Heterologous Tissue Culture Expression Signature Predicts Human Breast Cancer Prognosis

BACKGROUND: Cancer patients have highly variable clinical outcomes owing to many factors, among which are genes that determine the likelihood of invasion and metastasis. This predisposition can be reflected in the gene expression pattern of the primary tumor, which may predict outcomes and guide the choice of treatment better than other clinical predictors. METHODOLOGY/PRINCIPAL FINDINGS: We developed an mRNA expression-based model that can predict prognosis/outcomes of human breast cancer patients regardless of microarray platform and patient group. Our model was developed using genes differentially expressed in mouse plasma cell tumors growing in vivo versus those growing in vitro. The prediction system was validated using published data from three cohorts of patients for whom microarray and clinical data had been compiled. The model stratified patients into four independent survival groups (BEST, GOOD, BAD, and WORST: log-rank test p = 1.7×10(−8)). CONCLUSIONS: Our model significantly improved the survival prediction over other expression-based models and permitted recognition of patients with different prognoses within the estrogen receptor-positive group and within a single pathological tumor class. Basing our predictor on a dataset that originated in a different species and a different cell type may have rendered it less sensitive to proliferation differences and endowed it with wide applicability. SIGNIFICANCE: Prognosis prediction for patients with breast cancer is currently based on histopathological typing and estrogen receptor positivity. Yet both assays define groups that are heterogeneous in survival. Gene expression profiling allows subdivision of these groups and recognition of patients whose tumors are very unlikely to be lethal and those with much grimmer outlooks, which can augment the predictive power of conventional tumor analysis and aid the clinician in choosing relaxed vs. aggressive therapy

Performance of Papanicolaou Testing and Detection of Cervical Carcinoma In Situ in Participants of Organized Cervical Cancer Screening in South Korea

BACKGROUND: The present study measured the performance of the Papanicolaou (Pap) test and detection of cervical carcinoma in situ (CIS) and cancer in participants of organized cervical cancer screening in South Korea, and examined differences in the proportion of CIS according to socio-demographic factors. METHODS: Data were obtained from the National Cancer Screening Program and National Health Insurance Cancer Screening Program databases. We analyzed data from 4,072,997 screenings of women aged 30 years or older who underwent cervical cancer screening by Pap test between January 1, 2005 and December 31, 2006. We calculated the performances of the Pap test and compared that according to socio-demographic factors. RESULTS: The positivity rate for all screenings was 6.6%. The cancer detection rate (CDR) and interval cancer rate (ICR) were 0.32 per 1,000 screenings, and 0.13 per 1,000 negative screenings, respectively. About 63.4% of screen-detected CIS+ cases (CIS or invasive cervical cancer) were CIS. The CDR and ICR, and percentage of CIS among all CIS+ were significantly different by age group and health insurance status. The odds ratios of CDR and ICR were higher for Medical Aid Program (MAP) recipients compared with National Health Insurance (NHI) beneficiaries. The likelihood of a detected CIS+ case to be CIS was significantly lower among MAP recipients than among NHI beneficiaries. CONCLUSIONS: The difference in performance of cervical cancer screening among different socio-demographic groups may indicate an important influence of socio-demographic factors on preventive behavior. The findings of the study support the critical need for increasing efforts to raise awareness and provide more screening in at-risk populations, specifically low-income groups

Fractionation of a Herbal Antidiarrheal Medicine Reveals Eugenol as an Inhibitor of Ca2+-Activated Cl− Channel TMEM16A

The Ca2+-activated Cl− channel TMEM16A is involved in epithelial fluid secretion, smooth muscle contraction and neurosensory signaling. We identified a Thai herbal antidiarrheal formulation that inhibited TMEM16A Cl− conductance. C18-reversed-phase HPLC fractionation of the herbal formulation revealed >98% of TMEM16A inhibition activity in one out of approximately 20 distinct peaks. The purified, active compound was identified as eugenol (4-allyl-2-methoxyphenol), the major component of clove oil. Eugenol fully inhibited TMEM16A Cl− conductance with single-site IC50∼150 µM. Eugenol inhibition of TMEM16A in interstitial cells of Cajal produced strong inhibition of intestinal contraction in mouse ileal segments. TMEM16A Cl− channel inhibition adds to the list of eugenol molecular targets and may account for some of its biological activities

A comparison of the Charlson comorbidity index derived from medical records and claims data from patients undergoing lung cancer surgery in Korea: a population-based investigation

<p>Abstract</p> <p>Background</p> <p>Calculating the Charlson comorbidity index (CCI) from medical records is a time-consuming and expensive process. The objectives of this study are to 1) measure agreement between medical record and claims data for CCI in lung cancer patients and 2) predict health outcomes of lung cancer patients based on CCIs from both data sources.</p> <p>Methods</p> <p>We studied 392 patients who underwent surgery for pathologic stages I-III of lung cancer. The kappa value was used to measure the agreement between the 17 comorbidities of the CCI prevalence obtained from medical records and claims data. Multiple linear regression analyses were used to evaluate the relationships between CCI and length of stay and reimbursement cost.</p> <p>Results</p> <p>Out of 17 comorbidities identified in the Charlson comorbidity index, ten had a higher prevalence, four had a lower prevalence and three had a similar prevalence in claims data to those of medical records. The kappa values calculated from the two databases ranged from 0.093 to 0.473 for nine comorbidities. In predicting length of stay and reimbursement cost after surgical resection for lung cancer patients, the CCI scores derived from both the medical records and claims data were not statistically significant.</p> <p>Conclusions</p> <p>Poor agreement between medical record data and claims data may result from different motivations for collecting data. Further studies are needed to determine an appropriate method for predicting health outcomes based on these data sources.</p

The economic burden of musculoskeletal disease in Korea: A cross sectional study

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal diseases are becoming increasingly important due to population aging. However, studies on the economic burden of musculoskeletal disease in Korea are scarce. Therefore, we conducted a population-based study to measure the economic burden of musculoskeletal disease in Korea using nationally representative data.</p> <p>Methods</p> <p>This study used a variety of data sources such as national health insurance statistics, the Korea Health Panel study and cause of death reports generated by the Korea National Statistical Office to estimate the economic burden of musculoskeletal disease. The total cost of musculoskeletal disease was estimated as the sum of direct medical care costs, direct non-medical care costs, and indirect costs. Direct medical care costs are composed of the costs paid by the insurer and patients, over the counter drugs costs, and other costs such as medical equipment costs. Direct non-medical costs are composed of transportation and caregiver costs. Indirect costs are the sum of the costs associated with premature death and the costs due to productivity loss. Age, sex, and disease specific costs were estimated.</p> <p>Results</p> <p>Among the musculoskeletal diseases, the highest costs are associated with other dorsopathies, followed by disc disorder and arthrosis. The direct medical and direct non-medical costs of all musculoskeletal diseases were $4.18 billion and$338 million in 2008, respectively. Among the indirect costs, those due to productivity loss were $2.28 billion and costs due to premature death were$79 million. The proportions of the total costs incurred by male and female patients were 33.8% and 66.2%, respectively, and the cost due to the female adult aged 20-64 years old was highest. The total economic cost of musculoskeletal disease was $6.89 billion, which represents 0.7% of the Korean gross domestic product.</p> <p>Conclusions</p> <p>The economic burden of musculoskeletal disease in Korea is substantial. As the Korean population continues to age, the economic burden of musculoskeletal disease will continue to increase. Policy measures aimed at controlling the cost of musculoskeletal disease are therefore required.</p

Bio-anthropological Studies on Human Skeletons from the 6th Century Tomb of Ancient Silla Kingdom in South Korea

In November and December 2013, unidentified human skeletal remains buried in a mokgwakmyo (a traditional wooden coffin) were unearthed while conducting an archaeological investigation near Gyeongju, which was the capital of the Silla Kingdom (57 BCE– 660 CE) of ancient Korea. The human skeletal remains were preserved in relatively intact condition. In an attempt to obtain biological information on the skeleton, physical anthropological, mitochondrial DNA, stable isotope and craniofacial analyses were carried out. The results indicated that the individual was a female from the Silla period, of 155 ± 5 cm height, who died in her late thirties. The maternal lineage belonged to the haplogroup F1b1a, typical for East Asia, and the diet had been more C3- (wheat, rice and potatoes) than C4-based (maize, millet and other tropical grains). Finally, the face of the individual was reconstructed utilizing the skull (restored from osseous fragments) and three-dimensional computerized modelling system. This study, applying multi-dimensional approaches within an overall bio-anthropological analysis, was the first attempt to collect holistic biological information on human skeletal remains dating to the Silla Kingdom period of ancient Korea

Identification of S100A8-correlated genes for prediction of disease progression in non-muscle invasive bladder cancer

<p>Abstract</p> <p>Background</p> <p><it>S100 calcium binding protein A8 </it>(<it>S100A8</it>) has been implicated as a prognostic indicator in several types of cancer. However, previous studies are limited in their ability to predict the clinical behavior of the cancer. Here, we sought to identify a molecular signature based on <it>S100A8 </it>expression and to assess its usefulness as a prognostic indicator of disease progression in non-muscle invasive bladder cancer (NMIBC).</p> <p>Methods</p> <p>We used 103 primary NMIBC specimens for microarray gene expression profiling. The median follow-up period for all patients was 57.6 months (range: 3.2 to 137.0 months). Various statistical methods, including the leave-one-out cross validation method, were applied to identify a gene expression signature able to predict the likelihood of progression. The prognostic value of the gene expression signature was validated in an independent cohort (n = 302).</p> <p>Results</p> <p>Kaplan-Meier estimates revealed significant differences in disease progression associated with the expression signature of <it>S100A8</it>-correlated genes (log-rank test, <it>P </it>< 0.001). Multivariate Cox regression analysis revealed that the expression signature of <it>S100A8</it>-correlated genes was a strong predictor of disease progression (hazard ratio = 15.225, 95% confidence interval = 1.746 to 133.52, <it>P </it>= 0.014). We validated our results in an independent cohort and confirmed that this signature produced consistent prediction patterns. Finally, gene network analyses of the signature revealed that <it>S100A8</it>, <it>IL1B</it>, and <it>S100A9 </it>could be important mediators of the progression of NMIBC.</p> <p>Conclusions</p> <p>The prognostic molecular signature defined by <it>S100A8</it>-correlated genes represents a promising diagnostic tool for the identification of NMIBC patients that have a high risk of progression to muscle invasive bladder cancer.</p

Impaired Inflammatory Responses in Murine Lrrk2-Knockdown Brain Microglia

LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1β and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation