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Supplementary Figure S1 - PDF file 115K, Gene expression of PNLIP, CLPS, PNLIRP1 and PNLIPRP2 in Panc1, MIApaca2 and non-tumorigenic hTERT-HPNE cell lines

Supplementary Materials and Methods - PDF file 88K, Additional description of materials and methods

Supplementary Table S11: Differentially expressed genes comparing prostate tumors from nicotine-treated TRAMP mice with tumors from untreated mice (reference).

Table S3: List of 1820 differentially expressed genes between short and long survival groups

Supplementary Table S2 - PDF file 64K, A list of 55 metabolites differentially expressed in two independent cohorts of PDAC cases

Supplementary Table 9: Genes differently expressed between nicotine-treated and untreated 22Rv1 cells.

Supplementary methods: Describes additional details of generation of stable NOSTRIN overexpressing cells, western blotting, measurement of Nitric Oxide production, Xcelligence real-time migration assay and Luciferase Reporter Assay; Supplementary figure legends

Supplementary Table S6: Increased expression of genes regulating synaptic signal transduction in the cancerous prostate of nicotine�treated TRAMP mice.

Supplemetary Table 5: Genes differently expressed between current and never and between current and past/never smokers in the combined cohort of 67 prostate tumors

Supplementary Table 7: Genes differently expressed between current and never smokers in microdissected prostate tumors.

Figure S1: Representative pictures of immunohistochemical staining, showing NOSTRIN expression largely in the tumor cells in the patient with long survival. Figure S2: NOSTRIN overexpression sensitizes the Panc1 pancreatic cancer cells to gemcitabine. Figure S3: (a) A negative correlation existed between miR-222 and NOSTRIN expression in tumors from PDAC cases (N=37). (b) miR-222 expression does not show any significant association with survival. (ns=non significant).

Supplementary Figure S1: Weight curves for untreated TRAMP mice and TRAMP mice treated with nicotine for 80 days. Supplementary Figure S2: Ig lambda� and Ig kappa�positive B lymphocytes in cancerous prostate tissue by in�situ hybridization. Supplementary Figure S3: qRT�PCR validation of six genes up�regulated among current smokers. Supplementary Figure S4: Analysis of prostate tumors using Bioconductor limma R. Supplementary Figure S5: Gene Set Enrichment Analysis (GSEA) highlighting common features between smoking�related gene signatures in prostate tumors, nicotine�induced gene signatures in human prostate cancer cells, and gene signatures archived in the GSEA database. Supplementary Figure S6: Expression of various nicotinic acetylcholine receptor (AChR) subunits in human prostate cancer cell lines, prostate tumors, and adjacent non�tumor prostate tissues. Supplementary Figure S7: Nicotine�mediated Akt activation in human immortalized prostate epithelial cells and prostate cancer cell lines. Supplementary Figure S8: Effect of nicotine on the mobility of human prostate cancer cell lines. Supplementary Figure S9: Nicotine enhances cell surface integrin expression and extracellular matrix binding (ECM) of 22Rv1 human prostate cancer cells. Supplementary Figure S10: Nicotine enhances proliferation of RWPE�1 in complete K�SFM medium but not in K�SFM medium without EGF and bovine pituitary extract. Supplementary Figure S11: Nicotine did not enhance proliferation of 22Rv1 and PC�3 human prostate cancer cells. Supplementary Figure S12: Lymphotoxin�β plasma levels in prostate cancer patients (Case) and population�based controls (Control) by smoking status.

Supplemetary Table 8: Genes differently expressed between current and never in microdissected tumors using the Bioconductor limma R package.

PDF file - 612K, Table S1. Characteristics of patient population. Figure S1. An inverse association between FOXL1 and ZEB1 expressions in pancreatic cancer cell lines. Figure S2. Oncomine analysis on differential expression of FOXL1 in multiple publicly available microarray datasets of pancreatic cancer. Figure S3. The effect of silencing FOXL1 by siRNA on cell growth, apoptosis and invasion in pancreatic cancer cells. Figure S4. The regulation of apoptosis-related gene expression by overexpression of FOXL1 in Panc1 cells.

BACKGROUND Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described. OBJECTIVES The objective of this study was to identify dietary predictors of plasma TMAO concentrations. METHODS TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations. RESULTS In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high‐ (>median, N=31) and low‐NOS2 (inducible nitric oxide synthase) (•(nitric oxide)‐mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (N=63,P= 0.01). Gene expression analysis in PDAC tumors (N=63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine‐2,3‐dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)‐target genes includingNFE2L2(NRF2),SERPINB2, IL1b,IL6andIL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO•donor induced IDO1, kynurenine production, and the expression of AHR‐target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO•‐induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.

Objective: The safety and effect of intra-arterial (IA) tirofiban, a glycoprotein IIb/IIIa inhibitor, during the stent retriever mechanical thrombectomy (MT) was investigated. Methods: From January 2015 to May 2019, a total of 327 patients underwent mechanical thrombectomy of large artery occlusions (LAO). Patients were classified into two groups: MT with IA tirofiban (MTT) group and MT only (MTO, without IA tirofiban) group. Clinical outcomes, radiological results, and various complications, such as post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding, and hemorrhagic transformation of infarct were evaluated by comparing the MTT group and MTO group. In addition, subgroup analysis was performed for patients who underwent MT with prior intravenous (IV) tissue plasminogen activator (t-PA). Results: The MTT group needed a lower mean number of stent passes and showed a re-occlusion rate as compared with the MTO group (P=0.038 and 0.022, respectively). Between the two groups, there were no statistically significant differences in post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding complications, or hemorrhagic transformation of infarct (P = 0.511, 0.397, 0.429, and 0.355, respectively). In the subgroup analysis, similar findings were observed. Conclusion: The use of IA tirofiban during MT seems to be safe and potentially more effective than only MT without IA tirofiban, even in patients who used IV t-PA before MT.

Despite the development of sensors and LED lighting technologies, smart lighting technology is a still challenging topic. No smart lighting system with built-in RADAR and camera has yet been reported that is both energy-saving and efficient for searching for missing persons. Herein we design a smart lighting system based on RADAR and a camera sensor. The RADAR detects moving obstacles including pedestrians and the camera records by means of RADAR motion detection in event mode. Selected images corresponding to persons of interest are very useful for quick searching for missing persons.

Several antecedent studies had reported close relationship between low body weight and Parkinson's disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.

Purpose To report short-term surgical outcomes of single-stage simultaneous rescue and sutureless intrascleral fixation of dislocated intraocular lens (IOLs). Methods Sixteen eyes of 16 patients who underwent simultaneous rescue and intrascleral fixation of dislocated 3-piece IOLs were retrospectively evaluated. Partial thickness limbal-based scleral flaps (2.0 × 2.0 mm) were created, and a 22-gauge round needle was used to create a sclerotomy at 1.5 mm from the limbus under the previously created scleral flap, and a 23-gauge trans pars plana vitrectomy was performed. Bimanual maneuvers using two 23-gauge end-grasping forceps under chandelier illumination and a wide-angle viewing system enabled 1 step rescue of IOLs from the posterior vitreous cavity with 1 hand and simultaneous haptic externalization through sclerotomy with the other hand. An externalized haptic was placed into the 3-mm intrascleral tunnel created using a bent 26-gauge needle. Fibrin glue was used to fixate haptics and close the scleral flaps. Results Intraocular lenses were successfully rescued and sclera-fixated through intrascleral tunnels in all 16 eyes (mean age, 56.56 ± 19.89 years). The mean preoperative logarithm of the minimum angle of resolution best-corrected visual acuity was 0.92 ± 0.68, and this significantly improved at 6 months to 0.289 ± 0.36 (P = 0.003). During the follow-up period (10.1 ± 3.21 months), no significant change of endothelial cell count or central foveal thickness was noted postoperatively (P = 0.203 and P = 0.979, respectively). There were no significant postoperative complications such as IOL dislocation, IOL decentration, retinal detachment, endophthalmitis, or postoperative hypotony. Conclusion Simultaneous rescue and sutureless intrascleral haptic fixation of dislocated 3-piece IOLs using bimanual maneuvers is an effective, safe, and minimally invasive surgical method to rescue and fixate the dislocated IOL without further explant.

Background and Aims Resistance rates of Helicobacter pylori to clarithromycin, metronidazole, and quinolone are over 30% in South Korea. The aim of this prospective study was to evaluate the ultimate eradication rate of H. pylori after first, second, or third-line therapy in Korea. Methods A cohort of 2202 patients with H. pylori was treated with proton pump inhibitor (PPI)-based triple therapy for seven days. In case of treatment failure or recurrence, moxifloxacin-based triple therapy (MA) or bismuth-based quadruple therapy (QUAD) was randomly given. When the second-line treatment failed or H. pylori recurred, the unused MA or QUAD was used as a third-line treatment. Results Eighty-six patients had recurrence at least once during consecutive lines of treatments. Among 2116 patients (intention-to-treat [ITT]) without recurrence, 1644 (77.7%, per-protocol [PP]) completely followed our treatment flow. The ITT and PP rates of first-line treatment were 69.8% and 89.3%. After second line, they reached 78.4% (ITT) and 98.4% (PP). The “final” eradication rate up to third line treatment were 80.0% (1692/2116) and 99.8% (1641/1644), respectively. Resistance to clarithromycin showed significantly lower eradication rate (OR 0.358, P

Our research team investigated the elemental composition and the presence of various toxic organic compounds, such as polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), in estuary surface sediments to trace the spatial distribution of the sources of pollution deposited in Nakdong River, Busan, South Korea. The spatial patterns of elemental composition and toxic organic compounds were determined from the measurements of total organic carbon (TOC), total nitrogen, total sulfur, PAHs, and PCBs. The sediments had TOC contents of between 0.02 and 1.80 wt% (avg. 0.34 wt%), depending on the amount of clay-sized particles. The concentrations of PAHs and PCBs (10.8-167.7 ng g

Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.

Background The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection. Aims To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance. Methods Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined. Results In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies. Conclusions Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance.

The objective of the present study was to develop and validate a new non-Newtonian shear-thinning standard viscosity fluid (SVF). The SVF exhibiting the non-Newtonian shear-thinning viscosity behavior of whole blood was necessary to evaluate the analytical performance of a blood viscometer according to Clinical Laboratory and Standards Institute (CLSI) guideline. The study utilized three different concentrations of maltose solution in water to cover high-, medium-, and low-viscosity ranges of whole blood. The SVFs could simulate whole blood viscosity over a wide range of shear rates and showed a long-term stability for at least 56 days with the coefficients of variations less than 5% in the viscosity measurements.

The objective of the present study was to investigate the feasibility of using a gliding arc (GA) discharge to inactivate microorganisms in water. Microbubble generators were utilized to uniformly disperse gas bubbles that contain H 2 O 2 in water. In addition, the residual effect of H 2 O 2 in plasma-treated water was assessed by continuous quantitative measurement of microbiological colony forming units (cfu) in water after the completion of GA discharge. Application of the GA plasma discharge to water decreased pH from 6.15 to 3.55 after 25-min treatment, and the lowered pH was maintained for 4 h after treatment ceased. The present study showed a total 6-log reduction in the cfu counts of Escherichia Coli with plasma treatment of 25 min duration: 4-log reduction from 10 6 to 10 2 during treatment and an additional 2-log reduction from 10 2 to 10 0 during the 2 h after treatment. The use of microbubble generators significantly enhanced the benefit of H 2 O 2 in acidic water, increasing the bacterial inactivation ability of the plasma treatment with GA discharge.

A new botulinum toxin type A (NBoNT) produced from the same strain of Clostridium botulinum as onabotulinumtoxinA (OBoNT) is widely used in Asia.To compare the efficacy and safety of NBoNT and OBoNT for moderate to severe glabellar wrinkles.A double-blind, randomized, active-controlled, phase III study was performed. Three hundred fourteen patients were randomized at a 1:1 ratio to receive 20 U of toxin. The primary end point was the responder rate according to investigator live assessment at maximum frown at week 4. Secondary end points were responder rates according to investigator live assessment with frowning and at rest at weeks 8, 12, and 16, with additional photographic assessment by a panel of blinded raters 4 weeks after injection. Subjective satisfaction scores were also evaluated.Four weeks after treatment, responder rates for maximum frown were 93.7% (133/142) in the NBoNT group and 94.5% (138/146) in the OBoNT group. For secondary end points, there was no significant difference between the two groups for any variable at any time point. Noninferiority of NBoNT was confirmed. There were no serious adverse effects with either toxin.NBoNT is equally as effective as OBoNT for the treatment of glabellar frown lines. Both toxins were well tolerated.

MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.

Background and Aims: To assess the validity of biopsy-based tests (histology, culture, and urease test) and serology in detecting current H. pylori infection for the peptic ulcer patients who had gastric bleeding. Methods: A total of 398 peptic ulcer patients were enrolled and divided into two groups, according to the presence or absence of bleeding. The diagnosis for current H. pylori infection was verified using the gold standard combining individual H. pylori tests. Sensitivity, specificity, and positive and negative predictive values of the culture, Campylobacter-like organism (CLO) test (urease test), histology, and serology were compared. Results: Of the total study population (N = 398), 157 (39.4%) patients were categorized into the bleeding group. The sensitivities of the culture (40.0%) and CLO (85.0%) in the bleeding group were significantly lower than culture (58.1%) and CLO (96.4%) in the nonbleeding group (p = .012 and p

Hematocrit has been considered as an important marker of oxygen carrying capacity of the blood associated with whole blood viscosity to assess the mortality risk of both cardiovascular, cerebral, and kidney diseases. The present study developed a new on-line conductivity cell to measure the hematocrit of whole blood using a bipolar square-wave voltage signal at a frequency of 5 kHz. By applying such a voltage signal to a blood flowing in a range of 1.2–3.0 mL/min, the electrolyte effect of blood plasma, the conductive and capacitive effects of blood cells, and the sedimentation effect of erythrocytes on the conductivity of whole blood could be minimized for an accurate hematocrit measurement. The coefficient of correlation between the present method and conventional microcentrifuge method showed an excellent linear relationship. A new equation between the specific conductance and Hct of whole blood was obtained: C = 12.561 − 0.1527 Hct (P

The present study investigated the effect of perforated circular finned-tube (PCFT) on the convective heat transfer performance of circular finned-tube heat exchangers. The air-side convective heat transfer coefficients increased by 3.55% and 3.31% for 2-hole and 4-hole PCFT cases, respectively. The increase in the convective heat transfer coefficient was related to the reduction of the recirculation region by introducing the perforations at the flow-separation locations on the finned tube. The pressure drop across the finned-tube bundles increased by 0.68% and 2.08% for the 2-hole PCFT and 4-hole PCFT cases, respectively. The greater pressure drop in the case of the 4-hole PCFT might be due to excessive flow disturbances produced by multiple perforations. The fin factor defined as the ratio of the % increase of the convective heat transfer coefficient and that of the pressure drop was 5.19 for the 2-hole PCFT case, whereas that was 1.59 for the 4-hole PCFT case.

The whole blood viscosity (WBV) is one of the major independent indicators for the risk of cardiovascular disease, stroke, and peripheral arterial diseases. Furthermore, oxidized LDL molecules are known to cause atherosclerotic plaques in arteries, and it is one of the key components that increase WBV. The present study attempted to reduce WBV by coagulating plasma proteins and lipid molecules from blood plasma using non-thermal dielectric barrier discharge (DBD) and removing them through filtration. The DBD treatment was found to produce coagulated particles in blood plasma. After filtration of the coagulated particles, WBV decreased by 9.1 and 17.7% for both systolic and diastolic blood viscosities, respectively. The present results suggest that the removal of excess plasma proteins and lipid molecules might be feasible using DBD treatment.

Objectives Clinicians have long noted that infected cholesteatomas are more aggressive than uninfected ones without data to support these observations. The purpose of this study is to determine the etiological role of biofilm forming P. aeruginosa (PA) and the virulence factor, type IV pili, in the pathogenesis of experimental cholesteatomas.

Agrobacterium-mediated transformation of Carrizo citrange [Citrus sinensis (L.) Osbeck × Poncirus trifoliata (L.) Raf.] with a binary vector containing a novel bifunctional reporter–selection fusion gene comprising an in-frame fusion between the manA gene and egfp gene is detailed. This system combined the phosphomannose isomerase positive selection system with the ability to monitor gene expression in a non-destructive manner using EGFP. Transgenic plants stably expressing the EGFP protein were regenerated following Agrobacterium-mediated transformation using a vector containing this fusion gene. We also obtained comparable transformation efficiencies when Carrizo explants were transformed using another Agrobacterium strain containing a binary vector with a bifunctional egfp–nptII fusion gene. Regenerating shoots were selected on medium containing 15 g L−1 mannose supplemented with 5 g L−1 sucrose for the manA-based selection or on medium containing 100 mg L−1 kanamycin for the nptII-based selection. Our results indicated that the mannose-based antibiotic-free selection combined with visual identification of transgenic shoots using EGFP allows for early elimination of escape non-transgenic shoots and can provide a viable alternative to antibiotic-based selection systems in the genetic transformation of citrus and other crops.

Background and Aims: The eradication rate of proton-pump inhibitor-based triple therapy for Helicobacter pylori infection is low due to increasing antibiotics resistance, especially clarithromycin. Recently, it was reported in Europe that a 10-day sequential strategy produced good outcomes. The aim of this study was to assess the efficacy of sequential therapy as first-line treatment for eradication of H. pylori in clinical practice in Korea. Materials and Methods: A total of 98 patients (mean age 55.2 years and male 47, female 51) with proven H. pylori infection received 10-day sequential therapy (20 mg of rabeprazole, and 1 g of amoxicillin, twice daily for the first 5 days, followed by 20 mg of rabeprazole, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily for the remaining 5 days). Eradication was evaluated 4 weeks later, after completion of treatment by 13C-urea breath testing. Eradication rates were calculated by intention-to-treat (ITT) and by per protocol (PP). Compliance and adverse events were also assessed in study group. Results: The eradication rate of sequential therapy was 91.8% (90/98) by ITT and same result was reported by PP analysis (89/97). The study group consisted of 66 H. pylori associated gastritis, 7 gastric ulcer, and 25 duodenal ulcer patients (67.3%, 7.1%, 25.5%, respectively). Mild adverse events happened frequently (21.4%) but the treatment was well tolerable. The most common adverse event was a bitter taste (9.2%) followed by nausea and diarrhea (4.1%). Conclusions: Ten-day sequential therapy is found to effectively eradicate H. pylori infection as first-line treatment in Korea.

Gastric cancer is believed to develop by a multistage process. Intestinal metaplasia (IM) is regarded as a premalignant condition; it is classified into subtypes I, II and III. The aim of this study was to evaluate whether the subtypes of IM were associated with progression to gastric cancer.The study cohort consisted of 861 subjects, categorized as controls, gastric ulcers, dysplasia and cancer. The IM was scored histologically using the Sydney classification for the antrum and the body of the stomach. The biopsies were stained with high iron diamine and alcian blue (pH 2.5) (HID-AB2.5), and the IM was subtyped as I, II or III.The proportion of IM subtypes I, II and III were 14.5%, 47.2% and 38.3% in the antrum, and 28.1%, 57.8% and 14.1% in the body of the stomach, respectively. These distributions did not show significant differences depending on disease or Helicobacter pylori positivity. In cases that were H. pylori-positive, the prevalence of IM subtype II in the cancer and dysplasia groups was higher than in the control group in the body of the stomach (P0.05). The proportion of IM subtype III in the antrum increased in proportion with age (P = 0.036).IM subtyping was not found to play a major role in the prediction of gastric cancer development in Korea. IM subtype III was associated with aging, and IM subtype II appeared to be related to gastric carcinogenesis in the presence of H. pylori infection.

The effect of sodium stannate on Plasma electrolyte oxidation (PEO) process of AZ91 Mg alloy was systematically investigated. The oxide layer formed on an AZ91 Mg alloy created using an electrolyte containing sodium stannate formed a much thicker layer consisting of: MgO, SnO, Mg 2 SiO 4 , and MgF 2 . The result of EDS analysis shows a tin enriched zone at the oxide layer/substrate interface. Corrosion resistance of the sample coated from the electrolyte containing sodium stannate was determined to be superior to that of the sample coated from the electrolyte without sodium stannate. As a result of salt spray test for 120 hrs, severe filiform corrosion is observed on the thin oxide layer of AZ91 Mg alloy without sodium stannate. However, the sample of the electrolyte containing sodium stannate shows localized pitting corrosion. Tin ions in the electrolyte influence on the growth rate of the oxide layer, especially resulting in a formation of dense barrier layer. The co-existence of dense MgO and SnO in the oxide layer could improve the corrosion resistance of the AZ91 Mg alloy.

The factors that determine whether a breast carcinoma will develop into inflammatory breast cancer (IBC) remain poorly understood. Recent evidence indicates that the tumor stroma influences cancer phenotypes. We tested the hypotheses that the gene expression signature of the tumor stroma is a distinctive feature of IBC. We used laser capture microdissection to obtain enriched populations of tumor epithelial cells and adjacent stromal cells from 15 patients with IBC and 35 patients with invasive, noninflammatory breast cancer (non-IBC). Their mRNA expression profiles were assessed using Affymetrix GeneChips. In addition, a previously established classifier for IBC was evaluated for the resulting data sets. The gene expression profile of the tumor stroma distinguished IBC from non-IBC, and a previously established IBC prediction signature performed better in classifying IBC using the gene expression profile of the tumor stroma than it did using the profile of the tumor epithelium. In a pathway analysis, the genes differentially expressed between IBC and non-IBC tumors clustered in distinct pathways. We identified multiple pathways related to the endoplasmic stress response that could be functionally significant in IBC. Our findings suggest that the gene expression in the tumor stroma may play a role in determining the IBC phenotype.

Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p

Background: A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor suppressor protein. We investigated whether genetic variants in MDM2 were associated with breast cancer incidence and survival and whether the variant status could interact with the tumor p53 status to modify breast cancer survival. Methods: We used multivariable logistic and Cox regression analyses to study the relationship of SNP309 status and the status of a second MDM2 SNP in exon 12 at codon 354 (SNP354) with breast cancer incidence and with diseasespecifi c survival among 293 case patients and 317 cancer-free control subjects. Survival analysis included 248 of the 293 case patients who had known tumor p53 status. All statistical tests were two-sided. Results: We did not observe an association between SNP309 status and breast cancer incidence in the unstratifi ed analysis, but we did fi nd a statistically signifi cant association between SNP354 status and breast cancer incidence (odds ratio = 3.34, 95% confi dence interval [CI] = 1.88 to 5.93). We also discovered a statistically signifi cant interaction between SNP309 status and tumor p53 expression for breast cancer survival ( P interaction = .002). Among homozygous carriers of the common MDM2 SNP309 allele (T/T), a mutant p53 status (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03) and aberrant p53 protein expression (RR = 2.61, 95% CI = 1.22 to 5.57) in breast tumors were associated with poor survival. Tumor p53 status was not associated with breast cancer survival among carriers of the variant MDM2 SNP309 allele (G/T or G/G), which is consistent with a dominant effect of the variant allele. Conclusion: A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival. [J Natl Cancer Inst 2006;98: 911 – 9 ]

Summary A major obstacle to tuberculosis (TB) control is the problem of chronic TB infection (CTBI). Here we report that 5 ¢ -adenosinephosphosulphate reductase (CysH), an enzyme essential for the production of reduced- sulphur-containing metabolites, is critical for Myco- bacterium tuberculosis (Mtb) survival in chronic infec- tion phase in mice. Disruption of cysH rendered Mtb auxotrophic for cysteine and methionine, and attenu- ated virulence in BALB/c and C57BL/6 immunocom- petent mice. The mutant and wild-type Mtb replicated similarly during the acute phase of infection, but the mutant showed reduced viability during the persistent phase of the infection. The cysH mutant caused dis- ease and death after 4-7 weeks of infection in four different groups of mice - Rag1 -/- , NOS2 -/- , gp91phox -/- NOS2 -/- and gp91phox -/- mice given aminoguanidine (to suppress the effects of nitric oxide synthase 2 (NOS2)) - indicating minimal metabolic effect on the cysH mutant survival in these mice. The cysH mutant was also susceptible to peroxynitrite and hydrogen peroxide in vitro . These results show that CysH is important for Mtb protection during the chronic infection phase, and that resistance to nitrosative and oxidative stress may be the mechanism of this pro- tection. Thus, this metabolic gene of an intracellular pathogen could have a secondary role in protection against the host immune response. Finally the lack of an endogenous human orthologue of cysH and its possible role in defence against adaptive immunity renders CysH an attractive enzyme for further studies as a target for therapeutics active against CTBI.

Summary Sulfate assimilation is a critical component of both primary and secondary metabolism. An essential step in this pathway is the activation of sulfate through adenylation by the enzyme ATP sulfurylase (ATPS), forming adenosine 5′-phosphosulfate (APS). Proteobacterial ATPS overcomes this energetically unfavorable reaction by associating with a regulatory G protein, coupling the energy of GTP hydrolysis to APS formation. To discover the molecular basis of this unusual role for a G protein, we biochemically characterized and solved the X-ray crystal structure of a complex between Pseudomonas syringae ATPS (CysD) and its associated regulatory G protein (CysN). The structure of CysN•D shows the two proteins in tight association; however, the nucleotides bound to each subunit are spatially segregated. We provide evidence that conserved switch motifs in the G domain of CysN allosterically mediate interactions between the nucleotide binding sites. This structure suggests a molecular mechanism by which conserved G domain architecture is used to energetically link GTP turnover to the production of an essential metabolite.

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer–prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055–65. ©2015 AACR.

Objective: Olfactory dysfunction is present in the majority of patients with early-stage Parkinson disease (PD) and can precede the onset of motor symptoms by many years. We performed this study to evaluate whether normosmic patients with PD had different clinical features compared to hyposmic patients. Methods: We analyzed the data of 208 de novo patients with PD (mean age, 65.4 ± 9.7 years; range, 38–85 years; 104 men) who underwent both olfactory function tests and dopamine transporter (DAT) scans. Results: Normosmic patients were significantly younger and had fewer motor deficits than hyposmic patients with PD. Striatal subregional DAT activities were comparable between the 2 groups, but intersubregional gradients were significantly higher in normosmic than hyposmic PD. A general linear model showed that normosmic patients with PD showed significantly fewer motor deficits after controlling the patient9s age, sex, symptom duration, and DAT activity in the posterior putamen ( p = 0.016). Levodopa-equivalent dose at approximately 2.5 years follow-up tended to be lower in normosmic than in hyposmic PD ( p = 0.055). Conclusions: These results suggest that normosmic PD is a unique clinical phenotype with a more benign course, compared to hyposmic PD. Either less pathologic involvement in the olfactory system or a greater potential for olfactory neurogenesis in normosmic PD may contribute to this benign process compared to hyposmic PD.

In this article, we analyze the linear stability of tandem offloading systems in wind, current, and waves. The wind and current forces are evaluated with the help of published experimental data, while the hydrodynamic coefficients and wave drift forces are rigorously estimated by using a three-dimensional singularity distribution method based on potential theory. The bow hawser and mooring lines are described quasistatically by elastic catenary equations. In order to examine the linear static and dynamic stability of the system, the equations for surge, sway, and yaw are linearized. The effect of design parameters such as turret position, mooring stiffness, and hawser length and stiffness on stability is investigated based on linearized model. The stability analysis clarifies the mechanism of the limit cycle for tandem offloading systems, which is known as fishtailing motion. The theoretical results of the shape and amplitude of the limit cycle are found to be in good agreement with those of simulations and experiments.