The Largest Known Survival Analysis of Patients with Brain Metastasis from Thyroid Cancer Based on Prognostic Groups

PurposeTo analyze the clinical features and prognostic factors associated with the survival of patients with a very rare occurrence of brain metastasis (BM) from differentiated thyroid cancer (DTC).ResultsThe median age at BM was 63 years, and the median time from initial thyroid cancer diagnosis to BM was 3.8 years. The median survival and the 1-year actuarial survival rate after BM were 8.8 months and 47%, respectively. According to univariate and multivariate analyses, four good prognostic factors (GPFs) were identified including age ≤ 60 years, PS ≤ ECOG 2, ≤ 3 BM sites, and without extracranial metastasis prior to BM. Three prognostic groups were designed based on age and number of remaining GPFs: patients ≤ 60 years of age with at least 2 GPFs (Group A) had the most favorable prognosis with a median survival of 32.8 months; patients ≤ 60 years of age with fewer than 2 GPFs and those > 60 years of age with at least 2 GPFs (Group B) had an intermediate prognosis with a median survival of 9.4 months; and patients > 60 years of age with fewer than 2 GPFs (Group C) had the least favorable prognosis with a median survival of 1.5 months.ConclusionsThe survival of patients with BM form DTC differed among the prognostic groups based on the total number of good prognostic factors.     

BJ-1108, a 6-Amino-2,4,5-Trimethylpyridin-3-ol Analog,Inhibits Serotonin-Induced Angiogenesis and Tumor Growth through PI3K/NOX Pathway

5-Hydroxytryptamine (5-HT) induces proliferation of cancer cells and vascular cells. In addition to 5-HT production by several cancer cells including gastrointestinal and breast cancer, a significant level of 5-HT is released from activated platelets in the thrombotic environment of tumors, suggesting that inhibition of 5-HT signaling may constitute a new target for antiangiogenic anticancer drug discovery. In the current study we clearly demonstrate that 5-HT-induced angiogenesis was mediated through the 5-HT₁ receptor-linked Gβγ/Src/PI3K pathway, but not through the MAPK/ERK/p38 pathway. In addition, 5-HT induced production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS). In an effort to develop new molecularly targeted anticancer agents against 5-HT action in tumor growth, we demonstrate that BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, significantly inhibited 5-HT-induced angiogenesis. In addition, BJ-1108 induced a significant reduction in the size and weight of excised tumors in breast cancer cell-inoculated CAM assay, showing proportionate suppression of tumor growth along with inhibition of angiogenesis. In human umbilical vein endothelial cells (HUVECs), BJ-1108 significantly suppressed 5-HT-induced ROS generation and phosphorylation of PI3K/Akt but not of Src. Unlike NOX inhibitors, BJ-1108, which showed better antioxidant activity than vitamin C, barely suppressed superoxide anion induced by mevalonate or geranylgeranyl pyrophosphate which directly activates NOX without help from other signaling molecules in HUVECs, implying that the anti-angiogenic action of BJ-1108 was not mediated through direct action on NOX activation, or free radical scavenging activity. In conclusion, BJ-1108 inhibited 5-HT-induced angiogenesis through PI3K/NOX signaling but not through Src, ERK, or p38.     

Identification of transposable element-mediated deletions in 27 Korean individuals based on whole genome sequencing data

The human genome has various genomic structural variations such as insertion/deletions between human individuals. These structural variations have led to genomic fluidity and rearrangements in individuals and populations. To investigate Korean-specific structural genomic variations, we performed next generation sequencing with 30× mean coverage from 27 Korean individuals using illumina-HiSeq 2000 platform. We collected a total of 119 deletion loci as transposable element-mediated Korean-specific deletion (KSD) candidates. Of the 119 loci, 35 were filtered out due to computational overlapping regions. A total of 78 loci were validated by PCR amplification with 27 Korean individuals and 80 human individuals from four different populations. We confirmed deletion breakpoints of the 78 loci using Sanger sequencing. We also investigated different deletion mechanisms based on sequencing alignment analysis. We found at least one KSD locus in 80 human individual panel. It has not been previously reported in human genomes. Here, for the first time, we report transposable element-mediated KSD study based on whole genome sequencing data of 27 Korean.     

Genotype–phenotype correlation of Charcot-Marie-Tooth type 1E patients with <Emphasis Type="Italic">PMP22</Emphasis> mutations

Charcot-Marie-Tooth disease type 1E (CMT1E) is a demyelinating motor and sensory neuropathy with peripheral myelin protein 22 (PMP22) point mutations. The objective of this study was to identify genetic causes and determine genotype–phenotype correlation in two Korean demyelinating CMT patients based on whole exome sequencing (WES), histological examination of distal sural nerve, and magnetic resonance imaging (MRI) of leg. WES revealed two de novo PMP22 mutations in the two demyelinating CMT patients, including one novel p.Leu82Pro (c.245T>A) mutation in one patient and one previously reported p.Ser72Leu (c.215C>T) mutation in the other patient. Both mutation sites were located in the well conserved second transmembrane domain. No control had the same mutations. The affected individual with the novel p.Leu82Pro mutation showed early onset, scoliosis, and sensory ataxia with ability to walk without assistance. Histopathological examination showed severe damage of myelin and axons. No compound muscle action potentials (CMAPs) were evoked in the upper or lower limb nerves. Leg MRIs revealed mild fatty infiltration of the bilateral peronei muscles consistent with clinical manifestations. The patient with the p.Ser72Leu mutation showed developmental delay in infancy. No CMAPs were elicited. However, she was also able to walk without assistance. In spite of markedly severe electrophysiological defects, leg MRIs showed almost normal findings except slight muscle atrophies of the lower legs. Both patients presented similar clinical features including no CMAPs in electrophysiological tests and mild fatty replacement in the lower leg MRI. Therefore, there was a good genotype–phenotype correlation in both cases.     

Time-Staged Gamma Knife Stereotactic Radiosurgery for Large Cerebral Arteriovenous Malformations: A Preliminary Report

ObjectiveWe retrospectively analyzed our experience with time-staged gamma knife stereotactic radiosurgery (GKS) in treating large arteriovenous malformation(AVM)s;≥ 10 cm³).MethodsForty-five patients who underwent time-staged GKS (2-stage, n = 37;3-stage,n = 8) between March 1998 and December 2011 were included. The mean volume treated was 20.42±6.29 cm³ (range, 10.20–38.50 cm³). Obliteration rates of AVMs and the associated complications after GKS were evaluated.ResultsMean AVM volume (and median marginal dose) at each GKS session in the 37 patients who underwent 2-stage GKS was 19.67±6.08 cm³ (13 Gy) at session 1 and 6.97±6.92 cm³ (17 Gy) at session 2. The median interval period was 39 months. After follow-up period of 37 months, the complete obliteration rate was 64.9%. The mean AVM volume (and median marginal dose) at each GKS session in the 8 patients who underwent 3-stage GKS was 23.90±6.50 cm³ (12.25 Gy), 19.43±7.46 cm³ (13.5 Gy), 7.48±6.86 cm³ (15.5 Gy) at session 1, 2, and 3, respectively. The median interval duration between each GKS session was 37.5 and 38 months, respectively. After a median follow-up period of 47.5 months, 5 patients (62.5%) achieved complete obliteration. Postradiosurgical hemorrhage developed in 5 patients (11.1%) including one case of major bleeding and 4 cases of minor bleeding. No patient suffered from clinically symptomatic radiation necrosis following radiation.ConclusionTime-staged GKS could be an effective and safe treatment option in the management of large AVMs.     

Age- and Gender-Related Mean Hearing Threshold in a Highly-Screened Population: The Korean National Health and Nutrition Examination Survey 2010–2012

Background

In evaluating hearing disability in medicolegal work, the apportionment of age- and gender-related sensorineural hearing loss should be considered as a prior factor, especially for the elderly. However, in the literature written in the English language no studies have reported on the age- and gender-related mean hearing threshold for the South Korean population.

Objective

This study aimed to identify the mean hearing thresholds in the South Korean population to establish reference data and to identify the age- and gender-related characteristics.

Methods

This study is based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2010–2012, which was conducted by the Korean government, the data of which was disclosed to the public. A total of 15,606 participants (unweighted) representing 33,011,778 Koreans (weighted) with normal tympanic membrane and no history of regular or occupational noise exposure were selected and analyzed in this study. The relationship between the hearing threshold level and frequency, age, and gender was investigated and analyzed in a highly-screened population by considering the sample weights of a complex survey design.

Results

A gender ratio difference was found between the unweighted and the weighted designs: male:female, 41.0%: 59.0% (unweighted, participants) vs. 47.2%:52.8% (weighted, representing population). As age increased, the hearing threshold increased for all frequencies. Hearing thresholds of 3 kHz, 4 kHz, and 6 kHz showed a statistical difference between both genders for people older than 30, with the 4 kHz frequency showing the largest difference. This paper presents details about the mean hearing threshold based on age and gender.

Conclusions

The data from KNHANES 2010–2012 showed gender differences at hearing thresholds of 3 kHz, 4 kHz, and 6 kHz in a highly-screened population. The most significant gender difference in relation to hearing threshold was observed at 4 kHz. The hearing thresholds at all of the tested frequencies worsened with increasing age. The mean hearing thresholds suggested in this study will be useful for the formulation of healthcare-related hearing policies and used as reference data for disability ratings for hearing loss due to various causes.     

Supply- and Demand-Side Factors Influencing Utilization of Infant and Young Child Feeding Counselling Services in Viet Nam

Adequate utilization of services is critical to maximize the impact of counselling on infant and young child feeding (IYCF), but little is known about factors affecting utilization. Our study examined supply- and demand-side factors associated with the utilization of IYCF counselling services in Viet Nam. We used survey data from mothers with children <2y (n = 1,008) and health staff (n = 60) from the evaluation of a program that embedded IYCF counseling into the existing government health system. The frequency of never users, one-time users, repeat users, and achievers of the recommended minimum number of visits at health facilities were 45.1%, 13.0%, 28.4% and 13.5%, respectively. Poisson regression showed that demand-generation strategies, especially invitation cards, were the key factors determining one-time use (Prevalence ratio, PR 3.0, 95% CI: 2.2–4.2), repeated use (PR 3.2, 95% CI: 2.4–4.2), and achievement of minimum visits (PR 5.5, 95% CI: 3.6–8.4). Higher maternal education was associated with higher utilization both for one-time and repeated use. Being a farmer, belonging to an ethnic minority, and having a wasted child were associated with greater likelihood of achieving the minimum recommended number of visits, whereas child stunting or illness were not. Distance to health center was a barrier to repeated visits. Among supply-side factors, good counselling skills (PR: 1.3–1.8) was the most important factor associated with any service use, whereas longer employment duration and greater work pressure of health center staff were associated with lower utilization. Population attributable risk estimations showed that an additional 25% of the population would have achieved the minimum number of visits if exposed to three demand-generation strategies, and further increased to 49% if the health staff had good counseling skills and low work pressure. Our study provides evidence that demand-generation strategies are essential to increase utilization of facility-based IYCF counselling services in Viet Nam, and may be relevant for increasing and sustaining use of nutrition services in similar contexts.     

Mice with low levels of Shc proteins display reduced glycolytic and increased gluconeogenic activities in liver

Shc proteins play a role in energy metabolism through interaction with the insulin receptor. The aim of this study was to determine whether Shc proteins influence liver glycolysis and gluconeogenesis under both fed and fasted states. Decreased glycolytic and increased gluconeogenic and transamination enzyme activities were observed in ShcKO versus WT mice. Levels of key regulatory metabolites, such as fructose-2,6-bisphosphate, matched the activity of metabolic pathways. Protein levels of glycolytic and gluconeogenic enzymes were not different. pAMPK protein levels increased with fasting and were higher in ShcKO versus WT mice. Therefore, Shc proteins play a role in shifting the metabolism from glucose oxidation to gluconeogenesis and lipid catabolism and should be considered as regulators of fuel selection. Fuel selection and utilization could play a critical role in healthy aging. Characterization of metabolic events in ShcKO mice would help to elucidate how metabolism is influenced by these proteins.