Clinical Significance of Mycobacterium kansasii Isolates from Respiratory Specimens

The clinical significance of Mycobacterium kansasii respiratory isolates is uncertain. The aims of this study were to determine the clinical relevance of M. kansasii isolates and to identify the clinical features and outcomes of M. kansasii lung disease. We reviewed the medical records of 104 patients from whom at least one respiratory M. kansasii isolate was obtained from January 2003 to July 2014 at Samsung Medical Center, South Korea. Of these 104 patients, 54 (52%) met the diagnostic criteria for nontuberculous mycobacterial lung disease; among them, 41 (76%) patients received antibiotic treatment for a median time of 15.0 months (interquartile range [IQR], 7.0–18.0 months). The remaining 13 (24%) without overt disease progression were observed for a median period of 24.0 months (IQR, 5.0–34.5 months). Patients with M. kansasii lung disease exhibited various radiographic findings of lung disease, including the fibrocavitary form (n = 24, 44%), the nodular bronchiectatic form (n = 17, 32%), and an unclassifiable form (n = 13, 24%). The fibrocavitary form was more common in patients who received treatment (n = 23, 56%), while the nodular bronchiectatic form was more common in patients with M. kansasii lung disease who did not receive treatment (n = 9, 70%). None of the patients with a single sputum isolate (n = 18) developed M. kansasii disease over a median follow-up period of 12.0 months (IQR, 4.0–26.5 months). In total, 52% of all patients with M. kansasii respiratory isolates exhibited clinically significant disease. Moreover, patients with M. kansasii lung disease displayed diverse radiographic findings in addition to the fibrocavitary form. The nodular bronchiectatic form was more common in patients with M. kansasii lung disease with an indolent clinical course. Thus, since the clinical significance of a single M. kansasii respiratory isolate is not definite, strict adherence to recommended diagnostic criteria is advised.     

c-MYC Copy-Number Gain Is an Independent Prognostic Factor in Patients with Colorectal Cancer

Background

The aim of this study was to determine the incidence and clinicopathological significance of c-MYC gene copy-number (GCN) gain in patients with primary colorectal cancer (CRC).

Methods

The c-MYC GCN was investigated in 367 consecutive CRC patients (cohort 1) by using dual-color silver in situ hybridization. Additionally, to evaluate regional heterogeneity, we examined CRC tissue from 3 sites including the primary cancer, distant metastasis, and lymph-node metastasis in 152 advanced CRC patients (cohort 2). KRAS exons 2 and 3 were investigated for mutations.

Results

In cohort 1, c-MYC gene amplification, defined by a c-MYC:centromere of chromosome 8 ratio ≥ 2.0, was detected in 31 (8.4%) of 367 patients. A c-MYC GCN gain, defined by ≥ 4.0 c-MYC copies/nucleus, was found in 63 (17.2%) patients and was associated with poor prognosis (P = 0.015). Multivariate Cox regression analysis showed that the hazard ratio for c-MYC GCN gain was 2.35 (95% confidence interval, 1.453–3.802; P < 0.001). In a subgroup of stage II-III CRC patients, c-MYC GCN gain was significantly associated with poor prognosis by univariate (P = 0.034) and multivariate (P = 0.040) analyses. c-MYC protein overexpression was observed in 201 (54.8%) out of 367 patients and weakly correlated with c-MYC GCN gain (ρ, 0.211). In cohort 2, the c-MYC genetic status was heterogenous in advanced CRC patients. Discordance between GCN gain in the primary tumor and either distant or lymph-node metastasis was 25.7% and 30.4%, respectively. A similar frequency for c-MYC GCN gain and amplification was observed in CRC patients with both wild-type and mutated KRAS.

Conclusions

c-MYC GCN gain was an independent factor for poor prognosis in consecutive CRC patients and in the stage II-III subgroup. Our findings indicate that the status of c-MYC may be helpful in predicting the patients’ outcome and for managing CRC patients.     

Korean Version of a Model to Estimate Survival in Ambulatory Patients with Hepatocellular Carcinoma (K-MESIAH)

MethodsUtilizing a cohort of 1,969 hepatocellular carcinoma (HCC) patients from the National Cancer Center of Korea between 2004 and 2009, a survival prediction model was developed using the Cox proportional hazards model. The model’s performance was evaluated using C-statistical and χ²-statistical analyses. External validation was performed using an independent cohort of 328 patients from the Seoul National University Bundang Hospital.ResultsTo develop the K-MESIAH, etiology was added to the original risk factors (age, Model for Endstage Liver Disease, albumin, size of the largest nodule, number of tumor nodules, vascular invasion, metastasis, and alpha fetoprotein) in the MESIAH. From the internal validation study, the C-statistics and χ²-statistics for one-, three-, and five-years of survival were 0.83 (95% Confidence Interval: 0.82−0.85), 49.07; 0.81 (95% Confidence Interval: 0.79−0.82), 28.95; and 0.80 (95% Confidence Interval: 0.79−0.81), 20.93, respectively. The K-MESIAH also showed a high prediction ability for the external validation cohort.ConclusionsA survival prediction model for Korean HCC patients was developed and validated to have a high level of performance. This K-MESIAH may be more useful in clinical practice and personalized care in a hepatitis B virus endemic area.     

Proteomic Analysis of Pure Human Airway Gland Mucus Reveals a Large Component of Protective Proteins

Airway submucosal glands contribute to innate immunity and protect the lungs by secreting mucus, which is required for mucociliary clearance and which also contains antimicrobial, anti-inflammatory, anti-proteolytic and anti-oxidant proteins. We stimulated glands in tracheal trimmings from three lung donors and collected droplets of uncontaminated mucus as they formed at the gland orifices under an oil layer. We analyzed the mucus using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Analysis identified 5486 peptides and 441 proteins from across the 3 samples (269–319 proteins per subject). We focused on 269 proteins common to at least 2 0f 3 subjects, of which 102 (38%) had protective or innate immunity functions. While many of these have long been known to play such roles, for many others their cellular protective functions have only recently been appreciated in addition to their well-studied biologic functions (e.g. annexins, apolipoproteins, gelsolin, hemoglobin, histones, keratins, and lumican). A minority of the identified proteins are known to be secreted via conventional exocytosis, suggesting that glandular secretion occurs via multiple mechanisms. Two of the observed protective proteins, major vault protein and prohibitin, have not been observed in fluid from human epithelial cultures or in fluid from nasal or bronchoalveolar lavage. Further proteomic analysis of pure gland mucus may help clarify how healthy airways maintain a sterile environment.     

PharmDB-K: Integrated Bio-Pharmacological Network Database for Traditional Korean Medicine

Despite the growing attention given to Traditional Medicine (TM) worldwide, there is no well-known, publicly available, integrated bio-pharmacological Traditional Korean Medicine (TKM) database for researchers in drug discovery. In this study, we have constructed PharmDB-K, which offers comprehensive information relating to TKM-associated drugs (compound), disease indication, and protein relationships. To explore the underlying molecular interaction of TKM, we integrated fourteen different databases, six Pharmacopoeias, and literature, and established a massive bio-pharmacological network for TKM and experimentally validated some cases predicted from the PharmDB-K analyses. Currently, PharmDB-K contains information about 262 TKMs, 7,815 drugs, 3,721 diseases, 32,373 proteins, and 1,887 side effects. One of the unique sets of information in PharmDB-K includes 400 indicator compounds used for standardization of herbal medicine. Furthermore, we are operating PharmDB-K via phExplorer (a network visualization software) and BioMart (a data federation framework) for convenient search and analysis of the TKM network. Database URL: http://pharmdb-k.org, http://biomart.i-pharm.org.     

Body Mass Index and Mortality in the General Population and in Subjects with Chronic Disease in Korea: A Nationwide Cohort Study (2002-2010)

Background

The association between body mass index (BMI) and mortality is not conclusive, especially in East Asian populations. Furthermore, the association has been neither supported by recent data, nor assessed after controlling for weight changes.

Methods

We evaluated the relationship between BMI and all-cause or cause-specific mortality, using prospective cohort data by the National Health Insurance Service in Korea, which consisted of more than one million subjects. A total of 153,484 Korean adults over 30 years of age without pre-existing cardiovascular disease or cancer at baseline were followed-up until 2010 (mean follow-up period = 7.91 ± 0.59 years). Study subjects repeatedly measured body weight 3.99 times, on average.

Results

During follow-up, 3,937 total deaths occurred; 557 deaths from cardiovascular disease, and 1,224 from cancer. In multiple-adjusted analyses, U-shaped associations were found between BMI and mortality from any cause, cardiovascular disease, and cancer after adjustment for age, sex, smoking status, alcohol consumption, physical activity, socioeconomic status, and weight change. Subjects with a BMI < 23 kg/m² and ≥ 30 kg/m² had higher risks of all-cause and cause-specific mortality compared with the reference group (BMI 23–24.9 kg/m²). The lowest risk of all-cause mortality was observed in subjects with a BMI of 25–26.4 kg/m² (adjusted hazard ratio [HR] 0.86; 95% CI 0.77 to 0.97). In subgroup analyses, including the elderly and those with chronic diseases (diabetes mellitus, hypertension, and chronic kidney disease), subjects with a BMI of 25–29.9 kg/m² (moderate obesity) had a lower risk of mortality compared with the reference. However, this association has been attenuated in younger individuals, in those with higher socioeconomic status, and those without chronic diseases.

Conclusion

Moderate obesity was associated more strongly with a lower risk of mortality than with normal, underweight, and overweight groups in the general population of South Korea. This obesity paradox was prominent in not only the elderly but also individuals with chronic disease.     

The Small Molecule R-(-)-β-O-Methylsynephrine Binds to Nucleoporin 153 kDa and Inhibits Angiogenesis

R-(-)-β-O-methylsynephrine (OMe-Syn) is a naturally occurring small molecule that was identified in a previous screen as an inhibitor of angiogenesis. In this study, we conducted two animal model experiments to investigate the in vivo antiangiogenic activity of OMe-Syn. OMe-Syn significantly inhibited angiogenesis in a transgenic zebrafish model as well as in a mouse retinopathy model. To elucidate the underlying mechanisms responsible for the antiangiogenic activity of OMe-Syn, we used phage display cloning to isolate potential OMe-Syn binding proteins from human cDNA libraries and identified nucleoporin 153 kDa (NUP153) as a primary binding partner of OMe-Syn. OMe-Syn competitively inhibited mRNA binding to the RNA-binding domain of NUP153. Furthermore, depletion of NUP153 in human cells or zebrafish embryos led to an inhibition of angiogenesis, in a manner similar to that seen in response to OMe-Syn treatment. These data suggest that OMe-Syn is a promising candidate for the development of a novel antiangiogenic agent and that inhibition of NUP153 is possibly responsible for the antiangiogenic activity of OMe-Syn.     

Cost-effectiveness of abatacept,rituximab, and TNFi treatment after previous failure with TNFi treatment in rheumatoid arthritis: a pragmatic multi-centre randomised trial

IntroductionFor patients with rheumatoid arthritis (RA) whose treatment with a tumour necrosis factor inhibitor (TNFi) is failing, several biological treatment options are available. Often, another TNFi or a biological with another mode of action is prescribed. The objective of this study was to compare the effectiveness and cost-effectiveness of three biologic treatments with different modes of action in patients with RA whose TNFi therapy is failing.MethodsWe conducted a pragmatic, 1-year randomised trial in a multicentre setting. Patients with active RA despite previous TNFi treatment were randomised to receive abatacept, rituximab or a different TNFi. The primary outcome (Disease Activity Score in 28 joints) and the secondary outcomes (Health Assessment Questionnaire Disability Index and 36-item Short Form Health Survey scores) were analysed using linear mixed models. Cost-effectiveness was analysed on the basis of incremental net monetary benefit, which was based on quality-adjusted life-years (calculated using EQ-5D scores), and all medication expenditures consumed in 1 year. All analyses were also corrected for possible confounders.ResultsOf 144 randomised patients, 5 were excluded and 139 started taking abatacept (43 patients), rituximab (46 patients) or a different TNFi (50 patients). There were no significant differences between the three groups with respect to multiple measures of RA outcomes. However, our analysis revealed that rituximab therapy is significantly more cost-effective than both abatacept and TNFi over a willingness-to-pay range of 0 to 80,000 euros.ConclusionsAll three treatment options were similarly effective; however, when costs were factored into the treatment decision, rituximab was the best option available to patients whose first TNFi treatment failed. However, generalization of these costs to other countries should be undertaken carefully.

Trial registration

Netherlands Trial Register number NTR1605. Registered 24 December 2008.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0630-5) contains supplementary material, which is available to authorized users.     

Age‐related sensitivity to endotoxin‐induced liver inflammation: Implication of inflammasome/IL‐1β for steatohepatitis

Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg⁻¹) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPARα and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1β production. Increased levels of IL-1β were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1β significantly induced lipid accumulation in hepatocytes through the regulation of PPARα and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/IL-1β pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/IL-1β pathway involved in lipid accumulation in the liver.