zymogram analyses, and the minor xylanases had molecular weights ranging from 45,000 to 28,000. High alpha-arabinofuranosidase activity was detected exclusively in the noncellulosomal fraction. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that cellulosomes derived from xylan-, cellobiose-, and cellulose-grown cultures had different subunit compositions. Also, when xylanase activity in the cellulosomes from the xylan-grown cultures was compared with that of cellobiose- and cellulose-grown cultures, the two major xylanases were dramatically increased in the presence of xylan. These results strongly indicated that C. cellulovorans is able to regulate the expression of xylanase activity and to vary the cellulosome composition depending on the growth substrate.

Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells.

We have examined the relationship between the expression and activation of the IL-6 receptor and the possible involvement of IL-6 in the resistance of radiation-induced apoptosis in pancreatic cancer cells. Levels of IL-6 in the incubation media measured with ELISA were 1900 pg/ml in CFPAC-1, 54 pg/ml in HPAC and less than 0.2 pg/ml in MIAPaCa-2 and AsPC-1. Western blot demonstrated gp80 protein (IL-6 receptor a subunit) in all pancreatic cancer cell lines except in AsPC-1. When immunoprecipitation was performed, the bands indicating phosphorylated gp130 (IL-6Rbeta) were observed in CFPAC-1 and HPAC, however, no band was found in MIAPaCa-2 or in AsPC-1 cells. RT-PCR and Western blot demonstrated that mRNA and protein expression for Bcl-2 and Bcl-XL was substantially increased by the IL-6 treatment in CEPAC-1 cells, but not in AsPC-1 cells. Neither exogenous IL-6 nor neutralizing anti-IL-6 mAb affected the proliferation of CFPAC-1 and AsPC-1 cells. However, the IL-6 treatment significantly attenuated the susceptibility to radiation in CFPAC-1 cells but not in AsPC-1 cells, and the neutralizing anti-IL-6 mAb significantly increased the radiosensitivity of CFPAC-1 cells. The results indicated that IL-6 might be produced in a paracrine and/or autocrine fashion in pancreatic cancer cells. In-6 inhibits radiation-induced apoptosis and enhances the survival of the cells through a functional receptor system, which is associated with the up-regulation of anti-apoptotic Bcl-2 family proteins, especially Bcl-XL.

A novel synthetic Arg-Gly-Asp-containing peptide cyclo(-RGDf==V-) is the potent inhibitor of angiogenesis.

Arg-Gly-Asp (RGD)-containing peptide is a ligand for integrin alpha(V)beta3 and acts as an angiogenic inhibitor. A novel cyclic RGD peptide, cyclo(-RGDf==V-) (f==V), was synthesized and its biological activities were characterized and compared with its analogs, cyclo(-RGDfV-) (fV) and cyclo(-RGDf-MeV-) (fMeV). It bound to integrin alpha(V)beta3 with almost the same affinity as the fV and fMeV analogs. All three compounds inhibited the adhesion and growth of HUVEC cells in a dose-dependent manner in vitro. Out of three, fMeV had the strongest effect, f==V was almost as strong as fMeV, and fV had the least effect. However, in vivo, f==V significantly decreased the intratumoral microvessel density (MVD) in the DLD-1 (human colon cancer cell) inoculated mice, while fMeV had little effect. These results suggest the potential usefulness of the cyclo(-RGDf==V-) as an antiangiogenic agent for clinical use in the future.

Kappa-opioid receptors on lymphocytes of a human lymphocytic cell line: morphine-induced up-regulation as evidenced by competitive RT-PCR and indirect immunofluorescence.

We have previously shown that classical brain-like kappa opioid receptors (KOR) are constitutively expressed in lymphocytic cells. including human CEM x174 T-B hybrid cells, Jurkat -T4 cells, human peripheral blood mononuclear cells (PBMC), human CD4+ cells and monkey PBMC (Biochem. Biophys. Res. Commun. 209 (1995) 1003). The present study further demonstrates that the KOR of lymphocytes are activated in the presence of extracellular morphine or U50,488H, a KOR selective agonist, and the activation causes an increase in the expression of KOR mRNA, as determined by a quantitative competitive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) procedure. The observed agonist-induced KOR up-regulation was blocked by treating the cells with either naloxone (a KOR-partially selective antagonist) or nor-binaltorphimine (a KOR-selective antagonist). Up-regulation of lymphocytic KOR by morphine was also evidenced by flow cytometric analysis of phycoerythrin (PE) amplification of fluorescein isothiocyanate-conjugated arylacetamide labeling of the KOR. Although morphine binds primarily to mu-opioid receptors, together with the previously reported phenomenon that morphine modulation of immune functions also exists in mu-opioid receptor knockout mice, the present study confirms that opioids such as morphine may exert their effects through multiple opioid receptor types and that the effects of morphine or endogenous opioids on immune cells could not be simply adduced from the anticipated effects of a synthetic, selective opioid receptor ligand.