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Abstract Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8bright CD244bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8bright CD244bright NK cells in birdshot chorioretinopathy.

Abstract Background This study investigated the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant systemic therapy (NAST) in patients with initially high nodal burden. Methods In the multicenter retrospective cohort, 388 individuals with cN1–3 breast cancer who underwent NAST and had SLNB followed by completion axillary lymph node dissection were included. In an external validation cohort, 267 patients with HER2+ or triple-negative breast cancer (TNBC) meeting similar inclusion criteria were included. Primary outcome was the false-negative rates (FNRs) of SLNB according to the MRI response and subtypes. We defined complete MRI responders as patients who experienced disappearance of suspicious features in the breast and axilla after NAST. Results In the multicenter retrospective cohort, 130 (33.5%) of 388 patients were of cN2-3, and 55 (14.2%) of 388 patients showed complete MRI responses. In hormone receptor-positive HER2− (n = 207), complete and non-complete responders had a high FNRs (31.3% [95% CI 8.6–54.0] and 20.9% [95% CI 14.1–27.6], respectively). However, in HER2+ or TNBC (n = 181), the FNR of complete MRI responders was 0% (95% CI 0–0), whereas that of non-complete responders was 33.3% (95% CI 20.8–45.9). When we validated our findings in the external cohort with HER2+ or TNBC (n = 267), of which 34.2% were cN2-3, the FNRs of complete were 7.1% (95% CI 0–16.7). Conclusions Our findings suggest that SLNB can be a reliable option for nodal status evaluation in selected patients who have responded well to NAST, especially in HER2+ and TNBC patients who show a complete MRI response.

Abstract Our aim was to develop a tool to accurately predict the possibility of non-sentinel lymph node metastasis (NSLNM) during surgery so that a surgeon might decide the extent of further axillary lymph node dissection intraoperatively for patients with 1–3 positive sentinel lymph node(s) (SLN) after neoadjuvant chemotherapy. After retrospective analysis of Asan Medical Center (AMC) database, we included 558 patients’ records who were treated between 2005 and 2019. 13 factors were assessed for their utility to predict NSLNM with chi-square and logistic regression with a bootstrapped, backward elimination method. Based on the result of the univariate analysis for statistical significance, number of positive SLN(s), number of frozen nodes, Progesterone Receptor (PR) positivity, clinical N stage were selected for the multivariate analysis and were utilized to generate a nomogram for prediction of residual nodal disease. The resulting nomogram was tested for validation by using a patient group of more recent, different time window at AMC. We designed a nomogram to be predictive of the NSLNM which consisted of 4 components: number of SLN(s), number of frozen nodes, PR positivity, and clinical N stage before neoadjuvant chemotherapy. The Area under the receiver operating characteristics curve (AUC) value of this formula was 0.709 (95% CI, 0.658–0.761) for development set and 0.715 (95% CI, 0.634–0.796) for validation set, respectively. This newly created AMC nomogram may provide a useful information to a surgeon for intraoperative guidance to decide the extent of further axillary surgery.

Purpose To investigate the correlation between computer-aided diagnosis (CAD) parameters in 3-tesla (T) MRI and pathologic immunohistochemical (IHC) markers in invasive carcinoma of no special type (NST). Materials and Methods A total of 94 female who were diagnosed with NST carcinoma and underwent 3T MRI using CAD, from January 2018 to April 2019, were included. The relationship between angiovolume, curve peak, and early and late profiles of dynamic enhancement from CAD with pathologic IHC markers and molecular subtypes were retrospectively investigated using Dwass, Steel, Critchlow-Fligner multiple comparison analysis, and univariate binary logistic regression analysis. Results In NST carcinoma, a higher angiovolume was observed in tumors of higher nuclear and histologic grades and in lymph node (LN) (+), estrogen receptor (ER) (-), progesterone receptor (PR) (-), human epidermal growth factor 2 (HER2) (+), and Ki-67 (+) tumors. A high rate of delayed washout and a low rate of delayed persistence were observed in Ki-67 (+) tumors. In the binary logistic regression analysis of NST carcinoma, a high angiovolume was significantly associated with a high nuclear and histologic grade, LN (+), ER (-), PR (-), HER2 (+) status, and non-luminal subtypes. A high rate of washout and a low rate of persistence were also significantly correlated with the Ki-67 (+) status. Conclusion Angiovolume and delayed washout/persistent rate from CAD parameters in contrast enhanced breast MRI correlated with predictive IHC markers. These results suggest that CAD parameters could be used as clinical prognostic, predictive factors.

Systemic-to-pulmonary artery fistulas are rare. This condition may be congenital, post-traumatic, or post-inflammatory and can cause infection, hemorrhage, or pulmonary hypertension. Here, we report a case of an intercostal-to-pulmonary artery fistula, incidentally detected during the evaluation of dyspnea in a 67-year-old female. Retrograde transcatheter coil embolization in a dilated draining pulmonary artery was initially attempted. However, another draining pulmonary artery developed after 5 months. The intercostal arteries or systemic feeders were successfully embolized through a transarterial access. At the 10-month follow-up, the abnormally dilated vessels had regressed, and dyspnea had improved. Sequential or simultaneous retro- and antegrade transcatheter embolization may successfully treat pleural arterio-arterial fistulas.

Abstract For residual N1 nodal disease following neoadjuvant chemotherapy (NAC) for patients with breast cancer, the optimal local therapy for axilla is an evolving area. We analyzed the long-term results of these patients according to axillary surgical methods using propensity score matching (PSM) to clarify whether omission of axillary lymph node dissection (ALND) is oncologically safe. This was a single institution retrospective study of patients with ypN1 from Asan Medical Center (AMC). We included 324 patients who had undergone axillary surgery with either sentinel lymph node biopsy (SLNB) only or ALND. The patients received NAC at AMC between 2008 and 2013. General indications for ALND included prominent nodes detected clinically before NAC, evident macrometastasis on multiple nodes during SLNB. Patients who had either micrometastasis or macrometastasis in 1 or 2 node(s) were included. SLNB was performed for patients with good responders to NAC with limited nodal burden. Patients were matched for baseline characteristics. After matching, we included 98 patients in each SLNB only group and ALND group respectively. We compared axillary recurrence-free survival (ARFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-free survival (BCSS) according to the surgical method. The median follow-up period was 71 months. Univariate and multivariate analyses revealed no statistically significant differences between the two groups for ARFS, DMFS, OS, and BCSS. After the propensity score matching, no significant statistical differences were observed in 5-year ARFS, DMFS, OS, and BCSS between the SLNB only group and ALND group. SLNB might be a possible option for ALND in patients with breast cancer who have limited axillary node metastasis after NAC without compromising survival outcomes.

Background/Aims: Extrahepatic comorbidities and comedication are important to consider in the treatment of chronic hepatitis C (CHC) patients with direct-acting antivirals (DAAs) due to the risk of drug-drug interaction (DDI) and the effect of comorbidities on clinical outcomes. This study aimed to investigate the detailed profiles of comorbidities and comedication among Korean CHC patients. Methods: All adult patients (≥18 years old) with a primary diagnostic code of CHC in 2013 were selected from the National Health Insurance claims database. For each patient, all ICD-10 codes listed as primary or secondary diagnoses and all prescribed medications were collected. Results: Among 47,104 CHC patients (median age, 57 years; male, 49.3%), 84.8% had at least one comorbidity for a mean number of 2.4, which increased with age. The most prevalent comorbidities were hypertension, esophagitis, dyslipidemia, diabetes mellitus, and peptic ulcer. Overall, 96.8% of the patients took at least one prescribed medication, with a mean of 8.1 medications/ year, and the three most common drug types were analgesics, gastrointestinal agents, and antibacterials. Use of at least one drug with a DDI risk category of “contraindicated medication” or “required dose-reduction/additional monitoring” was observed in 97% of the overall patients. The proportion of prescribed medications that were contraindicated with DAAs varied from 2.0% to 38.9% depending on the hepatitis C virus regimen. Conclusions: The majority of CHC patients had comorbidities; almost all patients took multiple prescribed medications, the number of which increased with age, and significant DDI risk was present in 97% of this Korean patient cohort. Comorbidities and comedication profiles should be considered during DAA therapy.

Background/Aims The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival. Methods Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017. Results The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients. Conclusions The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Ischemic colitis resulting from bowel preparation for colonoscopy is extremely rare, with only a small number of cases with polyethylene glycol having been reported. Here, we present a patient with ischemic colitis after administration of a low-volume oral sulfate solution (OSS). A 49-year-old female without any significant medical history experienced abdominal pain, vomiting, and hematochezia after ingestion of OSS. She complained of severe abdominal pain during colonoscopy, and diffuse edema, hyperemia, friability, and shallow erosions were present on the transverse, descending, and sigmoid colons. A mucosal biopsy revealed mixed lymphoid inflammatory cell infiltration with de-epithelialization, whereas an abdominal CT scan showed submucosal edema on the transverse colon. A diagnosis of ischemic colitis was made. The patient recovered with fluid and antibiotic therapy without significant sequelae. Although OSS is a clinically validated and generally safe bowel preparation agent, ischemic colitis is a rare complication that should be considered.

Background/Aims Non-selective β-blockers (NSBBs) are used for primary prevention of esophageal variceal hemorrhage (VH) in patients with portal hypertension, but a significant number of patients develop VH while on NSBB therapy. In this study, we sought to determine whether liver volume can predict the risk of primary prophylaxis failure in cirrhotic patients on NSBB therapy. Methods A retrospective cohort of 309 patients on prophylactic propranolol was analyzed. Liver volume was measured in portal venous phase images of multidetector computed tomography. Predictors of VH were assessed using a Cox proportional hazards model with competing-risks analysis. A nomogram was developed for estimation of the risk of primary prophylaxis failure. Results During a median follow-up of 36 months, 37 patients on propranolol developed VH. Liver volume index, the ratio of measured-to-expected liver volume, was an independent predictor of VH (adjusted hazard ratio [HR], 2.70; 95% confidence interval [CI], 1.37 to 5.33; p = 0.004) as were the presence of large varices and the absence of ascites. A nomogram-based volume score of > 0.6 was predictive of prophylaxis failure (HR, 7.54; 95% CI, 2.88 to 19.73; p < 0.001). Time-dependent receiver operating characteristic curve analysis revealed that a nomogram-based risk score had significantly better discriminatory power than the North Italian Endoscopy Club index in predicting prophylaxis failure at 6 and 8 years. Conclusions Liver volume index is an independent predictor of first VH and a nomogram-based volume score stratifies the VH risk in cirrhotic patients on propranolol prophylaxis.

Purpose To investigate the correlation of the strain elasticity of breast cancer with histologic features, immunohistochemical markers and molecular subtypes that are known to be factors related to prognosis. Materials and Methods B-mode ultrasound and strain elastography were performed in 123 patients (mean age, 53.4; range, 28–82) with invasive ductal carcinoma (IDC) (mean size, 1.54 cm; range, 0.4–7.0 cm). Histologic grade, lymph node (LN) status, lymphovascular invasion, immunohistochemical biomarkers [estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), CK5/6, epidermal growth factor receptor, and Ki-67] and molecular subtypes were determined from surgical pathology reports. The relationships between these factors and elasticity scores were evaluated. Results LN involvement was associated with a higher elasticity score which was statistically significant (p = 0.042). The tumor size, lymphovascular invasion, histologic grades, immunohistochemical markers and molecular subtypes had no significant correlation with the elasticity score (p > 0.05 for all). However, the IDCs with larger size and a positive lymphovascular invasion tended to have higher elasticity scores. Furthermore, higher histologic grade cancers and the HER2 overexpression-type tended to have lower elasticity scores. Conclusion The elasticity score of IDC had a significant correlation with LN involvement but no statistically significant correlation with the histologic features, immunohistochemical markers or molecular subtypes.

Background/Aims Snoring is the sound of turbulence and vibration of the upper respiratory tissues and has been identified as a risk factor of obstructive sleep apnea (OSA) and cardiovascular disease. The aim of this study was to identify associated clinical factors in snoring patients undergoing sedative endoscopy. Methods A total of 49 patients who snored during standard sedative endoscopy and 127 controls were prospectively enrolled from June 2015 to June 2016. The Korean version of the Berlin Questionnaire was used to identify risk factors of OSA. Clinical information, including comorbidities, was collected from electronic medical records. Results The snoring group showed a higher risk of OSA (42.9% vs. 26.8%, p = 0.039), and a higher prevalence of coronary artery disease (10.2% vs. 0.8%, p = 0.007) and advanced gastric cancer (12.2% vs. 2.4%, p = 0.015) compared with the control group. Multivariate analysis showed that coronary artery disease (odds ratio [OR], 13.93; 95% confidence interval [CI], 1.24 to 155.90; p = 0.033) and advanced gastric cancer (OR, 5.21; 95% CI, 1.01 to 26.98; p = 0.049) were significantly associated with snoring. However, a history of gastrectomy showed only a marginally significant association with snoring (OR, 2.16; 95% CI, 0.91 to 5.11; p = 0.079). Conclusions Patients who snore during sedative endoscopy may need to be evaluated for possible coronary artery disease.

In the era of climate change and rapid urbanisation, communities and infrastructures need to be planned and designed in a way that promotes sustainable living. The provision of clean and affordable energy is a key to this aim. This paper proposes a technology assessment approach that is based on the triple bottom line (environmental, social and economic) sustainability framework. This approach can be employed in the technology screening that is involved in the early stages of the energy master planning process and can be applied to different community typologies in various locations and climates. The developed approach is demonstrated through a new urban renewal project case study in Fishermans Bend, Melbourne, in which a set of technological options were screened according to the project’s goals. The connection between the energy master plan and local and global sustainable development goals is discussed and policy interventions are proposed. The results show that the proposed approach could effectively enable the evaluation of the technological sustainability performance of the community by demonstrating the design trade-offs and the implementation of the sustainability objectives during the energy master planning process. Moreover, the proposed approach could provide guidance for effective policy making. It was found that government energy policies, regulations and incentives play a vital role in the feasibility of an energy master plan. Lastly, the proposed approach could facilitate the achievement of local and international targets, such as the UN SDGs, by 2050.

Posterior epidural migration of a lumbar intervertebral disc fragment (PEMLIF) is uncommon because of anatomical barriers. It is difficult to diagnose PEMLIF definitively because of its relatively rare incidence and the ambiguity of radiological findings resembling spinal tumors. This case report describes a 76-year-old man with sudden-onset weakness and pain in both legs. Electromyography revealed bilateral lumbosacral polyradiculopathy with a mass-like lesion in L2-3 dorsal epidural space on lumbosacral magnetic resonance imaging (MRI). The lesion showed peripheral rim enhancement on T1-weighted MRI with gadolinium administration. The patient underwent decompressive L2-3 central laminectomy, to remove the mass-like lesion. The excised lesion was confirmed as an intervertebral disc. The possibility of PEMLIF should be considered when rim enhancement is observed in the epidural space on MRI scans and electrodiagnostic features of polyradiculopathy with sudden symptoms of cauda equina syndrome.

Background/AimsGastric juice plays a crucial role in the physiology of the stomach. The aim of this study is to evaluate associations among the pH of gastric juice, atrophic gastritis (AG), intestinal metaplasia (IM), pepsinogen, and Helicobacter pylori infection.Methods : Gastric biopsies and juice were collected from 46 subjects who underwent endoscopies at Seoul National University Bundang Hospital between November 2011 and March 2013. H. pylori, AG and IM were evaluated, and pepsinogen I or II, I/II ratio, and interleukin (IL)-1β levels were measured.Results : The mean pH of gastric juice was higher in the H. pylori-positive group (n=17) than that in the H. pylori-negative group (n=29) (4.54 vs 2.46, p=0.002). When patients were divided into pH

Background/AimsThe association between depression and chronic hepatitis C virus (HCV) infection or pegylated interferon α and ribavirin therapy (PR therapy) has not been extensively studied in Korea. We aimed to clarify the prevalence of depression and its incidence during PR therapy in chronic hepatitis C (CHC) patients.Methods : In this prospective, multicenter study, 114 CHC patients were screened for depression using two self-reported scales, the Beck Depression Inventory-I (BDI-I) and the Hospital Anxiety and Depression scale (HADS). The incidence of depression during PR therapy was evaluated in 62 patients who underwent PR therapy during the study period.Results : The prevalence of baseline depression was 17.5% according to the BDI-I score ≥10 criterion and 4.4% according to the HADS-D score ≥8 criterion in the 114 CHC patients, and it was significantly associated with an unmarried state. During PR therapy, depression developed in 34.6% according to the BDI-I scale and 29.5% according to the HADS-D, which negatively affected sustained virologic response (SVR).Conclusion : sThe prevalence of depression in Korean CHC patients appears to be low compared to that in Western patients; however, its incidence during PR therapy (approximately 30%) was similar to that of other populations, which led to a lower SVR rate. Active screening and multidisciplinary management of depression during PR therapy is warranted.

Background & aimsElastography point quantification is a convenient method for measuring liver stiffness. It can be performed simultaneously with conventional ultrasonography. This study aimed to evaluate its diagnostic performance for assessing hepatic fibrosis in patients with autoimmune liver disease (AILD), including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).MethodsThe diagnostic performance of elastography point quantification (ElastPQ) was evaluated and compared with that of serum fibrosis markers, including the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4), using the receiver operating characteristics analysis with histologic evaluation as the reference standard.ResultsIn 49 AIH patients, sensitivity and specificity of ElastPQ were 93.6% and 44.4%, respectively, for significant fibrosis (≥ F2, cutoff 4.47 kPa), and 63.6% and 86.8% for cirrhosis (F4, cutoff 9.28 kPa). In 41 PBC patients, they were 81.8% and 73.3%, respectively, for significant fibrosis (≥ F2, cutoff 5.56 kPa), and 100% and 81.6%, respectively, for advanced fibrosis (≥ F3, cutoff 6.04 kPa). The areas under the receiver operating characteristic curves of ElastPQ for significant fibrosis (0.77, 95% CI 0.67-0.86) and cirrhosis (0.81, 95% CI 0.65-0.96) were higher than those of APRI and FIB-4 in AILD patients. According to the multivariable analysis, histological activity, steatosis, and body max index (BMI) were not significant factors that influenced the result of ElastPQ.ConclusionsElastPQ exhibited better diagnostic performance-without the influence of confounding factors-for assessing hepatic fibrosis in AILD patients than serum fibrosis markers.

Background/AimsVitamin E improves the biochemical profiles and liver histology in nonalcoholic steatohepatitis, but the role of vitamin E is not clearly defined in the management of nonalcoholic fatty liver disease (NAFLD) which includes both simple steatosis and steatohepatitis. Co-morbid metabolic syndrome increases the probability of steatohepatitis in NAFLD. In this study, we aimed to determine the short-term effects of vitamin E and off-treatment durability of response in a propensity-score matched cohort of NAFLD patients with metabolic syndrome.MethodsA retrospective cohort was constructed by retrieving 526 consecutive NAFLD patients from the electronic medical record data warehouse of a tertiary referral hospital in South Korea. Among them, 335 patients (63.7%) had metabolic syndrome and were eligible for vitamin E therapy. In order to assess the effect of vitamin E, propensity score matching was used by matching covariates between control patients (n=250) and patients who received vitamin E (n=85).ResultsThe PS-matched vitamin E group (n=58) and control group (n=58) exhibited similar baseline metabolic profiles. After 6 months of vitamin E therapy, the mean ALT levels decreased significantly compared to PS-matched control (P

The aim of this study was to determine whether dynamic computed tomography (CT)-measured liver volume predicts the risk of hepatocellular carcinoma (HCC) when the CT scans do not reveal evidence of HCC in chronic hepatitis B (CHB) patients on surveillance.This retrospective multicentre cohort study included 1,246 patients who received entecavir and regular HCC surveillance in three tertiary referral centres in South Korea. Liver volumes were measured on portal venous phase CT images. A nomogram was developed based on Cox independent predictors and externally validated. Time-dependent receiver operating characteristic (ROC) analysis was performed for comparison with previous prediction models.Patients who received dynamic CT studies during surveillance had significantly higher risk for HCC compared to patients without CT studies (hazard ratio [HR] = 3.1; p < 0.001). Expected/measured liver volume ratio was an independent predictor of HCC (HR = 4.2; p = 0.002) in addition to age, sex and cirrhosis. The nomogram based on the four predictors discriminated risks for HCC (HR = 4.1 and 6.0 in derivation and validation cohort, respectively, for volume score > 150; p < 0.001). Time-dependent ROC analysis confirmed better performance of the volume score compared to HCC prediction models with conventional predictors (integrated area under curve = 0.758 vs. 0.661-0.712; p < 0.05).CT-measured liver volume is an independent predictor of future HCC, and nomogram-based liver volume score may stratify the risks of HCC in CHB patients who showed negative CT findings for HCC during surveillance.

Background/AimsPortal-vein thrombosis (PVT) develops in 10-25% of cirrhotic patients and may aggravate portal hypertension. There are few data regarding the effects of anticoagulation on nonmalignant PVT in liver cirrhosis. The aim of this study was to elucidate the safety, efficacy, and predictors of response to anticoagulation therapy in cirrhotic patients.MethodsPatients with liver cirrhosis and nonmalignant PVT were identified by a hospital electronic medical record system (called BESTCARE). Patients with malignant PVT, Budd-Chiari syndrome, underlying primary hematologic disorders, or preexisting extrahepatic thrombosis were excluded from the analysis. Patients were divided into two groups (treatment and nontreatment), and propensity score matching analysis was performed to identify control patients. The sizes of the thrombus and spleen were evaluated using multidetector computed tomography.ResultsTwenty-eight patients were enrolled in this study between 2003 and 2014: 14 patients who received warfarin for nonmalignant PVT and 14 patients who received no anticoagulation. After 112 days of treatment, 11 patients exhibited significantly higher response rates (complete in 6 and partial in 5) compared to the control patients, with decreases in thrombus size of >30%. Compared to nonresponders, the 11 responders were older, and had a thinner spleen and fewer episodes of previous endoscopic variceal ligations, whereas pretreatment liver function and changes in prothrombin time after anticoagulation did not differ significantly between the two groups. Two patients died after warfarin therapy, but the causes of death were not related to anticoagulation.ConclusionsWarfarin can be safely administered to cirrhotic patients with nonmalignant PVT. The presence of preexisting portal hypertension is a predictor of nonresponse to anticoagulation.

Endophytes have been recognized as a source for structurally novel and biologically active secondary metabolites. Among the host plants for endophytes, some medicinal plants that produce pharmaceuticals have been reported to carry endophytes, which could also produce bioactive secondary metabolites. In this study, the medicinal plant Aconitum carmichaeli was selected as a potential source for endophytes. An endophytic microorganism, Aureobasidium pullulans AJF1, harbored in the flower of Aconitum carmichaeli, was cultured on a large scale and extracted with an organic solvent. Extensive chemical investigation of the extracts resulted in isolation of three lipid type compounds (1−3), which were identified to be (3R,5R)-3,5-dihydroxydecanoic acid (1), (3R,5R)-3-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-5-hydroxydecanoic acid (2), and (3R,5R)-3-(((3R,5R)-5-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-3-hydroxydecanoyl)oxy)-5-hydroxydecanoic acid (3) by chemical methods in combination with spectral analysis. Compounds 2 and 3 had new structures. Absolute configurations of the isolated compounds (1−3) were established using modified Mosher’s method together with analysis of NMR data for their acetonide derivatives. All the isolates (1−3) were evaluated for antibiotic activities against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and their cytotoxicities against MCF-7 cancer cells. Unfortunately, they showed low antibiotic activities and cytotoxic activities.

Purpose:Local recurrence and distant metastasis are major prognostic factors associated with breast cancer. Lymphovascular invasion is an important pathway of metastatic spread. CD44 and D2-40 are assumed to be related with invasion of malignant cells to the adjacent lymphatic or vascular structures by different mechanisms. This study was conducted to examine whether CD44 and D2-40 expression together have prognostic value in invasive carcinoma of the breast. Methods:A total of 46 surgically resected tissue samples of invasive carcinoma of the breast were analyzed for immunohistochemical expression of CD44 and D2-40, along with other clinicopathologic factors. Association between patient related factors and disease free survival was evaluated by statistical analysis. Results:Disease free survival was shorter in CD44-positive patients (median, 66.5 months) than in CD44-negative patients (median, 112.6 months; P

Epidemiological data indicate that type 2 diabetes is associated with increased risk of hepatocellular carcinoma (HCC). However, risk stratification for HCC has not been fully elucidated in diabetic population. The aim of this study was to identify potential predictors of HCC in diabetic patients without chronic viral hepatitis. A cohort of 3,544 diabetic patients without chronic viral hepatitis or alcoholic cirrhosis was established and subjects were randomly allocated into a derivation and a validation set. A scoring system was developed by using potential predictors of increased risk of HCC from the Cox proportional hazards model. The performance of the scoring system was tested for validation by using receiver operating characteristics analysis. During median follow-up of 55 months, 36 cases of HCC developed (190 per 100,000 person-years). The 5- and 10-year cumulative incidences of HCC were 1.0%, and 2.2%, respectively. Multivariate Cox regression analysis showed that age > 65 years, low triglyceride levels and high gamma-glutamyl transferase levels were independently associated with an increased risk of HCC. DM-HCC risk score, a weighted sum of scores from these 3 parameters, predicted 10-year development of HCC with area under the receiver operating characteristics curve of 0.86, and discriminated different risk categories for HCC in the derivation and validation cohort. In conclusion, old age, low triglyceride level and high gamma-glutamyl transferase level may help to identify individuals at high risk of developing HCC in diabetic patients without chronic viral hepatitis or alcoholic cirrhosis.

Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels ≥ 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance.

The cholesterol oxide 7-ketocholesterol (7KCh) has been implicated in numerous age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer and age-related macular degeneration. It is formed by the autooxidation of cholesterol and especially cholesterol-fatty acid esters found in lipoprotein deposits. This molecule causes complex and potent inflammatory responses in vitro and in vivo. It is suspected of causing chronic inflammation in tissues exposed to oxidized lipoprotein deposits. In this study we have examined the inflammatory pathways activated by 7KCh both in cultured ARPE19 cells and in vivo using 7KCh-containing implants inserted into the anterior chamber of the rat eye. Our results indicate that 7KCh-induced inflammation is mediated mostly though the TLR4 receptor with some cross-activation of EGFR-related pathways. The majority of the cytokine inductions seem to signal via the TRIF/TRAM side of the TLR4 receptor. The MyD88/TIRAP side only significantly effects IL-1β inductions. The 7KCh-induced inflammation also seems to involve a robust ER stress response. However, this response does not seem to involve a calcium efflux-mediated UPR. Instead the ER stress response seems to be mediated by yet identified kinases activated through the TLR4 receptor. Some of the kinases identified are the RSKs which seem to mediate the cytokine inductions and the cell death pathway but do not seem to be involved in the ER stress response.

Activated microglia are known to be a major source of cellular neuroinflammation which causes various neurodegenerative diseases, including Alzheimer’s disease. In our continuing efforts to search for new bioactive phytochemicals against neuroinflammatory diseases, the 80% methanolic extract of Pteris multifida (Pteridaceae) roots was found to exhibit significant NO inhibitory activity in lipopolysaccharide (LPS)-activated BV-2 microglia cells. Three new ent-kaurane diterpenoids, pterokaurane M1 2-O-β-d-glucopyranoside (4), 2β,16α-dihydroxy-ent-kaurane 2,16-di-O-β-d-glucopyranoside (10), and 2β,16α,17-trihydroxy-ent-kaurane 2-O-β-d-glucopyranoside (12), were isolated along with nine other known compounds from P. multifida roots. The chemical structures of the new compounds were determined by 1D- and 2D-NMR, HR-ESI-MS, and CD spectroscopic data analysis. Among the isolates, compounds 1 and 7 significantly inhibited NO production in LPS-stimulated BV-2 cells reducing the expression of the cyclooxygenase-2 (COX-2) protein and the level of pro-inflammatory mediators such as prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. These results suggest that ent-kaurane diterpenes from P. multifida could be potential lead compounds that act as anti-neuroinflammatory agents.

Accumulation of 7-Ketocholesterol (7KCh) in lipid deposits has been implicated in a variety of chronic diseases including atherosclerosis, Alzheimer's disease and age-related macular degeneration. 7KCh is known to be pro-inflammatory and cytotoxic to various types of cultured cells but little is known about its effects in vivo. In this study we have investigated the effects of 7KCh in vivo by implanting biodegradable wafers into the anterior chamber of the rat eye. The wafers were prepared using a mixture of two biodegradable polymers with different amounts of 7KCh. The 7KCh-containing implants induced massive angiogenesis and inflammation. By contrast, no angiogenesis and very little inflammation were observed with cholesterol-containing implants. The neovessel growth was monitored by fluorescein angiography. Neovessels were observed 4 days post implantation and peaked between 7 to 10 days. The angiography and isolectin IB(4) labeling demonstrated that the neovessels originated from the limbus and grew through the cornea. Immunolabeling with anti-CD68 suggested that the 7KCh-containing implants had extensive macrophage infiltration as well as other cell types. A significant increase in VEGF was also observed in 7KCh-containing implants by fluorescent immunolabeling and by immunoblot of the aqueous humor (AH). Direct measurement of VEGF, IL-1β and GRO/KC demonstrated a marked elevation of these factors in the AH of the 7KCh-implants. In summary this study demonstrates two important things: 1) 7KCh is pro-angiogenic and pro-inflammatory in vivo and 2) implants containing 7KCh may be used to create a novel angiogenesis model in rats.