A Systematic Study of the Forbidden Pitch in the CD Through-Pitch Curve for Beyond 130nm

The forbidden pitch ＂dip＂ in the critical dimension （CD） through the pitch curve is a well-known optical proximity effect. The CD and CD process window near the ＂dip＂,usually found near a pitch range of 1.1 to 1.4 wavelength/ NA （numerical aperture）,is smaller when compared with other pitches. This is caused by inadequate imaging contrast for an unequal line and space grating. Although this effect is relatively well-known, its relationship with typical process condition parameters,such as the effective image blur caused by the photo-acid diffusion during the post exposure bake or the aberration in the imaging lens, has not been systematically studied. In this paper, we will examine the correlation between the image blur and the effect on the CD, including the decrease in the CD value （the depth of the ＂dip＂） and the CD process window. We find that both the decrease in the CD value and the focus latitude near the forbidden pitch correlate very well with the effective Gaussian image blur. Longer effective diffusion length correlates well with a smaller process window and a deeper CD ＂dip＂. We conclude that the dip depth is very sensitive to the change in image contrast.

Comparative study: Vonoprazan and proton pump inhibitors in Helicobacter pylori eradication therapy

AIMTo compare the effectiveness and safety of vonoprazan-based therapy with proton pump inhibitor (PPI)-based therapies to treat Helicobacter pylori (H. pylori).METHODSWe retrospectively analysed data from first-line (vonoprazan or PPI with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 d) (n = 1353) and second-line (vonoprazan or PPI with 250 mg metronidazole and 750 mg amoxicillin twice daily for 7 d) (n = 261) eradication treatments for H. pylori -positive patients with associated gastrointestinal diseases from April 2014 to December 2015 at Hattori Clinic, Japan. The primary endpoint was the eradication rate, which was assessed with a full analysis set. The secondary endpoints were adverse events and related factors.RESULTSAfter the first-line treatments, the eradication rates for vonoprazan, esomeprazol, rabeprazole, and lansoprazole were 87.9% (95%CI: 84.9%-90.5%), 71.6% (95%CI: 67.5%-75.5%), 62.9% (95%CI: 52.0%-72.9%), and 57.3% (95%CI: 50.4%-64.1%), respectively. The vonoprazan eradication rate was significantly higher than that of the PPIs (P < 0.01). Interestingly, smoking did not affect the H. pylori eradication rate in the vonoprazan group (P = 0.34), whereas it decreased the rates in the PPI groups (P = 0.013). The incidence of adverse events in the vonoprazan group was not different from the PPI group (P = 0.054), although the vonoprazan group exhibited a wider range of adverse events. Vonoprazan-based triple therapy was highly effective as a second-line treatment, with an eradication rate similar to that of PPI-based therapy.CONCLUSIONVonoprazan might be superior to PPIs in first-line H. pylori therapy, particularly for smokers. However, caution is required due to possible adverse events.

Diagnostic endoscopic ultrasonography:Assessment of safety and prevention of complications

Endoscopic ultrasonography (EUS) has gained wide acceptance as an important, minimally invasive diagnostic tool in gastroenterology, pulmonology, visceral surgery and oncology. This review focuses on data regarding risks and complications of non-interventional diagnostic EUS and EUS-guided fine-needle biopsy (EUS-FNB). Measures to improve the safety of EUS und EUS-FNB will be discussed. Due to the specific mechanical properties of echoendoscopes in EUS, there is a low but noteworthy risk of perforation. To minimize this risk, endoscopists should be familiar with the specific features of their equipment and their patients' specific anatomical situations (e.g., tumor stenosis, diverticula). Most diagnostic EUS complications occur during EUS-FNB. Pain, acute pancreatitis, infection and bleeding are the primary adverse effects, occurring in 1% to 2% ofpatients. Only a few cases of needle tract seeding and peritoneal dissemination have been reported. The mortality associated with EUS and EUS-FNB is 0.02%. The risks associated with EUS-FNB are affected by endoscopist experience and target lesion. EUS-FNB of cystic lesions is associated with an increased risk of infection and hemorrhage. Peri-interventional antibiotics are recommended to prevent cyst infection. Adequate education and training, as well consideration of contraindications, are essential to minimize the risks of EUS and EUS-FNB. Restricting EUS-FNB only to patients in whom the cytopathological results may be expected to change the course of management is the best way of reducing the number of complications.

Current research and treatment for gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest,especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene,BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential,and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure,targeted therapy in the form of tyrosine kinase inhibitors(TKIs) has revolutionized the management options. As the first-line TKI,imatinib offers treatment for advanced and metastatic GISTs,adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options,including prolonging the first-line TKI from 1 to 3 years,increasing the dose of TKI or switching to second-line TKI. Other newer TKIs,such as sunitinib and regorafenib,may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated,such as inhibitors of BRAF,heat shock protein 90,glutamine and mitogenactivated protein kinase signaling,as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe,North America and Asia are highlighted.

GA and PSO culled hybrid technique for economic dispatch problem with prohibited operating zones

This paper presents an efficient and reliable genetic algorithm (GA) based particle swarm optimization (PSO) tech- nique (hybrid GAPSO) for solving the economic dispatch (ED) problem in power systems. The non-linear characteristics of the generators, such as prohibited operating zones, ramp rate limits and non-smooth cost functions of the practical generator operation are considered. The proposed hybrid algorithm is demonstrated for three different systems and the performance is compared with the GA and PSO in terms of solution quality and computation efficiency. Comparison of results proved that the proposed algo- rithm can obtain higher quality solutions efficiently in ED problems. A comprehensive software package is developed using MATLAB.

Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis

To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined.METHODSCollagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry.RESULTSCT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease.CONCLUSIONFrom these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.

Omeprazole decreases magnesium transport across Caco-2 monolayers

AIM:To elucidate the effect and underlying mechanisms of omeprazole action on Mg 2+ transport across the intestinal epithelium.METHODS:Caco-2 monolayers were cultured in various dose omeprazole-containing media for 14 or 21 d before being inserted into a modified Ussing chamber apparatus to investigate the bi-directional Mg 2+ transport and electrical parameters.Paracellular permeability of the monolayer was also observed by the dilution potential technique and a cation permeability study.An Arrhenius plot was performed to elucidate the activation energy of passive Mg 2+ transport across the Caco-2 monolayers.RESULTS:Both apical to basolateral and basolateral to apical passive Mg 2+ fluxes of omeprazole-treated epithelium were decreased in a dose-and time-dependent manner.Omeprazole also decreased the paracellular cation selectivity and changed the paracellular selective permeability profile of Caco-2 epithelium to Li +,Na +,K +,Rb +,and Cs + from seriesⅦto seriesⅥof the Eisenman sequence.The Arrhenius plot revealed the higher activation energy for passive Mg 2+ transport in omeprazoletreated epithelium than that of control epithelium,indicating that omeprazole affected the paracellular channel of Caco-2 epithelium in such a way that Mg 2+ movement was impeded.CONCLUSION:Omeprazole decreased paracellular cation permeability and increased the activation energy for passive Mg 2+ transport of Caco-2 monolayers that led to the suppression of passive Mg 2+ absorption.

Response of BRCA1-mutated gallbladder cancer to olaparib: A case report

gallbladder cancer(gbc), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. the late diagnosis and abysmal prognosis present challenges to treatment. the overall 5-year survival rate for metastatic gbc patients is extremely low. BRC A1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European commission for the treatment of ovarian cancer with any BRCA1/2 mutations. the first case of BRCA1-mutated gbc patient who responded to olaparib treatment is reported here.

Mortality associated with gastrointestinal bleeding in children: A retrospective cohort study

To determine the clinical characteristics of children with gastrointestinal bleeding (GIB) who died during the course of their admission.METHODSWe interrogated the Pediatric Hospital Information System database, including International Classification of Diseases, Current Procedural Terminology and Clinical Transaction Classification coding from 47 pediatric tertiary centers extracting the population of patients (1-21 years of age) admitted (inpatient or observation) with acute, upper or indeterminate GIB (1/2007-9/2015). Descriptive statistics, unadjusted univariate and adjusted multivariate analysis of the associations between patient characteristics and treatment course with mortality was performed with mortality as primary and endoscopy a secondary outcome of interest. All analyses were performed using the R statistical package, v.3.2.3.RESULTSThe population with GIB was 19528; 54.6% were male, overall mortality was 2.07%; (0.37% in patients with the principal diagnosis of GIB). When considering only the mortalities in which GIB was the principal diagnosis, 48% (12 of 25 principal diagnosis GIB mortalities) died within the first 3 d of admission, whereas 19.8% of secondary diagnosis GIB patients died with 3 d of admission. Patients who died were more likely to have received octreotide (19.8% c.f. 4.04%) but tended to have not received proton pump inhibitor therapy in the first 48 h, and far less likely to have undergone endoscopy during their admission (OR = 0.489, P < 0.0001). Chronic liver disease associated with a greater likelihood of endoscopy. Mortalities were significantly more likely to have multiple complex chronic conditions.CONCLUSIONGIB associated mortality in children is highest within 7 d of admission. Multiple comorbidities are a risk factor whereas early endoscopy during the admission is protective.

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

Characterization of Angiotensin-? Converting Enzyme Inhibiting Peptide from Venerupis philippinarum with Nano-Liquid Chromatography in Combination with Orbitrap Mass Spectrum Detection and Molecular Docking

The complexity and diversity of peptide mixture from protein hydrolysates make their characterization difficult. In this study, a method combining nano LC-MS/MS with molecular docking was applied to identifying and characterizing a peptide with angiotensin-? converting enzyme(ACE-I) inhibiting activity from Venerupis philippinarum hydrolysate. Firstly, ethanol supernatant of V. philippinarum hydrolysate was separated into active fractions with chromatographic methods such as ion-exchange chromatography and high performance liquid chromatography in combination. Then seven peptides from active fraction were identified according to the searching result of the MS/MS spectra against protein databases. Peptides were synthesized and subjected to ACE-Iinhibition assay. The peptide NTLTLIDTGIGMTK showed the highest potency with an IC_(50) of 5.75 μmol L^(-1). The molecular docking analysis showed that the ACE-I inhibiting peptide NTLTLIDTGIGMTK bond with residues Glu123, Glu403, Arg522, Glu376, Gln281 and Asn285 of ACE-I. Therefore, active peptides could be identified with the present method rather than the traditional purification and identification strategies. It may also be feasible to identify other food-derived peptides which target other enzymes and receptors with the method developed in this study.

Immune checkpoint therapy for pancreatic cancer

Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy. However, due to small sample sizes, major results are not yet identifiable. The present article provides a clinical overview of immune checkpoint inhibition in pancreatic cancer. Pub Med, Clinical Trials.gov and American Society of Clinical Oncology's meeting abstracts were systematically searched for relevant clinical studies. Four articles, five abstracts and 25 clinical trials were identified and analyzed in detail.

Factors associated with complicated erosive esophagitis: A Japanese multicenter, prospective, cross-sectional study

AIMTo assess the clinical characteristics of patients with complicated erosive esophagitis (EE) and their associated factors.METHODSThis prospective, cross-sectional study included patients diagnosed with EE by upper gastrointestinal endoscopy between October 2014 and March 2015 at 106 Japanese hospitals. Data on medical history, general condition, gastrointestinal symptoms, lifestyle habits, comorbidities, and endoscopic findings were collected using a standard form to create a dedicated database. Logistic regression analysis was used to calculate adjusted odds ratios (aOR) and 95%CI for the association with complicated EE.RESULTSDuring the study period, 1749 patients diagnosed with EE, 38.3% of whom were prescribed proton pump inhibitors (PPIs) were included. Of them, 143 (8.2%) had EE complications. Esophageal bleeding occurred in 84 (4.8%) patients, esophageal strictures in 45 (2.6%) patients, and 14 (0.8%) patients experienced both. Multivariate analysis showed that increased age (aOR: 1.05; 95%CI: 1.03-1.08), concomitant use of psychotropic agents (aOR: 6.51; 95%CI: 3.01-13.61), and Los Angeles grades B (aOR: 2.69; 95%CI: 1.48-4.96), C (aOR: 15.38; 95%CI: 8.62-28.37), and D (aOR: 71.49; 95%CI: 37.47-142.01) were significantly associated with complications, whereas alcohol consumption 2-4 d/wk was negatively associated (aOR: 0.23; 95%CI: 0.06-0.61). Analyzing associated factors with each EE complication separately showed esophageal ulcer bleeding were associated with increased age (aOR: 1.05; 95%CI: 1.02-1.07) and Los Angeles grades B (aOR: 3.60; 95%CI: 1.52-8.50), C (aOR: 27.61; 95%CI: 12.34-61.80), and D (aOR: 119.09; 95%CI: 51.15-277.29), while esophageal strictures were associated with increased age (aOR: 1.07; 95%CI: 1.04-1.10), gastroesophageal reflux symptom (aOR: 2.51; 95%CI: 1.39-4.51), concomitant use of psychotropic agents (aOR: 11.79; 95%CI: 5.06-27.48), Los Angeles grades C (aOR: 7.35; 95%CI: 3.32-16.25), and D (aOR: 20.34; 95%CI: 8.36-49.53) and long-segment Barrett&#x02019;s esophagus (aOR: 4.63; 95%CI: 1.64-13.05).CONCLUSIONAging and severe EE were common associated factors, although there were more associated factors in esophageal strictures than esophageal ulcer bleeding. Despite the availability and widespread use of PPIs, EE complications are likely to remain a problem in Japan owing to the aging population and high-stress society.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

The use of non-steroidal anti-inflammatory drugs(NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of nonalcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Combined thrombectomy and intracoronary administration of glycoprotein IIb/IIIa inhibitors improves myocardial reperfusion in patients undergoing primary percutaneous coronary intervention： a meta-analysis

Background Suboptimal myocardial reperfusion is common in patients with ST-segment elevation myocardial infarction （STEMI） undergoing primary percutaneous coronary intervention （PPCI）. Furthermore, it results in increased infarct size and mortality rates. We performed a meta-analysis to evaluate the role of aspiration thrombectomy （AT） combined with intracoronary administration of glycoprotein IIb/IIIa inhibitors （GPI） in the improvement of myocardial reperfusion and clinical outcomes. Methods PubMed, Embase, Web of Science, and CENTRAL databases were searched for randomized controlled trials （RCTs） investigating combined AT and intracoronary GPI treatment versus AT alone. Outcomes of interest were thrombolysis in myocardial infarction myocardial perfusion grade （TMPG）, infarct size （IS） assessed by cardiac magnetic resonance imaging, left ventricular ejection fraction （LVEF）, major adverse cardiac events （MACE） at short-term （〈 1 month） and long-term （6-12 months） follow-up, and bleeding complications during the hospital stay. Results Eight trials involving 923 patients were included. Compared with AT alone, combined AT and intracoronary GPI significantly increased TMPG 3 flow （RR： 1.15, 95% CI： 1.04 to 1.26）, reduced IS [mean difference （MD）： -3.46, 95% CI： -5.18 to -1.73], and improved LVEF （MD： 1.44, 95% CI： 0.54 to 2.33）. Furthermore, GPI use decreased the risk of MACE at long-term follow-up （RR： 0.60, 95% CI： 0.37 to 0.98）. There was no significant difference between the two groups in the incidence of minor and major bleeding complications. Conclusions Our findings showed that compared with AT alone, combined AT and intracoronary GPI treatment resulted in improved myocardial reperfusion, better cardiac function, and MACE-free survival benefits at the long-term follow-up for patients with STEMI undergoing PPCI.

Gene therapy of liver cancer

The application of gene transfer technologies to the treatment of cancer has led to the development of new experimental approaches like gene directed enzyme/pro- drug therapy (GDEPT), inhibition of oncogenes and restoration of tumor-suppressor genes. In addition, gene therapy has a big impact on other fields like cancer immunotherapy, anti-angiogenic therapy and virotherapy. These strategies are being evaluated for the treatment of primary and metastatic liver cancer and some of them have reached clinical phases. We present a review on the basis and the actual status of gene therapy approaches applied to liver cancer.

Persistent severe hypomagnesemia caused by proton pump inhibitor resolved after laparoscopic fundoplication

Magnesium deficiency can cause a variety of symptoms, including potentially life-threatening complications such as seizures, cardiac arrhythmias and secondary electrolyte disturbances. Hypomagnesemia can be a serious adverse effect to proton pump inhibitor(PPI) therapy, which is worrying due to the widespread use of PPIs. Current evidence suggest that the mechanism of PPI induced hypomagnesemia is impaired intestinal magnesium absorption. In this report, we present the case of a long-term PPI user with persistent hypomagnesemia with severe symptoms at presentation. He was unable to stop PPI treatment because of severe reflux symptoms, and was dependent on weekly intravenous magnesium infusions, until his magnesium levels finally normalized without the need for supplementation after a successful laparoscopic fundoplication.

BRAF inhibitor treatment of melanoma causing colonic polyps:An alternative hypothesis

Colonic polyps may arise from BRAF inhibitor treatment of melanoma, possibly due to paradoxical activation of the mitogen-activated protein (MAP)-kinase pathway. In an alternative evidence based scenario, tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment, in the absence of mutations of MAPK genes. A minority of colorectal cancers develop by an alternative “serrated polyp pathway”. This article postulates a novel hypothesis, that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps. Serrated polyps are characterized by a CpG island methylation phenotype, MLH1 silencing and cellular senescence. They also have BRAF mutations. The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF: C-RAF heterodimers.

Contraindications for video capsule endoscopy

Video capsule endoscopy(VCE) has been applied in the last 15 years in an increasing field of applications. Although many contraindications have been put into perspective, some precautions still have to be considered. Known stenosis of the gastrointestinal tract is a clear contraindication for VCE unless surgery is already scheduled or at least has been considered as an optional treatment modality. In patients with a higher incidence of stenosis, as in an established diagnosis of Crohn's disease, clinical signs of obstruction, prior radiation or surgical small bowel resection, a preceding test with the self-dissolving patency capsule can override this contraindication. Endoscopic placement of the capsule should be considered in patients with swallowing disorders to avoid aspiration. Esophageal or gastric motility disorders may require endoscopic capsule transport or application of prokinetics if the real-time viewer proofs delayed transit. In pregnant women, VCE should be restricted to urgent cases where diagnosis cannot be postponed after delivery, as data on safety are missing. There is theoretical and clinical evidence that patients with implanted cardiac devices such as a pacemaker, cardioverters or left heart assist devices, can safely undergo VCE in spite of still existing contraindication by manufacturers. Children from the age of 2 years have safely undergone VCE. Although video capsules are not proven safe with magnetic resonance imaging(MRI), first single cases of patients incidentally undergoing MRI with an incorporated capsule have been reported, showing susceptibility artifacts but no signs of clinical harm.