Instability of membranes containing ionizable cationic lipids: Effects of the repulsive range of headgroups and tail structures.

The stability of membranes formed by ionizable cationic lipids, which constitute the primary components in lipid nanoparticles capable of endosomal escape, is explored using coarse-grained dissipative particle dynamics. Three types of ionizable model lipids with different tail structures are considered. Endosome acidification causes the ionization of lipids, leading to an increased repulsive range between their headgroups. When electrostatic repulsion is modeled as a conservative force with a long-range cutoff distance (rc,HH), the membrane and vesicle experience a loss of structural integrity and develop holes as rc,HH is beyond a critical value, which varies with the tail structure. When Coulombic repulsion is explicitly incorporated and intensified, a fully ionized lipid membrane undergoes a loss of structural integrity, displaying a qualitative similarity to the effect observed with the increase in rc,HH on the membrane stability. Qualitatively similar results are obtained for partially ionized membranes as the fraction of charged lipids increases. The stability of a mixed lipid membrane containing both ionizable and conventional lipids is also investigated. The disruption of the bilayer structure occurs for a sufficiently high charged fraction. The membrane instability can be attributed to the decrease in the packing parameter, which significantly deviates from unity as the interaction range increases.

Comparison of Different Hepatocyte Nuclear Factor 4α Clones for Invasive Mucinous Adenocarcinoma of the Lung.

Invasive mucinous adenocarcinoma (IMA) is a rare variant of adenocarcinoma that comprises mucinous epithelial cells. The expression of hepatocyte nuclear factor 4α (HNF4α) has been previously reported as a marker for IMA, but controversy remains regarding whether HNF4α is a reliable marker for lung IMAs. In the present study, we compared HNF4α expression levels between IMA and nonmucinous adenocarcinoma (NMA) cases using 2 different HNF4α clones. We used 2 HNF4α antibody clones, H1 and H1415, to examine HNF4α expression in 36 IMA and 40 NMA cases, which comprised the control group. HNF4α immunostaining intensity (range, 0 to 3) and percentage of intensity (range, 0% to 100%) were evaluated by 3 pathologists and ImageJ software, and average H-scores were calculated for each case. Interobserver agreement was assessed using intraclass correlation coefficient. Receiver-operating characteristic curve was used to analyze sensitivity and specificity of the clones. The mean H-score was higher in the IMA group than in the NMA group for both the H1415 (141.3 vs. 9.3) and H1 (67.3 vs. 3.4) clones. The intraclass correlation coefficient for agreement among the 4 observers was good (0.806 and 0.711). The H1415 clone exhibited comparable sensitivity (83.3% vs. 83.3%) with higher specificity (97.5% vs. 92.5%) compared with the H1 clone when using cutoff values of 36.2 (H1415) and 9.5 (H1), respectively. Our analyses suggest that HNF4α should be considered as a reliable marker for primary IMA of the lung. The H1415 clone should be preferred for use in clinical practice.

Scaling Behaviors of a Polymer Ejected from a Cavity through a Small Pore.

Langevin dynamics simulations are performed to investigate ejection dynamics of spherically confined flexible polymers through a pore. By varying the chain length N and the initial volume fraction ϕ_{0} of the monomers, two scaling behaviors for the ejection velocity v on the monomer number m in the cavity are obtained: v∼m^{1.25}ϕ_{0}^{1.25}/N^{1.6} for large m and v∼m^{-1.4} as m is small. A robust scaling theory is developed by dividing the process into the confined and the nonconfined stages, and the dynamical equation is derived via the study of energy dissipation. After trimming the prior stage related to the escape of the head monomer across the pore, the evolution of m is shown to be well described by the scaling theory. The ejection time exhibits two proper scaling behaviors: N^{(2/3ν)+y_{1}}ϕ_{0}^{-(2/3ν)} and N^{2+y_{2}} under the large and small ϕ_{0} or N conditions, respectively, where y_{1}=1/3, y_{2}=1-ν, and ν is the Flory exponent.

Expression of Helios in gastric tumor cells predicts better survival in gastric cancer patients.

PURPOSE: Helios belongs to Ikaros family, which plays an important role in the cell-fate decision and control cell proliferation; abnormal expressions in leukemia are associated with poor prognosis. In this study, we investigated the Helios expression between Helicobacter pylori infection and prognosis in gastric cancer patients. METHODS: A total of 67 gastric cancer patients who received partial or full gastrectomies were enrolled. Helios expression by immunohistochemistry and mRNA was investigated with the clinical stage, Helicobacter pylori infection, CD4 expression, FoxP3 expression and prognosis. RESULTS: From the immunohistochemistry stain, we found that the Helios was expressed in both cancer cell and tumor-infiltrated lymphocytes. The high expression of Helios in gastric tumor cells had a better median overall survival rate in gastric cancer patients (50.7 ± 3.2 vs. 34.1 ± 4.9 months; P = 0.015), Helicobacter pylori-infected patients (51.1 ± 3.5 vs. 30.4 ± 5.1 months; P = 0.007) and advanced gastric cancer patients (42.1 ± 5.5 vs. 23.2 ± 4.8 months; P = 0.043). From multivariate analysis, the Helios expression in gastric tumor cells was an independent factor to predict better survival in all gastric cancers (HR = 2.78; 95 % confidence interval [CI], 1.09-7.09; P = 0.032) and advanced gastric cancer patients (HR = 2.85; 95 % confidence interval [CI], 1.00-8.13; P = 0.03). CONCLUSIONS: Higher expression of Helios in gastric tumor cells predicts better survival in gastric cancer patients, especially for Helicobacter pylori-infected and advanced-stage gastric cancer patients.

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death.

Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG0/G1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with ß-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy.

Transpapillary biliary biopsy for malignant biliary strictures: comparison between cholangiocarcinoma and pancreatic cancer.

BACKGROUND: Tissue sampling for biliary stricture is important for differential diagnosis and further treatment. This study aims to assess the differences of transpapillary biliary biopsy for malignant biliary strictures between cholangiocarcinoma and pancreatic cancer. METHODS: From January 2010 to December 2013, we retrospectively studied 79 patients who suffered from biliary strictures and received transpapillary forceps biopsy after sphincterotomy for tissue sampling. The diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of forceps biopsy were calculated in all cases for both cholangiocarcinoma and pancreatic cancer patients. Possible factors that distinguish malignant strictures from benign strictures and which could affect the accuracy of tissue sampling were analyzed. RESULTS: There are 65 malignant and 14 benign biliary stricture patients enrolled. The malignant group has a significantly higher serum bilirubin level than the benign group, but age, clinical presentation, level of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and alkaline phosphatase are not. The sensitivity, specificity, PPV, and NPV of forceps biopsy for biliary stricture are 53.85, 100, 100, and 31.82%, respectively. The cholangiocarcinoma group has a higher sensitivity (73.53 versus 29.17%, p < 0.001), older age, lower CA 19-9 level, and more common hepatic duct strictures than the pancreatic group. The age, serum CEA, CA 19-9 and the alkaline phosphatase level, serum bilirubin level >10 mg/dL, tissue sampling ≧3 are not significant factors affecting diagnostic accuracy in forceps biopsy for pancreatobiliary strictures. There is neither major bleeding nor perforation in our study. CONCLUSIONS: Transpapillary forceps biopsy of biliary strictures after sphincterotomy for tissue sampling is safe and a significantly higher sensitive method in cholangiocarcinoma but not in pancreatic cancer.

Alpha-Fetoprotein Measurement Benefits Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis.

OBJECTIVES: Liver cirrhosis is a major risk factor for hepatocellular carcinoma (HCC), and all liver study societies recommend HCC surveillance in patients with cirrhosis. However, no ideal modality for HCC surveillance has been determined. The aim of this study is to assess the effectiveness of α-fetoprotein (AFP) measurement in HCC surveillance. METHODS: In this retrospective analysis, all patients with cirrhosis, who received HCC surveillance through ultrasound (US) and AFP measurement between January 2002 and July 2010, were followed up until June 2013. The performance effectiveness of surveillance using AFP, US, or both in HCC detection was compared. RESULTS: Overall, 1,597 patients were followed for a median duration of 4.75 (range 1.42-12) years. Over the 8563.25-person-year follow-up period, 363 patients (22.7%) developed HCCs. For HCC detection, the area under the receiver operator characteristic curve of surveillance AFP was 0.844 (95% confidence interval: 0.820-0.868, P<0.001). When the traditional cutoff value of 20 ng/ml was used, the sensitivity and specificity of AFP were 52.9% and 93.3%, respectively. US exhibited a sensitivity and specificity of 92.0% and 74.2%, respectively. A combination of US and AFP exhibited a sensitivity and specificity of 99.2% and 68.3%, respectively. By using cut-off at 20 ng/ml and AFP level increase ≥2 × from its nadir during the previous 1 year, the combination of US and AFP yielded a sensitivity of 99.2% and an improved specificity of 71.5%. CONCLUSIONS: The complementary use of AFP and US improved the effectiveness of HCC surveillance in patients with cirrhosis.

Role of flexible transnasal esophagoscopy and patient education in the management of globus pharyngeus.

BACKGROUND/PURPOSE: Globus pharyngeus and dysphagia are common complaints of patients referred to ear, nose, and throat (ENT) clinics. We aimed to establish an efficient method to rule out the presence of malignancy in patients with globus pharyngeus and dysphagia. METHODS: The use of flexible transnasal esophagoscopy (TNE) was evaluated in 30 patients with globus pharyngeus and 6 patients with dysphagia. The patients were immediately informed of the findings on TNE examination, and then treatments were planned. All patients were treated with lansoprazole for 2 weeks and provided education on lifestyle changes at the initial examination and at the 3-month follow-up. RESULTS: The patients reported an improvement in symptoms of globus pharyngeus after treatment (p<0.001). Follow-up TNE confirmed improvement with less dysphagia, erythema, and vocal cord edema evident (all p<0.001). CONCLUSION: The use of TNE and patient education are efficient management strategies for patients with symptoms of globus pharyngeus and dysphagia.

Serum HCV RNA level is not associated with insulin resistance and metabolic syndrome in chronic hepatitis C patients with genotype 1 or 2 infection.

BACKGROUND: Previous reports have indicated that insulin resistance (IR) is associated with chronic hepatits C virus (HCV) infection. However, the correlations between IR, metabolic syndrome (MS), and serum HCV RNA levels are still controversial. The aim of this study was to determine the relationships between IR, MS, and HCV RNA in patients with chronic genotype 1 or 2 HCV infection. METHODS: One hundred and twenty subjects with chronic genotype 1 or 2 HCV infection with complete clinical data were prospectively enrolled. Baseline and laboratory data were collected and analyzed. IR was defined as a homeostatic model assessment- IR (HOMA-IR) score > 2.5. RESULTS: Of the 120 patients, 47 (39.2%) had a HOMA-IR > 2.5, and 42 (35%) met the criteria for MS. IR was significantly associated with a high body mass index (p < 0.0001), high waist circumference (p < 0.0001) and high triglyceride level (p = 0.025). IR was an independent predictor of MS. However, in multivariate linear regression analysis, the serum HCV RNA level was not significantly different in chronic hepatitis C patients with or without IR (p = 0.761), and with or without MS (p = 0.292). CONCLUSIONS: IR and MS are not uncommon in patients with chronic hepatitis C. The serum HCV RNA level is not associated with the presence of IR or MS in chronic hepatitis C patients with genotype 1 or 2 infection. The impact of hepatitis C virus on IR is not dose responsive.

Post-tonsillectomy pulmonary complication in a patient with tonsillar myeloid sarcoma.

Myeloid sarcoma in a patient with myelodysplastic syndrome (MDS) manifesting as a non-healing tonsillar ulcer is an extremely rare occurrence. We report the case of a 57-year-old male smoker with a non-healing tonsillar ulcer who underwent tonsillectomy to rule out tonsillar carcinoma after failed antibiotic therapy. On postoperative day 2, he presented with a temperature of 40°C and white blood cell count of 34700/µL. Antibiotic therapy was begun; however, he died 1 day later due to pulmonary infection and septic shock. Though extremely rare, tonsillar involvement of MDS should be considered in the differential diagnosis of a non-healing tonsillar lesion. When definitive diagnosis requires a tissue sample, punch biopsy may be preferable to tonsillectomy in a patient who may be immunocompromised, and appropriate prophylactic antibiotics should be administered.

Analysis of acinic cell carcinoma of the parotid gland - 15 years experience.

CONCLUSION: In our experience, the prognosis for parotid gland acinic cell carcinoma (AciCC) is good. Surgery alone would be sufficient in early-stage tumor. Postoperative adjuvant treatment in advanced-stage patients or those with positive resection margins usually gives satisfactory control of the disease. OBJECTIVES: AciCC is a rare tumor in parotid gland malignancy. The aim of this study was to retrospectively analyze the experience in our hospital in treating this malignancy. METHODS: Twenty-five patients with AciCC diagnosed from 1983 to 2007 at the Chang Gung Memorial Hospital were retrospectively reviewed. RESULTS: Thirteen male and 12 female patients ranged in age from 16 to 84 years (mean 37.5 years) at the time of diagnosis. Most patients (92%) presented with symptoms of infra-auricular mass. The tumor stage distributions of the patients were 24%, 44%, 28%, and 4% for stages I, II, III, and IV, respectively. Thirteen patients underwent superficial parotidectomy and 12 patients underwent total parotidectomy. Four patients had positive resection margins. Ten patients had surgery and postoperative radiotherapy; one received surgery and postoperative chemo/radiotherapy. The 10-year disease-free and overall actuarial survivals were both 84% in a mean follow-up of 75.8 months.

Transnasal butorphanol for pain relief after uvulopalatopharyngoplasty - a hospital-based,randomized study.

BACKGROUND: Nasal spray of analgesic is a novel administration for postoperative pain control. In this study, we assessed the efficacy of transnasal butorphanol (TB) for pain relief following uvulopalatopharyngoplasty (UPPP) in obstructive sleep apnea (OSA) patients, and compared pain alleviation effect to oral mefenamic acid and intramuscular meperidine (M> or =&M). METHODS: A prospective, randomized, open label study was conducted in a tertiary care sleep center. Twelve OSA patients with full consciousness and at least moderate oropharyngeal pain (pain visual analogue scale [VAS] > or = 4) after UPPP were recruited. They were randomized to receive TB (n = 7) and M&M (n = 5). Oropharyngeal pain was measured by a VAS and the Clinical Global Impression in Severity (CGI-S) and Improvement (CGI-I) at the 12th, 24th, and 72th hours postoperatively. Postoperative pain related morbidities (PRMs) and quality of life in bodily pain (QOL-BP) were also evaluated 72 hours postoperatively. Adverse events incurred by pain treatment were carefully monitored during patients' hospitalizations. RESULTS: No major complication occurred throughout the study. Analysis of clinical measures revealed significantly improved VAS (p = 0.04), CGI-S (p = 0.03), and CGI-I (p = 0.02) in the TB group. However, no significant difference (p > 0.05) in the degree of pain relief was found between the two groups, as denoted by aforementioned three variables, PRMs, and QOL-BP. CONCLUSIONS: Administration of TB can significantly alleviate the wound pain after UPPP in OSA patients. This study also confirmed the safety of TB in patients undergoing oropharyngeal surgery.

Alleviation of wound pain after surgeries for obstructive sleep apnea.

OBJECTIVES: There has been growing awareness that alleviation of wound pain and associated symptoms after obstructive sleep apnea (OSA) surgeries may improve the quality of care. We performed a hospital-based study to compare the effectiveness and safety of two different regimens in the treatment of postoperative pain. STUDY DESIGN: A prospective, randomized, and parallel-group study. METHODS: Ninety OSA patients were enrolled for surgical treatments in this study. Forty-five patients (group 1) were randomized to receive intravenous ketorolac and another 45 patients (group 2) were given the conventional regimen of oral mefenamic acid and intramuscular meperidine after OSA surgeries for 3 days at hospital. Postoperative discomfort was measured by a self-assessment questionnaire on the 1st and 3rd days after surgery. Any adverse effect of pain treatment was carefully monitored. Patients' satisfaction with postoperative pain treatment was evaluated 1 month postoperatively. RESULTS: On the 1st postoperative day, group 1 patients had a significantly lower mean score in six out of eight pain-related symptoms than group 2 patients had (P<.05). At the 3rd postoperative day, significant differences remained for two symptoms. Group 1 patients were generally more satisfied with their pain treatment than were group 2 patients (P=.01). Increased risk of postoperative bleeding for group 1 was not observed in this study. CONCLUSIONS: A short-term administration of intravenous ketorolac is noninferior to the conventional regimen and represents a safe and effective treatment for wound pain, particularly in the 1st day, after OSA surgeries in selected patients.