Search tips
Search criteria

Results 1-25 (543)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  A New Anti-c-Met Antibody Selected by a Mechanism-Based Dual-Screening Method: Therapeutic Potential in Cancer 
Molecules and Cells  2012;34(6):523-529.
c-Met, the high affinity receptor for hepatocyte growth factor (HGF), is one of the most frequently activated tyrosine kinases in many human cancers and a target for cancer therapy. However, inhibitory targeting of c-Met with antibodies has proven difficult, because most antibodies have intrinsic agonist activity. Therefore, the strategy for reducing the agonism is critical for successful development of cancer therapies based on anti-c-Met antibodies. Here we developed a mechanism-based assay method for rapid screening of anti-c-Met antibodies, involving the determination of Akt phosphorylation and c-Met degradation for agonism and efficacy, respectively. Using the method, we identified an antibody, F46, that binds to human c-Met with high affinity (Kd = 2.56 nM) and specificity, and induces the degradation of c-Met in multiple cancer cells (including MKN45, a gastric cancer cell line) with minimal activation of c-Met signaling. F46 induced c-Met internalization in both HGF-dependent and HGF-independent cells, suggesting that the degradation of c-Met results from antibody-mediated receptor internalization. Further-more, F46 competed with HGF for binding to c-Met, resulting in the inhibition of both HGF-mediated invasion and angiogenesis. Consistently, F46 inhibited the proliferation of MKN45 cells, in which c-Met is constitutively activated in an HGF-independent manner. Xenograft analysis revealed that F46 markedly inhibits the growth of subcutaneously implanted gastric and lung tumors. These results indicate that F46, identified by a novel mechanism-based assay, induces c-Met degradation with minimal agonism, implicating a potential role of F46 in therapy of human cancers.
PMCID: PMC3887825  PMID: 23180291
Akt; anti-c-Met antibody; cancer therapy; c-Met; HGF
3.  Left Atrial Wall Dissection after Mitral Valve Replacement 
Left atrial dissection does occur, though rarely, after mitral valve surgery. A 68-year-old Korean female presented with moderate mitral stenosis, mild mitral regurgitation, moderate tricuspid regurgitation and mild aortic regurgitation. She was scheduled for mitral valve replacement and tricuspid annuloplasty. We experienced a left atrial dissection after weaning from cardiopulmonary bypass and decided not to repair it. The patient recovered uneventfully. We suggest that a specific type of left atrial dissection can be treated conservatively.
PMCID: PMC3816166  PMID: 24198922
Atrium; Dissection; Mitral valve
4.  Interruption of bispectral index monitoring by nerve integrity monitoring during tympanoplasty -A case report- 
Korean Journal of Anesthesiology  2013;64(2):161-163.
We report that intraoperative NIM-2 monitoring devices can interfere with bispectral index monitoring. A 45-year-old male with chronic otits media underwent tympanolasty under general anesthesia with NIM-2 monitoring and bispectral index monitoring at our institution. And then, bispectral index monitoring was severely interrupted by facial nerve monitoring.
PMCID: PMC3581786  PMID: 23459709
Bispectral index monitor; Facial nerve; Intraoperative monitoring; Tympanoplasy
5.  Subaortic Membrane Late after Surgical Correction of Tetralogy of Fallot 
We herein report a rare case of subaortic stenosis in association with a previous tetralogy of Fallot (TOF) surgical repair, which was not taken into account as a differential diagnosis. Echocardiography plays a pivotal role in identification of this rare combination. Therefore, echocardiography should be performed periodically during follow-up of patients with surgically corrected TOF. Given the clinical complications that can result from subaortic stenosis (i.e., aortic regurgitation and infective endocarditis), early and aggressive management of this rare combination should be performed.
PMCID: PMC3529246  PMID: 23269888
Tetralogy of Fallot; Ventricular outflow obstruction; Echocardiography
6.  Subarachnoid Hemorrhage Mimicking Leakage of Contrast Media After Coronary Angiography 
Korean Circulation Journal  2012;42(3):197-200.
We report a patient who developed subarachnoid hemorrhage (SAH) just after coronary angiography (CAG) with non-ionic contrast media (CM) and minimal dose of heparin. The 55-year-old man had a history of acute ST elevation myocardial infarction that had been treated with primary percutaneous coronary intervention and was admitted for a follow-up CAG. The CAG was performed by the transradial approach, using 1000 U of unfractionated heparin for the luminal coating and 70 mL of iodixanol. At the end of CAG, he complained of nausea and rapidly became stuporous. Brain CT showed a diffusely increased Hounsfield unit (HU) in the cisternal space, similar to leakage of CM. The maximal HU was 65 in the cisternal space. No vascular malformations were detected on cerebral angiography. The patient partially recovered his mental status and motor weakness after 2 days. Two weeks later, subacute SAH was evident on magnetic resonance imaging. The patient was discharged after 28 days.
PMCID: PMC3318092  PMID: 22493615
Subarachnoid hemorrhage; Iodixanol; Coronary angiography
7.  Non-Viral Gene Delivery via Membrane-Penetrating, Mannose-Targeting Supramolecular Self-Assembled Nanocomplexes 
PMCID: PMC3757134  PMID: 23417835
Non-Viral Gene Delivery; Supramolecular Self-Assembly; Mannose Targeting; Cell Penetrating Peptides
8.  Clinical Effect of Surgical Correction for Nasal Pathology on the Treatment of Obstructive Sleep Apnea Syndrome 
PLoS ONE  2014;9(6):e98765.
This study aimed to evaluate the hypothesis that relief of nasal obstruction in subjects with obstructive sleep apnea (OSA) would lead to reduce OSA severity and to discuss the available evidence on the clinical efficacy of nasal surgery as a treatment modality for OSA.
Study Design
Twenty-five subjects who had reduced patency of nasal cavity and narrowing of retroglossal or retropalatal airways were diagnosed with OSA and underwent nasal surgery, such as septoplasty or turbinoplasty to correct nasal pathologies. The effect of the surgery on nasal patency was quantified by measuring minimal cross-sectional area (MCA) using acoustic rhinometry. The watch-PAT-derived respiratory disturbance index (RDI), apnea and hypopnea index (AHI), lowest oxygen saturation, and valid sleep time were measured before and after nasal surgery.
The present study shows that the AHI and RDI decreased significantly and the lowest oxygen saturation and valid sleep time rose after nasal surgery in 25 OSA subjects. In addition, a reduction in subjective symptoms was observed in subjects and mean MCA increased after nasal surgery. Fourteen subjects were classified as responders and 11 subjects as non-responders. Responders showed considerable improvement of their subjective symptoms and the AHI and RDI were significantly lower after surgery. We found that the changes between pre- and post-operative AHI and RDI values were minimal in 11 non-responders. However, daytime somnolence and REM sleep time improved after nasal surgery in non-responders.
Our study provides evidence that the surgical treatment of nasal pathology improves nasal airway patency and reduces OSA severity in 56% subjects. Furthermore, correction of nasal pathology appears to result in improved sleep quality in both responder and non-responders OSA subjects.
PMCID: PMC4045850  PMID: 24896824
9.  Chromatin CKAP2, a New Proliferation Marker, as Independent Prognostic Indicator in Breast Cancer 
PLoS ONE  2014;9(6):e98160.
The level of proliferation activity is a strong prognostic or predictive indicator in breast cancer, but its optimal measurement is still in debate, necessitating new proliferation markers. In the present study, the prognostic significance of the CKAP2-positive cell count (CPCC), a new proliferation marker, was evaluated, and the results were compared with those for the mitotic activity index (MAI).
This study included 375 early-stage breast cancer samples collected from two institutions between 2000 and 2006. Immunohistochemical staining was performed using a CKAP2 monoclonal antibody. Cox proportional hazard regression models were fitted to determine the association between the CPCC and relapse-free survival (RFS) amongst three groups formed on the basis of the CPCC or MAI value: groups 2 and 3 showing the middle and highest values, respectively, and group 1 the lowest.
After adjustment for age, T stage, N stage, HER2 status, estrogen receptor status, progesterone receptor status, institution, and year of surgical resection, the CPCC was associated with a significantly worse RFS {hazard ratio [HR]  = 4.10 (95% CI: 1.64–10.29) for group 2; HR  = 4.35 (95% CI: 2.04–10.35) for group 3}. Moreover, its prognostic significance was similar to or higher than that based on the MAI {HR  = 2.05 (95% CI: 0.94–4.65) for group 2; HR  = 2.35 (95% CI: 1.09–5.10) for group 3}. In subgroup analyses, the CPCC showed a prognostic significance in the luminal A and triple-negative subgroups, but not in the HER2-positive subgroup.
Chromatin CKAP2 is an independent prognostic marker for RFS in early-stage breast cancer, and could potentially replace the MAI in clinical evaluation of proliferation activity. Additionally, our study results suggest that the prognostic significance of proliferation activity differs among the various subgroups of breast cancer.
PMCID: PMC4041571  PMID: 24887265
10.  Clinical Demographics and Outcomes in Mechanically Ventilated Patients in Korean Intensive Care Units 
Journal of Korean Medical Science  2014;29(6):864-870.
Knowledge of clinical demographics and outcomes of mechanically ventilated patients is important but there are few prospectively collected data in Korea. The objective of the present study was to describe the current status of mechanically ventilated patients in Korea as of 2010. We analyzed the data of Korean patients (275 patients in 12 Korean intensive care units [ICU]) participating in a multinational prospective cohort study on mechanical ventilation. The most common indication for mechanical ventilation was pneumonia (23%). Pressure-limited ventilation modes were preferred over volume-cycled ventilation modes. Non-invasive positive pressure ventilation was used in only seven (2%) patients as the initial ventilatory support. Median duration of mechanical ventilation was 7 days and ICU mortality was 36%. The multiple logistic regression model revealed that the Simplified Acute Physiology Score II (SAPS II) score at ICU admission (odds ratio [OR], 1.034; 95% confidence interval [CI], 1.001-1.036; P=0.033), peak pressure (OR, 1.054; 95% CI, 1.016-1.095; P=0.006), and the number of failed organs (OR, 2.132; 95% CI, 1.634-2.781; P<0.001) were independently associated with ICU mortality. This study provides a snapshot of current practice of mechanical ventilation in Korea.
Graphical Abstract
PMCID: PMC4055823  PMID: 24932091
Respiration, Artificial; Epidemiology; Data collection; Outcome; Korea
11.  Supramolecular self-assembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation 
PMCID: PMC3800743  PMID: 23610013
oral siRNA delivery; TNF-α; inflammation; supramolecular self-assembly; multi-function
12.  Additive Effect between IL-13 Polymorphism and Cesarean Section Delivery/Prenatal Antibiotics Use on Atopic Dermatitis: A Birth Cohort Study (COCOA) 
PLoS ONE  2014;9(5):e96603.
Although cesarean delivery and prenatal exposure to antibiotics are likely to affect the gut microbiome in infancy, their effect on the development of atopic dermatitis (AD) in infancy is unclear. The influence of individual genotypes on these relationships is also unclear. To evaluate with a prospective birth cohort study whether cesarean section, prenatal exposure to antibiotics, and susceptible genotypes act additively to promote the development of AD in infancy.
The Cohort for Childhood of Asthma and Allergic Diseases (COCOA) was selected from the general Korean population. A pediatric allergist assessed 412 infants for the presence of AD at 1 year of age. Their cord blood DNA was subjected to interleukin (IL)-13 (rs20541) and cluster-of-differentiation (CD)14 (rs2569190) genotype analysis.
The combination of cesarean delivery and prenatal exposure to antibiotics associated significantly and positively with AD (adjusted odds ratio, 5.70; 95% CI, 1.19–27.3). The association between cesarean delivery and AD was significantly modified by parental history of allergic diseases or risk-associated IL-13 (rs20541) and CD14 (rs2569190) genotypes. There was a trend of interaction between IL-13 (rs20541) and delivery mode with respect to the subsequent risk of AD. (P for interaction = 0.039) Infants who were exposed prenatally to antibiotics and were born by cesarean delivery had a lower total microbiota diversity in stool samples at 6 months of age than the control group. As the number of these risk factors increased, the AD risk rose (trend p<0.05).
Cesarean delivery and prenatal antibiotic exposure may affect the gut microbiota, which may in turn influence the risk of AD in infants. These relationships may be shaped by the genetic predisposition.
PMCID: PMC4029558  PMID: 24848505
13.  USP8 modulates ubiquitination of LRIG1 for Met degradation 
Scientific Reports  2014;4:4980.
The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301.
PMCID: PMC4021411  PMID: 24828152
14.  Minimally Invasive Transforaminal Lumbar Interbody Fusion with Unilateral Pedicle Screw Fixation: Comparison between Primary and Revision Surgery 
BioMed Research International  2014;2014:919248.
Minimally invasive surgery with a transforaminal lumbar interbody fusion (MIS TLIF) is an important minimally invasive fusion technique for the lumbar spine. Lumbar spine reoperation is challenging and is thought to have greater complication risks. The purpose of this study was to compare MIS TLIF with unilateral screw fixation perioperative results between primary and revision surgeries. This was a prospective study that included 46 patients who underwent MIS TLIF with unilateral pedicle screw. The patients were divided into two groups, primary and revision MIS TLIF, to compare perioperative results and complications. The two groups were similar in age, sex, and level of operation, and were not significantly different in the length of follow-up or clinical results. Although dural tears were more common with the revision group (primary 1; revision 4), operation time, blood loss, total perioperative complication, and fusion rates were not significantly different between the two groups. Both groups showed substantial improvements in VAS and ODI scores one year after surgical treatment. Revision MIS TLIF performed by an experienced surgeon does not necessarily increase the risk of perioperative complication compared with primary surgery. MIS TLIF with unilateral pedicle screw fixation is a valuable option for revision lumbar surgery.
PMCID: PMC4053265  PMID: 24949483
15.  School Choice and Educational Inequality in South Korea 
Journal of school choice  2012;6(2):158-183.
This study examined the choice debate in South Korea, which centers on the residentially based school assignment policy called the High School Equalization Policy (HSEP). Using a nationally representative sample of South Korean 11th graders, the study further explored the role of the HSEP in educational equality by investigating how HSEP implementation was related to the separation of low and high socioeconomic status (SES) students between schools and how the socioeconomic composition of a school was related to student achievement. Results showed that the odds that low SES students were separated into low SES schools was smaller in the regions of HSEP implementation, where students were randomly assigned to a school based on place of residence, than in the regions of non-HSEP implementation, where students were allowed to choose a school. Results also showed that student achievement significantly depended on the socioeconomic composition of a school students attended in the regions of non-HSEP implementation, whereas this was not the case in the regions of HSEP implementation. We discussed the implications of these findings for the potential impact of school choice policies on educational inequality.
PMCID: PMC4019447  PMID: 24834021
16.  Fasting serum insulin levels and insulin resistance are associated with colorectal adenoma in Koreans 
Insulin has been associated with the risk of colorectal cancer (CRC). However, few studies have evaluated the association between insulin and colorectal adenoma. We investigated the relationship between fasting serum insulin levels or homeostasis model assessment of insulin resistance (HOMA‐IR) and colorectal adenoma.
Materials and Methods
We retrospectively enrolled 15,427 participants who underwent both fasting serum insulin measurement and colonoscopy for a routine health examination at Asan Medical Center from January 2007 to December 2008. Participants with a history of any cancer, previous colectomy or polypectomy, those taking antidiabetic medications, and inflammatory bowel disease, non‐specific colitis, non‐adenomatous polyps only or CRC on colonoscopic findings were excluded. Finally, 3,606 participants with histologically confirmed colorectal adenoma and 6,019 controls with no abnormal findings on colonoscopy were included. Participants were categorized into quartiles (Q) based on fasting serum insulin levels and HOMA‐IR.
Fasting serum insulin and HOMA‐IR were significantly higher in participants with colorectal adenomas compared with controls. Multivariate regression analysis adjusting for age, sex, smoking habits, drinking habits and family history of CRC showed that participants with higher quartiles of fasting serum insulin levels (odd ratio [OR] 1.17 for 2nd Q, 1.19 for 3rd Q, and 1.42 for 4th Q, P < 0.05) or HOMA‐IR (OR 1.18 for 2nd Q and 1.45 for 4th Q, P < 0.05) showed significantly increased ORs of colorectal adenoma compared with the lowest quartiles.
These findings showed that increased serum insulin levels and insulin resistance were significantly associated with the presence of colorectal adenoma.
PMCID: PMC4020334  PMID: 24843778
Insulin; Insulin resistance; Colorectal adenoma
17.  From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes 
Natural product reports  2013;30(5):600-604.
The initial enthusiasm following the discovery of a pharmacologically active natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin’s pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of carfilzomib (Kyprolis™), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.
PMCID: PMC3815659  PMID: 23575525
18.  High-flexion Prosthesis Improves Function of TKA in Asian Patients Without Decreasing Early Survivorship 
Two previous studies recently raised the possibility of a high risk of early femoral components loosening with high-flexion (HF) prostheses in Asian populations and suggested that the high failure rate of HF TKAs was associated with HF ability. However, these findings are controversial given other studies reporting a low incidence of aseptic failures in HF prostheses.
We therefore determined (1) the rate of achieving postoperative HF after HF TKA; (2) whether the aseptic loosening rate of HF prostheses is high; and (3) whether the survivorship was worsened in patients who achieved postoperative deep knee flexion in our cohort of Korean patients.
We retrospectively reviewed 488 patients who had 698 primary TKAs using the NexGen® Legacy Posterior-Stabilized Flex system implanted from 2003 to 2010. There were 40 men and 448 women with a mean age of 68 years. We obtained Hospital for Special Surgery scores, maximal flexion, and radiographs. The minimum followup for functional and radiographic evaluations was 2 years (median, 4.8 years; range, 2–8.7 years). We performed a survival analysis on all patients for aseptic loosening.
Three hundred sixty knees (52%) could achieve ≥ 135° maximum flexion. Six of the 698 knees (0.9%) developed aseptic loosening (three femoral and three tibial). The survival at 5 years for aseptic loosening was 99.1%. The overall survival for aseptic failure did not differ between knees that achieved HF and those that did not.
We observed a low incidence of early aseptic loosening of HF designs in this series. Our findings suggest HF TKAs have high survival in Asian patients at 5 years although half of the patients attained maximum flexion more than 135° postoperatively.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3613537  PMID: 23104044
19.  What are the associative factors of adjacent segment degeneration after anterior cervical spine surgery? Comparative study between anterior cervical fusion and arthroplasty with 5-year follow-up MRI and CT 
European Spine Journal  2012;22(5):1078-1089.
It is well known that arthrodesis is associated with adjacent segment degeneration (ASD). However, previous studies were performed with simple radiography or CT. MRI is most sensitive in assessing the degenerative change of a disc, and this is the first study about ASD by radiography, CT and MRI. We sought to factors related to ASD at cervical spine by an MRI and CT, after anterior cervical spine surgery.
Materials and methods
This is a retrospective cross-sectional study of cervical disc herniation. Patients of cervical disc herniation with only radiculopathy were treated with either arthroplasty (22 patients) or ACDF with cage alone (21 patients). These patients were required to undergo MRI, CT and radiography preoperatively, as well as radiography follow-up for 3 months and 1 year, and we conducted a cross-sectional study by MRI, CT and radiography including clinical evaluations 5 years after. Clinical outcomes were assessed using VAS and NDI. The fusion rate and ASD rate, and radiologic parameters (cervical lordosis, operated segmental height, C2-7 ROM, operated segmental ROM, upper segmental ROM and lower segmental ROM) were measured.
The study groups were demographically similar, and substantial improvements in VAS (for arm) and NDI (for neck) scores were noted, and there were no significant differences between groups. Fusion rates were 95.2 % in the fusion group and 4.5 % in the arthroplasty group. ASD rates of the fusion and arthroplasty groups were 42.9 and 50 %, respectively. Among the radiologic parameters, operated segmental height and operated segmental ROM significantly decreased, while the upper segmental ROM significantly increased in the fusion group. In a comparative study between patients with ASD and without ASD, the clinical results were found to be similar, although preexisting ASD and other segment degeneration were significantly higher in the ASD group. C2-7 ROM was significantly decreased in ASD group, and other radiologic parameters have no significant differences between groups.
The ASD rate of 46.5 % after ACDF or arthroplasty, and arthroplasty did not significantly lower the rate of ASD. ASD occurred in patients who had preexisting ASD and in patients who also had other segment degeneration. ASD may be associated with a natural history of cervical spondylosis rather than arthrodesis.
PMCID: PMC3657045  PMID: 23242622
Adjacent segment degeneration; ACDF; Arthroplasty; Spondylosis
21.  Postpolypectomy Fever, a Rare Adverse Event of Polypectomy: Nested Case-Control Study 
Clinical Endoscopy  2014;47(3):236-241.
Although postpolypectomy fever (PPF) without colon perforation or hemorrhage is rare, its incidence and risk factors have not been investigated. The objective of this study was to analyze the incidence and risk factors for PPF among inpatients.
Seven patients with PPF were matched with 70 patients without PPF from a total of 3,444 patients who underwent colonoscopic polypectomy. The PPF incidence during index hospitalization after colonoscopy was calculated, and univariate and multivariate analyses were performed to calculate the adjusted odds ratios (ORs) for risk factors.
PPF without bleeding or perforation in the colon occurred in seven patients (0.2%). The median age was 58 years for cases and 61 years for controls. The median interval from polypectomy to occurrence of fever was 7 hours, and the median duration of fever was 9 hours. Polyp size >2 cm (adjusted OR, 1.08; 95% confidence interval [CI], 1.01 to 1.15; p=0.02) and hypertension (adjusted OR, 14.40; 95% CI, 1.23 to 180.87; p=0.03) were associated with a significantly increased risk of PPF. PPF increased the length of hospitalization.
Although the crude incidence of PPF is low, PPF may prolong hospitalization. Risk factors for PPF include hypertension and large polyps.
PMCID: PMC4058541  PMID: 24944987
Postpolypectomy syndrome; Colonoscopic polypectomy
22.  The distribution and impact of viral lineages in domains of life 
PMCID: PMC4012193  PMID: 24817866
viruses; evolution; replicon; capsids; virion morphotype; diversity; domains of life
23.  Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition 
World Journal of Hepatology  2014;6(4):207-216.
Liver injuries are repaired by fibrosis and regeneration. The cause of fibrosis and diminished regeneration, especially in liver cirrhosis, is still unknown. Epithelial-mesenchymal transition (EMT) has been found to be associated with liver fibrosis. The possibility that EMT could contribute to hepatic fibrogenesis reinforced the concept that activated hepatic stellate cells are not the only key players in the hepatic fibrogenic process and that other cell types, either hepatic or bone marrow-derived cells could contribute to this process. Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis, more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders. The debate on the authenticity of EMT or on its contribution to the fibrogenic process has become very animated. The overall result is a general confusion on the meaning and on the definition of several key aspects. The aim of this article is to describe how EMT participates to hepatic fibrosis and discuss the evidence of supporting this possibility in order to reach reasonable and useful conclusions.
PMCID: PMC4009476  PMID: 24799989
Epithelial-mesenchymal transition; Liver; Fibrosis; Transforming growth factor-beta1; Biological markers
24.  Conformational Substates of Myoglobin Intermediate Resolved by Picosecond X-ray Solution Scattering 
Conformational substates of proteins are generally considered to play important roles in regulating protein functions, but an understanding of how they influence the structural dynamics and functions of the proteins has been elusive. Here, we investigate the structural dynamics of sperm whale myoglobin associated with the conformational substates using picosecond X-ray solution scattering. By applying kinetic analysis considering all of the plausible candidate models, we establish a kinetic model for the entire cycle of the protein transition in a wide time range from 100 ps to 10 ms. Four structurally distinct intermediates are formed during the cycle, and most importantly, the transition from the first intermediate to the second one (B → C) occurs biphasically. We attribute the biphasic kinetics to the involvement of two conformational substates of the first intermediate, which are generated by the interplay between the distal histidine and the photodissociated CO.
Biophysical Chemistry and Biomolecules
PMCID: PMC3985870  PMID: 24761190
25.  Computational Design of Binding Proteins to EGFR Domain II 
PLoS ONE  2014;9(4):e92513.
We developed a process to produce novel interactions between two previously unrelated proteins. This process selects protein scaffolds and designs protein interfaces that bind to a surface patch of interest on a target protein. Scaffolds with shapes complementary to the target surface patch were screened using an exhaustive computational search of the human proteome and optimized by directed evolution using phage display. This method was applied to successfully design scaffolds that bind to epidermal growth factor receptor (EGFR) domain II, the interface of EGFR dimerization, with high reactivity toward the target surface patch of EGFR domain II. One potential application of these tailor-made protein interactions is the development of therapeutic agents against specific protein targets.
PMCID: PMC3977815  PMID: 24710267

Results 1-25 (543)