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1.  Genistein from Vigna angularis Extends Lifespan in Caenorhabditis elegans 
Biomolecules & Therapeutics  2015;23(1):77-83.
The seed of Vigna angularis has long been cultivated as a food or a folk medicine in East Asia. Genistein (4′,5,7-trihydroxyisoflavone), a dietary phytoestrogen present in this plant, has been known to possess various biological properties. In this study, we investigated the possible lifespan-extending effects of genistein using Caenorhabditis elegans model system. We found that the lifespan of nematode was significantly prolonged in the presence of genistein under normal culture condition. In addition, genistein elevated the survival rate of nematode against stressful environment including heat and oxidative conditions. Further studies demonstrated that genistein-mediated increased stress tolerance of nematode could be attributed to enhanced expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). Moreover, we failed to find genistein-induced significant change in aging-related factors including reproduction, food intake, and growth, indicating genistein exerts longevity activity independent of affecting these factors. Genistein treatment also led to an up-regulation of locomotory ability of aged nematode, suggesting genistein affects healthspan as well as lifespan of nematode. Our results represent that genistein has beneficial effects on the lifespan of C. elegans under both of normal and stress condition via elevating expressions of stress resistance proteins.
doi:10.4062/biomolther.2014.075
PMCID: PMC4286753  PMID: 25593647
Vigna angularis; Genistein; Caenorhabditis elegans; Lifespan extension; Stress tolerance
2.  p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells 
Cell Cycle  2013;12(10):1578-1587.
p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5′ and 3′ UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer.
doi:10.4161/cc.24739
PMCID: PMC3680537  PMID: 23624843
Axin2; GSK-3; Snail; epithelial-mesenchymal transition (EMT); microRNA-34 (miRNA-34; miR-34); p53
3.  Radicicol Inhibits iNOS Expression in Cytokine-Stimulated Pancreatic Beta Cells 
Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-α, IFN-γ, and IL-1β). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-κB/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity.
doi:10.4196/kjpp.2013.17.4.315
PMCID: PMC3741488  PMID: 23946691
β cells; ERK1/2; iNOS; NO
4.  Pseudomyxoma Peritonei: A Rare Cause of Oliguric Acute Kidney Injury 
Chonnam Medical Journal  2013;49(2):87-90.
Pseudomyxoma peritonei is a rare clinical condition that causes the accumulation of mucinous ascites, which gradually results in the compression of intra-abdominal organs. Most published reports of pseudomyxoma peritonei concern the mass effect of the resulting ascites, which presents as abdominal pain or intestinal ileus in severe cases. However, few reports of renal complications of the disease have been published. Here, we present a case of oliguric acute kidney injury caused by external compression by pseudomyxoma peritonei. After decompression with external drainage, the patient's renal function rapidly improved.
doi:10.4068/cmj.2013.49.2.87
PMCID: PMC3759688  PMID: 24010072
Acute kidney injury; Oliguria; Pseudomyxoma peritonei
5.  Silibinin Inhibits LPS-Induced Macrophage Activation by Blocking p38 MAPK in RAW 264.7 Cells 
Biomolecules & Therapeutics  2013;21(4):258-263.
We demonstrate herein that silibinin, a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), inhibits LPS-induced activation of macrophages and production of nitric oxide (NO) in RAW 264.7 cells. Western blot analysis showed silibinin inhibits iNOS gene expression. RT-PCR showed that silibinin inhibits iNOS, TNF-α, and IL1β. We also showed that silibinin strongly inhibits p38 MAPK phosphorylation, whereas the ERK1/2 and JNK pathways are not inhibited. The p38 MAPK inhibitor abrogated the LPS-induced nitrite production, whereas the MEK-1 inhibitor did not affect the nitrite production. A molecular modeling study proposed a binding pose for silibinin targeting the ATP binding site of p38 MAPK (1OUK). Collectively, this series of experiments indicates that silibinin inhibits macrophage activation by blocking p38 MAPK signaling.
doi:10.4062/biomolther.2013.044
PMCID: PMC3819897  PMID: 24244809
Silibinin; Macrophages; p38 MAPK; Nitric oxide
6.  Effects of contiguous scars in dermoscopic evaluation of clinically atypical melanocytic nevi 
doi:10.1016/j.jaad.2011.05.028
PMCID: PMC3329219  PMID: 22507589
Dermoscopy; atypical nevi; atypical melanocytic nevi; biopsy; scar
7.  The Frequency of Reexpansion Pulmonary Edema after Trocar and Hemostat Assisted Thoracostomy in Patients with Spontaneous Pneumothorax 
Yonsei Medical Journal  2012;54(1):166-171.
Purpose
Several risk factors for development of reexpansion pulmonary edema (REPE) after drainage of pneumothoraces have been reported, but the association between the method of thoracostomy and the development of REPE is unknown. The aim of this study was to compare the frequency of REPE after treatment of spontaneous pneumothorax with trocar or hemostat assisted closed thoracostomy.
Materials and Methods
We performed a prospective, observational study including 173 patients with spontaneous pneumothorax who visited the emergency department from January 2007 to December 2008. In 2007, patients were treated with hemostat-assisted drainage, whereas patients in 2008 were treated with trocar-assisted drainage. The main outcome was the development of REPE, determined by computed tomography of the chest 8 hours after closed thoracostomy. Outcomes in both groups were compared using univariate and multivariate analyses.
Results
Ninety-two patients were included, 48 (42 males) of which underwent hemostat-assisted drainage and 44 (41 males) underwent trocar-assisted drainage. The groups were similar in mean age (24±10 vs. 26±14 respectively). The frequencies of REPE after hemostat- and trocar-assisted drainage were 63% (30 patients) and 86% (38 patients) respectively (p=0.009). In multivariate analysis, trocar-assisted drainage was the major contributing factor for developing REPE (odds ratio=5.7, 95% confidence interval, 1.5-21). Age, gender, size of pneumothorax, symptom duration and laboratory results were similar between the groups.
Conclusion
Closed thoracostomy using a trocar is associated with an increased risk of REPE compared with hemostat-assisted drainage in patients with spontaneous pneumothorax.
doi:10.3349/ymj.2013.54.1.166
PMCID: PMC3521265  PMID: 23225814
Pneumothorax; thoracostomy; pulmonary edema
8.  Three-dimensional finite element analysis of the deformation of the human mandible: a preliminary study from the perspective of orthodontic mini-implant stability 
Korean Journal of Orthodontics  2012;42(4):159-168.
Objective
The aims of this study were to investigate mandibular deformation under clenching and to estimate its effect on the stability of orthodontic mini-implants (OMI).
Methods
Three finite element models were constructed using computed tomography (CT) images of 3 adults with different mandibular plane angles (A, low; B, average; and C, high). An OMI was placed between #45 and #46 in each model. Mandibular deformation under premolar and molar clenching was simulated. Comparisons were made between peri-orthodontic mini-implant compressive strain (POMI-CSTN) under clenching and orthodontic traction forces (150 g and 200 g).
Results
Three models with different mandibular plane angles demonstrated different functional deformation characteristics. The compressive strains around the OMI were distributed mesiodistally rather than occlusogingivally. In model A, the maximum POMI-CSTN under clenching was observed at the mesial aspect of #46 (1,401.75 microstrain [µE]), and similar maximum POMI-CSTN was observed under a traction force of 150 g (1,415 µE).
Conclusions
The maximum POMI-CSTN developed by clenching failed to exceed the normally allowed compressive cortical bone strains; however, additional orthodontic traction force to the OMI may increase POMI-CSTN to compromise OMI stability.
doi:10.4041/kjod.2012.42.4.159
PMCID: PMC3481986  PMID: 23112947
Orthodontic mini-implant; Stability; Neuromuscular force; Anatomy; Finite element method
9.  Dependence Potential of Propofol: Behavioral Pharmacology in Rodents 
Biomolecules & Therapeutics  2012;20(2):234-238.
Propofol is an anesthetic commonly used to provide sedation or to induce and maintain an anesthetic stated. However, there are reports which indicate propofol may cause psychological dependence or be abused. In the present study, we used various behavioral tests including climbing test, jumping test, conditioned place preference, and self-administration test to assess the dependence potential and abuse liability of propofol compared to a positive control (methamphetamine) or a negative control (saline or intralipid). Among the tests, the conditioned place preference test was conducted with a biased method, and the selfadministration test was performed under a fixed ratio (FR) 1 schedule, 1 h per session. No difference was found in the climbing test and jumping test, but propofol (30 mg/kg, i.p.) increased the rewarding effect in the conditioned place preference test, and it showed a positive reinforcing effect compared to the vehicle. These results indicate that propofol tends to show psychological dependence rather than physical dependence, and it seems not to be related with dopaminergic system.
doi:10.4062/biomolther.2012.20.2.234
PMCID: PMC3792224  PMID: 24116301
Propofol; Psychological dependence; Physical dependence; Animal behavioral test
10.  Zap70 functions to maintain stemness of mouse embryonic stem cells by negatively regulating Jak1/Stat3/c-Myc signaling 
Stem cells (Dayton, Ohio)  2010;28(9):1476-1486.
Zeta-chain associated protein kinase-70 (Zap70), a Syk family tyrosine kinase, has been reported to be present exclusively in normal T cells, Natural Killer (NK) cells, and B cells, serving as a pivotal regulator of antigen-mediated receptor signaling and development. In this study, we report that Zap70 is expressed in undifferentiated mouse embryonic stem cells (mESCs) and may critically regulate self-renewal and pluripotency in mESCs. We found that Zap70 knocked-down mESCs (Zap70KD) show sustained self-renewal and defective differentiation. In addition, we present evidence that the sustained self-renewal in Zap70KD is associated with enhanced Jak/Stat3 signaling and c-Myc induction. These altered signaling appears to result from up-regulated LIFR and down-regulated SHP-1 phosphatase activity. Based on these results, we propose that, in undifferentiated mESCs, Zap70 plays important roles in modulating the balance between self-renewal capacity and pluripotent differentiation ability as a key regulator of the Jak/Stat3/c-Myc signaling pathway.
doi:10.1002/stem.470
PMCID: PMC3164580  PMID: 20641039
Zap70; mouse embryonic stem cells; Jak/Stat3; c-Myc; SHP-1; LIFR; self-renewal; pluripotency; stemness
11.  Seroprevalence of Toxoplasma gondii Infection and Characteristics of Seropositive Patients in General Hospitals in Daejeon, Korea 
To figure out the epidemiological status and relevance with other diseases in toxoplasmosis, we checked serum IgG antibody titers of 1,265 patients and medical records of seropositive patients. Seropositive rates were 6.6% by latex agglutination test (LAT) and 6.7% by ELISA. No significant differences were detected between sexes and age groups. The peak seroprevalence was detected in the 40-49-year-old age group. According to clinical department, Toxoplasma-positive rates were high in patients in psychiatry, ophthalmology, health management, emergency medicine, and thoracic surgery. Major coincidental diseases in seropositive cases were malignant neoplasms, diabetes mellitus, arthritis, chronic hepatitis B, chronic renal diseases, schizophrenia, and acute lymphadenitis, in the order of frequency. In particular, some patients with chronic hepatitis B and malignant neoplasms had high antibody titers. These results revealed that the seroprevalence of toxoplasmosis in a general hospital-based study was similar to that in a community-based study, and T. gondii seropositivity may be associated with neoplasms, diabetes, and other chronic infections.
doi:10.3347/kjp.2009.47.2.125
PMCID: PMC2688793  PMID: 19488418
Toxoplasma gondii; comorbidity; general hospital; seroprevalence; Daejeon
12.  Molecular and Cytogenetic Characterization of Two Azoospermic Patients with X-Autosome Translocation 
Purpose: To report two azoospermic patients with reciprocal X–autosome translocations.
Methods: Cytogenetic analysis utilizing GTG-banding and Yq microdeletions shown by polymerase chain reaction (PCR) with 12 sequence-tagged site (STS) markers for Y chromosome microdeletions.
Results: Cytogenetic analysis showed one man with 46,Y,t(X;19)(q22;q13.3) and the other with 46,Y,t(X;8)(p22;q11). Neither had any Yq microdeletions shown. The patient with 46,Y, t(X;8)(p22;q11) showed a slightly lower than normal testosterone level. By NCBI-Blast search, we found four testis-specific genes, t-complex-associated-testis-expressed 1-like (TCTE1L), Ferritin, heavy polypeptide-like 17 (FTHL17), Testis expressed sequence 13A (TEX13A), and Testis expressed sequence 13B (TEX13B) located near breakpoints on X chromosome. FTHL17, TEX13A, and TEX13B are spermatogonially-expressed, germ-cell-specific genes.
Conclusion: This is the first clinical report of azoospermia with reciprocal X–autosome translocations on Xp22 and q22. These translocations on Xp22 and q22 may be direct genetic risk factors for azoospermia.
doi:10.1023/A:1025437329427
PMCID: PMC3455837  PMID: 14531651
Azoospermia; infertility; spermatogonia; translocation
13.  MeCP2: a novel Huntingtin interactor 
Human Molecular Genetics  2013;23(4):1036-1044.
Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Förster Resonance Energy Transfer approaches. Htt–MeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD.
doi:10.1093/hmg/ddt499
PMCID: PMC3900110  PMID: 24105466
14.  Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma 
Purpose
To elucidate the mechanistic basis for efficacy of intrathecal rituximab. We evaluated complement activation as well as the pharmacokinetics of intraventricular rituximab in patients who participated in two phase 1 multicenter studies.
Experimental Design
We evaluated complement activation as a candidate mediator of rituximab within the CNS. Complement C3 and C5b-9 were quantified by ELISA in serial CSF specimens after intraventricular rituximab administration. We determined rituximab concentration profiles in CSF and serum. A population three- compartment pharmacokinetic model was built to describe the disposition of rituximab following intraventricular administration. The model was derived from results of the first trial and validated with results of the second trial.
Results
Complement C3 and C5b-9 were reproducibly activated in CSF after intraventricular rituximab. Ectopic expression of C3 mRNA and protein within CNS lymphoma lesions was localized to myeloid cells. Constitutive high C3 activation at baseline was associated with adverse prognosis. A PK model was built which contains three distinct compartments to describe the distribution of rituximab within the neuroaxis after intraventricular administration.
Conclusions
We provide the first evidence of C3 activation within the neuroaxis with intraventricular immunotherapy and suggest that complement may contribute to immunotherapeutic responses of rituximab in CNS lymphoma. Penetration of rituximab into neural tissue is supported by this pharmacokinetic model and may contribute to efficacy. These findings have general implications for intraventricular immunotherapy. Our data highlight potential innovations to improve efficacy of intraventricular immunotherapy both via modulation of the innate immune response as well as innovations in drug delivery.
doi:10.1158/1078-0432.CCR-13-0474
PMCID: PMC3944388  PMID: 24190981
Complement; Immunotherapy; Non-Hodgkin’s Lymphoma; Rituximab; Pharmacokinetics
15.  Controlling Mechanical Properties of Cell-Laden Hydrogels by Covalent Incorporation of Graphene Oxide 
Graphene-based materials are useful reinforcing agents to modify the mechanical properties of hydrogels. Here, we present an approach to covalently incorporate graphene oxide (GO) into hydrogels via radical copolymerization to enhance the dispersion and conjugation of GO sheets within the hydrogels. GO is chemically modified to present surface-grafted methacrylate groups (MeGO). In comparison to GO, higher concentrations of MeGO can be stably dispersed in a pre-gel solution containing methacrylated gelatin (GelMA) without aggregation or significant increase in viscosity. In addition, the resulting MeGO-GelMA hydrogels demonstrate a significant increase in fracture strength with increasing MeGO concentration. Interestingly, the rigidity of the hydrogels is not significantly affected by the covalently incorporated GO. Therefore, our approach can be used to enhance the structural integrity and resistance to fracture of the hydrogels without inadvertently affecting their rigidity, which is known to affect the behavior of encapsulated cells. The biocompatibility of MeGO-GelMA hydrogels is confirmed by measuring the viability and proliferation of the encapsulated fibroblasts. Overall, this study highlights the advantage of covalently incorporating GO into a hydrogel system, and improves the quality of cell-laden hydrogels.
doi:10.1002/smll.201302182
PMCID: PMC3946390  PMID: 24127350
methacrylated graphene oxide (MeGO); methacrylated gelatin (GelMA); hydrogel; toughness; cell encapsulation
16.  Detection of Japanese Encephalitis Virus Genotype V in Culex orientalis and Culex pipiens (Diptera: Culicidae) in Korea 
PLoS ONE  2015;10(2):e0116547.
Japanese encephalitis virus (JEV) causes significant viral encephalitis and is distributed throughout the Asian countries. The virus is known to be transmitted by Culex tritaeniorhynchus, which mainly breeds in rice paddies in Korea. In this study, we investigated the presence of other mosquito species that can transmit JEV as a second or regional vector. We selected five cities where patients have experienced JE in the last 5 years as mosquito-collecting locations and subdivided them into four collection sites according to the mosquito habitats (cowshed, downtown area, forest, and swamp). Mosquitoes were caught using the BG-Sentinel trap, CDC black-light trap, Fay-Prince trap, and Gravid trap. A total of 993 pools from 22,774 mosquitoes were prepared according to their species, collection date, and site. We performed a SYBR Green 1-based real-time RT-PCR assay to detect JEV from the mosquito pools. A total of six JEV-positive pools were detected from Culex orientalis and Culex pipiens caught in the Gangwon-do and Gyeonngi-do provinces. All the detected JEVs were revealed as genotype V by phylogenetic analysis of the envelope gene. Our findings confirm that a new genotype of JEV was introduced in Korea and suggest that two mosquito species may play a role in JEV transmission.
doi:10.1371/journal.pone.0116547
PMCID: PMC4319795  PMID: 25658839
17.  EIF4EBP1 Overexpression Is Associated with Poor Survival and Disease Progression in Patients with Hepatocellular Carcinoma 
PLoS ONE  2015;10(2):e0117493.
Objective
EIF4EBP1 acts as a crucial effector in mTOR signaling pathway. Studies have suggested that EIF4EBP1 plays a critical role in carcinogenesis. However, the clinical significance and biological role of EIF4EBP1 in hepatocellular carcinoma (HCC) have not been elucidated. Therefore, we aimed to investigate the clinical significance of EIF4EBP1 in HCC.
Methods
Total 128 cases of HCCs were included in this study. EIF4EBP1 expression in HCC tissues was detected by qRT-PCR, Western blot and immunohistochemistry, respectively. Then the relationships between EIF4EBP1 expression and clinical features as well as survival were analyzed.
Results
The expression level of EIF4EBP1 mRNA is significantly higher in 60% (24/40) of fresh HCC tissues than that in the matched adjacent nontumor liver (NCL) tissues (P = 0.044). Similarly, EIF4EBP1 protein is notably upregulated in 8 HCC tissues (randomly selected from the 40 HCCs) measured by Western blot and is significantly increased in another 88 paraffin-embedded HCCs (53%, 47/88) by immunohistochemistry compared with the matched NCLs (P < 0.001). EIF4EBP1 protein expression in HCC tissues is significantly correlated with serum AFP (P = 0.003) and marginally significantly associated with pathological grade (P = 0.085), tumor number (P = 0.084), tumor embolus (P = 0.084) and capsulation (P = 0.073). Patients with higher EIF4EBP1 protein expression have a much worse 5-year overall survival (40.3% vs 73.6%) and 5-year disease-free survival (33.0% vs 49.0%) than those with low expression. Furthermore, Cox regression analysis shows that EIF4EBP1 protein is an independent prognostic factor for overall survival (HR, 2.285; 95% CI, 1.154–4.527; P = 0.018) and disease-free survival (HR, 1.901; 95% CI, 1.067–3.386; P = 0.029) in HCC patients.
Conclusions
Our results demonstrate for the first time that EIF4EBP1 mRNA and protein are markedly up-regulated in HCC tissues, and the protein overexpression is significantly associated with poor survival and progression, which provide a potential new prognostic marker and therapeutic target for HCC patients.
doi:10.1371/journal.pone.0117493
PMCID: PMC4319970  PMID: 25658620
18.  Switch-Loop Flexibility Affects Transport of Large Drugs by the Promiscuous AcrB Multidrug Efflux Transporter 
Multidrug efflux transporters recognize a variety of structurally unrelated compounds for which the molecular basis is poorly understood. For the resistance nodulation and cell division (RND) inner membrane component AcrB of the AcrAB-TolC multidrug efflux system from Escherichia coli, drug binding occurs at the access and deep binding pockets. These two binding areas are separated by an 11-amino-acid-residue-containing switch loop whose conformational flexibility is speculated to be essential for drug binding and transport. A G616N substitution in the switch loop has a distinct and local effect on the orientation of the loop and on the ability to transport larger drugs. Here, we report a distinct phenotypical pattern of drug recognition and transport for the G616N variant, indicating that drug substrates with minimal projection areas of >70 Å2 are less well transported than other substrates.
doi:10.1128/AAC.02733-13
PMCID: PMC4136034  PMID: 24914123
19.  Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal 
Neurology  2014;82(4):317-325.
Objective:
To estimate rates of progression from mild cognitive impairment (MCI) to dementia and of reversion from MCI to being cognitively normal (CN) in a population-based cohort.
Methods:
Participants (n = 534, aged 70 years and older) enrolled in the prospective Mayo Clinic Study of Aging were evaluated at baseline and every 15 months to identify incident MCI or dementia.
Results:
Over a median follow-up of 5.1 years, 153 of 534 participants (28.7%) with prevalent or incident MCI progressed to dementia (71.3 per 1,000 person-years). The cumulative incidence of dementia was 5.4% at 1 year, 16.1% at 2, 23.4% at 3, 31.1% at 4, and 42.5% at 5 years. The risk of dementia was elevated in MCI cases (hazard ratio [HR] 23.2, p < 0.001) compared with CN subjects. Thirty-eight percent (n = 201) of MCI participants reverted to CN (175.0/1,000 person-years), but 65% subsequently developed MCI or dementia; the HR was 6.6 (p < 0.001) compared with CN subjects. The risk of reversion was reduced in subjects with an APOE ε4 allele (HR 0.53, p < 0.001), higher Clinical Dementia Rating Scale–Sum of Boxes (HR 0.56, p < 0.001), and poorer cognitive function (HR 0.56, p < 0.001). The risk was also reduced in subjects with amnestic MCI (HR 0.70, p = 0.02) and multidomain MCI (HR 0.61, p = 0.003).
Conclusions:
MCI cases, including those who revert to CN, have a high risk of progressing to dementia. This suggests that diagnosis of MCI at any time has prognostic value.
doi:10.1212/WNL.0000000000000055
PMCID: PMC3929198  PMID: 24353333
20.  The systematic study of circulating tumor cell isolation using lithographic microfilters† 
RSC advances  2014;9:4334-4342.
Circulating tumor cells (CTCs) disseminated into peripheral blood from a primary, or metastatic, tumor can be used for early detection, diagnosis and monitoring of solid malignancies. CTC isolation by size exclusion techniques have long interested researchers as a simple broad based approach, which is methodologically diverse for use in both genomic and protein detection platforms. Though a variety of these microfiltration systems are employed academically and commercially, the limited ability to easily alter microfilter designs has hindered the optimization for CTC capture. To overcome this problem, we studied a unique photo-definable material with a scalable and mass producible photolithographic fabrication method. We use this fabrication method to systematically study and optimize the parameters necessary for CTC isolation using a microfiltration approach, followed by a comparison to a “standard” filtration membrane. We demonstrate that properly designed microfilters can capture MCF-7 cancer cells at rate of 98 ± 2% if they consist of uniform patterned distributions, ≥160 000 pores, and 7 μm pore diameters.
doi:10.1039/C3RA46839A
PMCID: PMC4299665  PMID: 25614802
21.  Revealing Cell-Surface Intramolecular Interactions in the BlaR1 Protein of Methicillin-Resistant Staphylococcus aureus by NMR Spectroscopy 
Biochemistry  2013;53(1):10-12.
In methicillin-resistant Staphylococcus aureus, β-lactam antibiotic resistance is mediated by the transmembrane protein BlaR1. The antibiotic-sensor domain BlaRS and the L2 loop of BlaR1 are on the membrane surface. We used NMR to investigate interactions between BlaRS and a water-soluble peptide from L2. This peptide binds BlaRS proximal to the antibiotic acylation site as an amphipathic helix. BlaRS acylation by penicillin G does not disrupt binding. These results suggest a signal transduction mechanism whereby the L2 helix, partially embedded in the membrane, propagates conformational changes caused by BlaRS acylation through the membrane via transmembrane segments, leading to antibiotic resistance.
doi:10.1021/bi401552j
PMCID: PMC3939675  PMID: 24359467
22.  Microfluidics-Assisted Fabrication of Gelatin-Silica Core-Shell Microgels for Injectable Tissue Constructs 
Biomacromolecules  2014;15(1):283-290.
Microfabrication technology provides a highly versatile platform for engineering hydrogels used in biomedical applications with high-resolution control and injectability. Herein, we present a strategy of microfluidics-assisted fabrication photocrosslinkable gelatin microgels, coupled with providing protective silica hydrogel layer on the microgel surface to ultimately generate gelatin-silica core-shell microgels for applications as in vitro cell culture platform and injectable tissue constructs. A microfluidic device having flow-focusing channel geometry was utilized to generate droplets containing methacrylated gelatin (GelMA), followed by a photocrosslinking step to synthesize GelMA microgels. The size of the microgels could easily be controlled by varying the ratio of flow rates of aqueous and oil phases. Then, the GelMA microgels were used as in vitro cell culture platform to grow cardiac side population cells on the microgel surface. The cells readily adhered on the microgel surface and proliferated over time while maintaining high viability (~90%). The cells on the microgels were also able to migrate to their surrounding area. In addition, the microgels eventually degraded over time. These results demonstrate that cell-seeded GelMA microgels have a great potential as injectable tissue constructs. Furthermore, we demonstrated that coating the cells on GelMA microgels with biocompatible and biodegradable silica hydrogels via sol-gel method provided significant protection against oxidative stress which is often encountered during and after injection into host tissues, and detrimental to the cells. Overall, the microfluidic approach to generate cell-adhesive microgel core, coupled with silica hydrogels as a protective shell, will be highly useful as a cell culture platform to generate a wide range of injectable tissue constructs.
doi:10.1021/bm401533y
PMCID: PMC3922064  PMID: 24344625
23.  Treatment outcomes of extended-field radiation therapy and the effect of concurrent chemotherapy on uterine cervical cancer with para-aortic lymph node metastasis 
Purpose
To review the clinical outcomes of extended-field radiation therapy (EFRT) and to analyze prognostic factors significant for survival in patients receiving EFRT for uterine cervical carcinoma with para-aortic node (PAN) metastasis.
Patients and methods
We retrospectively reviewed 90 patients with stage IB-IVA cervical cancer and PAN metastasis between 1987 and 2012. Median age was 50 (range, 24–77). Patients received median 70.2 Gy (range, 56–93) to point A and median 50.4 Gy (range, 45–60.4) to PAN over median 69 elapsed days (range, 43–182). Forty-six patients (51.1%) received concurrent chemotherapy. Survival was calculated using the Kaplan–Meier method. We analyzed prognostic factors for overall actuarial survival (OS) and progression-free survival (PFS) using a Cox regression method.
Results
The median follow-up period for surviving patients was 55 months (range, 3–252). Seventy patients (77.8%) had complete remission. Forty-six patients experienced treatment failure as follows: 11 patients (12.2%) as local recurrence, 19 (21%) as regional recurrence and 33 (36.7%) as distant metastasis. The 5-yr OS and PFS were 62.6% and 43.9%, respectively. Treatment response was the only statistically independent prognostic factors for OS (p= 0.04) and PFS (p< 0.001) on multivariate analysis. Grade 3 or 4 hematologic gastrointestinal and urogenital toxicities were observed in about 10% of patients.
Conclusions
Our institutional experiences showed that EFRT was an effective treatment for cervical cancer patients with PAN metastasis. The addition of chemotherapy to EFRT seems to have uncertain survival benefit with higher hematologic toxicity.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0320-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13014-014-0320-5
PMCID: PMC4311470  PMID: 25582425
Cervical cancer; Treatment outcome; Chemotherapy; Para-aortic lymph node; Extended-field radiation therapy
24.  Identification of Intermediate- to High-Risk Papillary Thyroid Carcinoma Patients Who May Be Safely Managed without the Performance of Delayed Stimulated Thyroglobulin Measurements following Total Thyroidectomy and Radioactive Iodine Therapy 
Background. The measurement of stimulated thyroglobulin (sTg) after total thyroidectomy and remnant radioactive iodine (RAI) ablation is the gold standard for monitoring disease status in patients with papillary thyroid carcinomas (PTCs). The aim of this study was to determine whether sTg measurement during follow-up can be avoided in intermediate- and high-risk PTC patients. Methods. A total of 346 patients with PTCs with an intermediate or high risk of recurrence were analysed. All of the patients underwent total thyroidectomy as well as remnant RAI ablation and sTg measurements. Preoperative and postoperative parameters were included in the analysis. Results. Among the preoperative parameters, age below 45 years and preoperative Tg above 19.4 ng/mL were significant risk factors for predicting detectable sTg during follow-up. Among the postoperative parameters, thyroid capsular invasion, lymph node metastasis, and ablative Tg above 2.9 ng/mL were independently correlated with a detectable sTg range. The combination of ablative Tg less than 2.9 ng/mL with pre- and postoperative independent risk factors for detectable sTg increased the negative predictive value for detectable sTg up to 98.5%. Conclusions. Based on pre- and postoperative parameters, a substantial proportion of patients with PTCs in the intermediate- and high-risk classes could avoid aggressive follow-up measures.
doi:10.1155/2015/318916
PMCID: PMC4306371  PMID: 25649811
25.  25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine 
Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life.
doi:10.1002/adma.201303233
PMCID: PMC3925010  PMID: 24741694

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