Optimising the management of dysplastic lesions in the oesophagus with photodynamic therapy

The outcome of patients suffering from adeno and squamous carcinoma of the oesophagus remains poor. In the west, the incidence of adenocarcinoma has increased dramatically, with most cases occurring in association with Barrett's oesophagus (BE). Both adeno and squamous carcinoma are believed to progress through worsening degrees of dysplasia. This thesis assesses the role of Elastic Scattering Spectroscopy (ESS) as an objective diagnostic test for dysplasia and Photodynamic Therapy (PDT) with 5-aminolevulinic acid (ALA) as a less invasive treatment option. It also looks for a better understanding of the factors influencing mucosal healing after PDT. Using ESS, the sensitivity and specificity was 83% for distinguishing HGD/cancer from LGD/non dysplastic BE. Low dose ALA (30mg/kg) PDT eradicated 38% of HGD in BE compared with 67% eradication with a higher dose (60mg/kg). The higher dose also decreased the length of BE. In a study comparing red with green light (fixed light doses) for treating HGD, at 30 mg/kg ALA, 63% and 13 % of patients were clear of HGD with red and green laser respectively. At 60 mg/kg, the corresponding figures were 78% and 33% for the same light dose. 5 of 5 patients with LGD in BE and 4 of 5 patients with HGD in squamous mucosa had their dysplasia eradicated with ALA PDT. Successful PDT involves healing by regeneration of normal squamous mucosa. My in vitro studies created a PDT wound model using malignant oesophageal cell lines to assess the role of different cytokines in healing. Keratinocyte Growth Factor (KGF) was found to promote wound healing after PDT and significantly encouraged (p 0.001) the development of squamous cell lines. In conclusion: 1. ESS can differentiate dysplasia and early cancer from non-dysplastic and normal mucosa (sensitivity and specificity 83%). 2. PDT using high dose (60mg/kg) ALA (but not low dose) is effective in eradicating HGD in BE using red light. 3. The cytokine, KGF may promote healing with squamous mucosa after PDT. 4. Larger scale clinical trials are now required to confirm these results

Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle–specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance

Effect of Chongkukjang on histamine-induced skin wheal response: A randomized, double-blind, placebo-controlled trial

AbstractBackgroundStudies in animals have demonstrated the antiallergenic properties of Chongkukjang (CKJ), a traditional Korean food made by fermentation of soybean with Bacillus subtilis. CKJ might therefore be used as an ingredient in a functional food designed to suppress allergies. The purpose of this study was to investigate the effect of CKJ on histamine-induced skin wheal response in healthy participants.MethodsA randomized, double-blind, placebo-controlled trial was conducted. Sixty participants (48 women and 12 men) were randomly assigned to one of two groups: One group received 35 g CKJ daily for 12 weeks, and the other received a placebo at the same dosing frequency. A skin prick test with histamine (10 mg/mL) was conducted on the ventral forearm 10 cm from the elbow, and assessed 15 minutes later. Outcomes included measurement of efficacy [skin wheal response, immunoglobulin E (IgE), histamine, interferon-gamma, interleukin-4, eosinophil, and eosinophil cationic protein (ECP)], and safety (adverse events, laboratory test results, electrocardiogram, anthropometric values, and vital signs).ResultsFifty-five participants (28 in the CKJ group and 27 in the placebo group) completed the study. After 12 weeks of supplementation, participants in the CKJ group showed a significant reduction in histamine-induced skin wheal areas compared with placebo group (p < 0.05). At 12 weeks, the CKJ group showed a significant improvement in percentage change from baseline in histamine-induced wheal area, compared with the placebo group (p < 0.05). CKJ did not influence blood levels of IgE, histamine, interferon-gamma, interleukin-4, eosinophil, or ECP.ConclusionOral administration of CKJ for 12 weeks resulted in a reduction of the skin wheal response to histamine, with no apparent adverse effects. Trial registration: ClinicalTrials.gov: NCT01402141

Mediators of the Effect of Obesity on Stroke and Heart Disease Risk: Decomposing Direct and Indirect Effects

Background: The prevalence of overweight and obesity are well known risk factors of atherosclerotic cardiovascular disease (ASCVD). We aimed to examine the association between body mass index (BMI) and ASCVD over a 23-year follow-up in young adults. We also qualified how much of the effects of obesity on ASCVD were mediated through blood pressure, cholesterol, and glucose. Methods: Data are from the Korean Life Course Health Study, a cohort study of 226,955 Korean young adults aged 20–39. At baseline, the participants undertook routine health assessments where their BMI was measured in 1992–1994; and the metabolic mediators including systolic blood pressure (SBP), fasting serum glucose (FSG), and total cholesterol (TC) were re-measured in 2002–2004. The main outcomes of the study include incident events of ischemic heart disease (IHD), stroke, and ASCVD between 2005 and 2015. Cox proportional model was used to calculate adjusted hazard ratios (HRs) for ASCVD. Results: In both men and women, the direct effect of BMI on ASCVD was greater than the indirect effect. The percentage of excess HR of BMI mediated by all of the metabolic mediators, including SBP, FSG, and TC, was 45.7% for stroke and 18.7% for IHD in men and 27.5% for stroke and 17.6% for IHD in women. Conclusion: High BMI in young adults increases the risk of metabolic mediators in their middle age, and metabolic mediators explain the adverse effects of high BMI on stroke risk than IHD risk

Safety and immunogenicity of Salmonella enterica serovar Typhimurium llaB in mice

The safety and immunogenicity of an attenuated recombinant Salmonella vaccine strain, Salmonella enterica serovar Typhimurium llaB, was assessed. This vaccine strain could survive in low pH condition, and its ability of intracellular survival did not differ from that of S. enterica serovar Typhimurium UK1, which is the wild-type of the vaccine strain. The mortality of the mice orally administered with the vaccine strain was 50% at the dose of 10(7) CFU. All mice administered with 105 or 103 CFU of the vaccine strain survived for 3 days postinoculation (pi). However, all mice administered with more than 103 CFU of the vaccine strain died within 3 days pi. To examine the protective effect of the vaccine strain. mice were orally immunized with 10(4) and 10(6) CFU of the bacteria. Control mice were given with 0.5 ml of phosphate buffered saline (PBS). After 8 days, the mice were challenged with 10(9) CFU of S. enterica serovar Typhimurium UK1 and mortality was examined for 5 days. The survival rates of the mice immunized with 10(4) and 10(6) CFU of the vaccine strain were 60% and 80%, respectively, whereas all control mice died within 2 days after challenging. To investigate the immunogenicity of S. enterica serovar Typhimurium HaB, mice were orally immunized with 10(5) or 10(6) CFU ml of the vaccine strain. Five mice of each group were sacrificed at 5 and 12 days after immunization, and results showed that immunization of the vaccine strain led to increases of IgG1, IgG2. and IgM titers against S. enterica serovar Typhimurium UK1 in mouse sera, cytokine expressions such as IL-2, IL-4, IL-6 and IL-10 in spleen.. and the lymphocyte proliferation response to mitogens (concanavalin A or LPS) stimulation.N

Survival in untreated hepatocellular carcinoma: A national cohort study.

This study aimed to analyze the proportion, characteristics and prognosis of untreated hepatocellular carcinoma (HCC) patients in a large representative nationwide study. A cohort study was conducted using the National Health Insurance Service (NHIS) database in Korea. A total of 63,668 newly-diagnosed HCC patients between January 2008 and December 2013 were analyzed. Patients were categorized into treatment group and no treatment group using claim codes after HCC diagnosis. The proportion of untreated HCC patients was 27.6%, decreasing from 33.4% in 2008 to 24.8% in 2013. Compared to treated patients, untreated patients were more likely to be older (P < 0.001), female (P < 0.01), to have a distant SEER stage (P < 0.001), severe liver disease (P < 0.001), and lower income (P < 0.001). The fully-adjusted hazard ratio for all-cause mortality comparing untreated to treated patients was 3.11 (95% CI, 3.04-3.18). The risk of mortality was higher for untreated patients in all pre-defined subgroups, including those with distant SEER stage and those with severe liver disease. About one fourth of newly diagnosed HCC patients did not receive any HCC-specific treatment. Untreated patients showed higher risk of mortality compared to treated patients in all subgroups. Further studies are needed to identify obstacles for HCC treatment and to improve treatment rates