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1.  A Case of Organizing Pneumonia Associated with FOLFIRI Chemotherapy 
The combination chemotherapy of irinotecan with 5-fluorouracil and leucovorin (FOLFIRI regimen) was recently proven to be beneficial in patients with advanced colorectal cancer. Pulmonary toxicity is very rare in adverse effects of irinotecan. No case of organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia) associated with FOLFIRI chemotherapy has been reported. We experienced a case of a 62-year-old man who presented persistent dry cough and progressive dyspnea after receiving chemotherapy with FOLFIRI regimen. After surgical lung biopsy, the patient was diagnosed with FOLFIRI chemotherapy-induced organizing pneumonia which was successfully treated with steroid therapy.
PMCID: PMC4286784  PMID: 25580143
Irinotecan; IFL Protocol; Cryptogenic Organizing Pneumonia; Colorectal Neoplasmsoxaliplatin
2.  Cancer of the supernumerary ovary in Mayer-Rokitansty-Küster-Hauser Syndrome: A case report 
Oncology Letters  2012;5(2):598-600.
Mayer-Rokitansty-Küster-Hauser (MRKH) syndrome is a Müllerian anomaly that presents with varying degrees of uterovaginal aplasia and is secondarily associated with cervicothoracic, auditory and skeletal anomalies. However, MRKH syndrome patients have normal and functional ovaries. A supernumerary ovary is an extremely rare form of an ectopic ovary and there are no reported cases of MRKH syndrome with cancer of the supernumerary ovary in the current literature. A 31-year-old female with a history of MRKH syndrome that was diagnosed 4 years previously presented with abdominal pain and a suspected malignant pelvic mass was identified. During the staging surgery, both ovaries were separated from the main mass, observed and removed. A third ovary was discovered in the pelvic mass and the diagnosis of primary ovarian cancer from the third ovary was confirmed by immunohistochemistry. We report the first known case of cancer of the supernumerary ovary in a patient with MRKH syndrome. Although both ovaries were confirmed to be normal in the patient with MRKH syndrome, we propose that an ovarian neoplasm should be considered in the diagnosis of a pelvic mass.
PMCID: PMC3573030  PMID: 23420814
Mayer-Rokitansty-Küster-Hauser syndrome; supernumerary ovary; ovarian cancer; pelvic mass; amenorrhea
3.  Predominance of Community-Associated Methicillin-Resistant Staphylococcus aureus Strains Carrying Staphylococcal Chromosome Cassette mec Type IVA in South Korea▿  
Journal of Clinical Microbiology  2007;45(12):4021-4026.
Studies on the molecular epidemiologic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains have demonstrated their genetic and geographical diversity. In addition, it has been reported that there are genetic differences between community-associated (CA) and health care-associated (HA) MRSA strains. Therefore, we investigated the major epidemiologic characteristics of CA MRSA isolates in South Korea and compared them with those of HA MRSA strains. Distributions of staphylococcal chromosome cassette mec (SCCmec) types and other molecular features, including the Panton-Valentine leukocidin (PVL) gene, were studied in 138 invasive MRSA isolates. Multiplex type IVA SCCmec was identified as the major CA MRSA infection type (53.1%), with a significantly higher prevalence than in HA MRSA (P < 0.001). One major group of type IVA strains carried a larger atypical class B mec element and new subtypes of ccrA2 (96% amino acid homology). The PVL gene was detected in one USA300-like isolate only. Seven major clone types determined by combinational grouping (genetic background SCCmec typing) showed representative patterns of antimicrobial susceptibilities. We concluded that less multi-drug-resistant strains of clone types B-I and D-1 (genetic background, B and D complexes; type IVA SCCmec) predominate in CA MRSA and that international PVL-positive strains have not spread in South Korea as yet.
PMCID: PMC2168574  PMID: 17942660
4.  Ovarian mature cystic teratoma containing homunculus: a case report. 
Journal of Korean Medical Science  2003;18(6):905-907.
We report a partial fetus-like structure (homunculus) in benign ovarian mature cystic teratoma removed from a 23-yr-old female. The cyst displayed various tissues derived from the three germ layers. The homunculus had a distinguished fetal cranial structure with one upper extremity. A partially developed osteocartilagenous skeleton was identified in the cranial structure of the homunculus. Intracranial structures such as cerebral cortex, retinal pigment, and leptomeninges were extruded from the partially disrupted calvarium.
PMCID: PMC3055135  PMID: 14676454
5.  Radial intercalation is regulated by the Par complex and the microtubule-stabilizing protein CLAMP/Spef1 
The Journal of Cell Biology  2014;206(3):367-376.
During radial intercalation of epithelial cells, Par3 and aPKC promote the apical positioning of centrioles, whereas CLAMP stabilizes microtubules along the axis of migration.
The directed movement of cells is critical for numerous developmental and disease processes. A developmentally reiterated form of migration is radial intercalation; the process by which cells move in a direction orthogonal to the plane of the tissue from an inner layer to an outer layer. We use the radial intercalation of cells into the skin of Xenopus laevis embryos as a model to study directed cell migration within an epithelial tissue. We identify a novel function for both the microtubule-binding protein CLAMP and members of the microtubule-regulating Par complex during intercalation. Specifically, we show that Par3 and aPKC promote the apical positioning of centrioles, whereas CLAMP stabilizes microtubules along the axis of migration. We propose a model in which the Par complex defines the orientation of apical migration during intercalation and in which subcellular localization of CLAMP promotes the establishment of an axis of microtubule stability required for the active migration of cells into the outer epithelium.
PMCID: PMC4121976  PMID: 25070955
6.  Rapid Increase of Health Care Utilization and Cost due to Benign Prostatic Hyperplasia in Korean Men: Retrospective Population-based Analysis Using the Health Insurance Review and Assessment Service Data 
Journal of Korean Medical Science  2015;30(2):180-185.
Using the Korean public health insurance database, we analyzed patients diagnosed as benign prostatic hyperplasia (BPH) from 2004 to 2008. Age and year-specific amount and seasonal variation of hospital visits (HV), duration of treatment (DT), the total and per capita amount of insurance payment (TAIP, PCIP) were evaluated. A total of 12,088,995 HV were studied. Total HV increased 1.7 times and DT almost doubled in 2008 compared to those in 2004. HV, DT, and TAIP showed linearly increasing patterns year by year. In a time series analysis, HV increased in winter and demonstrated seasonality in a 12-month cycle. In a Poisson regression analysis, the annual variations of HV, DT, TAIP, and PCIP were different by age groups. In patients older than 40 yr, HV significantly increased 1.10-1.16 times compared to that of the previous year. DT markedly increased in their 60s and 80s patients. The rate of increase in PCIP was steeper in patients 50 yr and older than in the others.Health care utilization due to BPH was rapidly increasing in Korea and it was remarkable in the elderly population. Seasonal variation of HV demonstrated that health care utilization increased in winter.
Graphical Abstract
PMCID: PMC4310945  PMID: 25653490
Prostatic Hyperplasia; Epidemiology; Insurance Claim Review
7.  Household and area income levels are associated with smoking status in the Korean adult population 
BMC Public Health  2015;15:39.
Some previous studies have suggested that area-level characteristics have effects on smoking. The aim of this study was to evaluate the associations between household income and area income on smoking in Korean adults.
This study was based on the Korean Community Health Survey (KCHS) performed in South Korea, between September and November 2009. In total, 222,242 subjects (103,124 men and 119,118 women) were included in the analysis. Information on smoking status was collected using a standardized questionnaire. Income status was determined by monthly household income. Household income was categorized as: <1 million won; <2 million won; <3 million won; and ≥3 million won. Area-level income categorized as quartiles. Data were analyzed using multilevel regression models. The analysis was conducted separately urban and rural, by sex.
The lowest household income group had a higher risk of smoking than the highest household income group in both urban and rural areas for both men and women after adjusting for individual characteristics (urban men: odds ration [OR], 1.44; 95% confidence interval [CI], 1.36–1.53; rural men: OR, 1.33; 95% CI, 1.25–1.42; urban women: OR, 2.38; 95% CI, 2.06–2.76; rural women: OR, 1.51; 95% CI, 1.25–1.83). In men, the lowest area-level income group had a higher risk for smoking than the highest area-level income group in urban areas after adjusting for individual characteristics and household income (OR, 1.17; 95% CI, 1.02–1.33). In women, the lowest area-level income group had a lower risk for smoking than the highest area-level income group in rural areas after adjusting for individual characteristics and household income (OR, 0.52; 95% CI, 0.39–0.70). However, no association was observed between area-level income and smoking in rural areas for men or in urban areas for women.
The results showed that smoking is strongly associated with household income status in both men and women, and area-level income is partly associated with smoking. Effects of area-level income on smoking differed by sex and region. These findings suggest that area characteristics have contextual effects on health related behavior independent of individual characteristics.
PMCID: PMC4314795  PMID: 25636365
Smoking; Household income; Area-level income; Multilevel analysis
8.  Concepts and Definitions for “Actively Dying,” “End of Life,” “Terminally Ill,” “Terminal Care,” and “Transition of Care”: A Systematic Review 
The terms “actively dying,” “end of life,” “terminally ill,” “terminal care,” and “transition of care” are commonly used but rarely and inconsistently defined.
We conducted a systematic review to examine the concepts and definitions for these terms.
We searched MEDLINE, PsycINFO, Embase, and CINAHL for published peer-reviewed articles from 1948 to 2012 that conceptualized, defined, or examined these terms. Two researchers independently reviewed each citation for inclusion and then extracted the concepts/definitions when available. We also searched 10 dictionaries, four palliative care textbooks, and 13 organization Web sites, including the U.S. Federal Code.
One of 16, three of 134, three of 44, two of 93, and four of 17 articles defined or conceptualized actively dying, end of life, terminally ill, terminal care, and transition of care, respectively. Actively dying was defined as “hours or days of survival.” We identified two key defining features for end of life, terminally ill, and terminal care: life-limiting disease with irreversible decline and expected survival in terms of months or less. Transition of care was discussed in relation to changes in 1) place of care (e.g., hospital to home), 2) level of professions providing the care (e.g., acute care to hospice), and 3) goals of care (e.g., curative to palliative). Definitions for these five terms were rarely found in dictionaries, textbooks, and organizational Web sites. However, when available, the definitions were generally consistent with the concepts discussed previously.
We identified unifying concepts for five commonly used terms in palliative care and developed a preliminary conceptual framework toward building standardized definitions.
PMCID: PMC3870193  PMID: 23796586
Actively dying; end of life; systematic review; terminal care; terminally ill; terminology; transition of care
14.  Protective Effect of Liriodendrin Isolated from Kalopanax pictus against Gastric Injury 
Biomolecules & Therapeutics  2015;23(1):53-59.
In this study, we investigated the inhibitory activities on gastritis and gastric ulcer using liriodendrin which is a constituent isolated from Kalopanax pictus. To elucidate its abilities to prevent gastric injury, we measured the quantity of prostaglandin E2 (PGE2) as the protective factor, and we assessed inhibition of activities related to excessive gastric acid be notorious for aggressive factor and inhibition of Helicobacter pylori (H. pylori) colonization known as a cause of chronic gastritis, gastric ulcer, and gastric cancer. Liriodendrin exhibited higher PGE2 level than rebamipide used as a positive control group at the dose of 500 μM. It was also exhibited acid-neutralizing capacity (10.3%) and H+/K+-ATPase inhibition of 42.6% (500 μM). In pylorus-ligated rats, liriodendrin showed lower volume of gastric juice (4.38 ± 2.14 ml), slightly higher pH (1.53 ± 0.41), and smaller total acid output (0.47 ± 0.3 mEq/4 hrs) than the control group. Furthermore liriodendrin inhibited colonization of H. pylori effectively. In vivo test, liriodendrin significantly inhibited both of HCl/EtOH-induced gastritis (46.9 %) and indomethacin-induced gastric ulcer (46.1%). From these results, we suggest that liriodendrin could be utilized for the treatment and/or protection of gastritis and gastric ulcer.
PMCID: PMC4286750  PMID: 25593644
Liriodendrin; Prostaglandin E2; H+/K+-ATPase; Gastritis; Gastric ulcer
15.  7α-Hydroxycholesterol Elicits TLR6-Mediated Expression of IL-23 in Monocytic Cells 
Biomolecules & Therapeutics  2015;23(1):84-89.
We investigated the question of whether 7-oxygenated cholesterol derivatives could affect inflammatory and/or immune responses in atherosclerosis by examining their effects on expression of IL-23 in monocytic cells. 7α-Hydroxycholesterol (7αOHChol) induced transcription of the TLR6 gene and elevated the level of cell surface TLR6 protein in THP-1 monocytic cells. Addition of an agonist of TLR6, FSL-1, to TLR6-expressing cells by treatment with 7αOHChol resulted in enhanced production of IL-23 and transcription of genes encoding the IL-23 subunit α (p19) and the IL-12 subunit β (p40). However, treatment with 7-ketocholesterol (7K) and 7β-hydroxycholesterol (7βOHChol) did not affect TLR6 expression, and addition of FSL-1 to cells treated with either 7K or 7βOHChol did not influence transcription of the genes. Pharmacological inhibition of ERK, Akt, or PI3K resulted in attenuated transcription of TLR6 induced by 7αOHChol as well as secretion of IL-23 enhanced by 7αOHChol plus FSL-1. Inhibition of p38 MAPK or JNK resulted in attenuated secretion of IL-23. These results indicate that a certain type of 7-oxygenated cholesterol like 7αOHChol can elicit TLR6-mediated expression of IL-23 by monocytic cells via PI3K/Akt and MAPKs pathways.
PMCID: PMC4286754  PMID: 25593648
7alpha-hydroxycholesterol; IL-23; Macrophages; Toll-like receptor 6
16.  Alterations of Colonic Contractility in an Interleukin-10 Knockout Mouse Model of Inflammatory Bowel Disease 
Inflammatory bowel disease is commonly accompanied by colonic dysmotility and causes changes in intestinal smooth muscle contractility. In this study, colonic smooth muscle contractility in a chronic inflammatory condition was investigated using smooth muscle tissues prepared from interleukin-10 knockout (IL-10−/−) mice.
Prepared smooth muscle sections were placed in an organ bath system. Cholinergic and nitrergic neuronal responses were observed using carbachol and electrical field stimulation with L-NG-nitroarginine methyl ester (L-NAME). The expression of interstitial cells of Cajal (ICC) networks, muscarinic receptors, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) was observed via immunofluorescent staining.
The spontaneous contractility and expression of ICC networks in the proximal and distal colon was significantly decreased in IL-10−/− mice compared to IL-10+/+ mice. The contractility in response to carbachol was significantly decreased in the proximal colon of IL-10−/− mice compared to IL-10+/+ mice, but no significant difference was found in the distal colon. In addition, the expression of muscarinic receptor type 2 was reduced in the proximal colon of IL-10−/− mice. The nictric oxide-mediated relaxation after electrical field stimulation was significantly decreased in the proximal and distal colon of IL-10−/− mice. In inflamed colon, the expression of nNOS decreased, whereas the expression of iNOS increased.
These results suggest that damage to the ICC network and NOS system in the proximal and distal colon, as well as damage to the smooth muscle cholinergic receptor in the proximal colon may play an important role in the dysmotility of the inflamed colon.
PMCID: PMC4288096  PMID: 25537671
Colon; Contractility; Inflammatory bowel diseases; Interleukin-10
17.  Clinical Experience of Morel-Lavallee Syndrome 
Archives of Plastic Surgery  2015;42(1):91-93.
PMCID: PMC4297816  PMID: 25606498
18.  Abnormal Activation of the Social Brain Network in Children with Autism Spectrum Disorder: An fMRI Study 
Psychiatry Investigation  2014;12(1):37-45.
The aim of this study is to investigate abnormal findings of social brain network in Korean children with autism spectrum disorder (ASD) compared with typically developing children (TDC).
Functional magnetic resonance imaging (fMRI) was performed to examine brain activations during the processing of emotional faces (happy, fearful, and neutral) in 17 children with ASD, 24 TDC.
When emotional face stimuli were given to children with ASD, various areas of the social brain relevant to social cognition showed reduced activation. Specifically, ASD children exhibited less activation in the right amygdala (AMY), right superior temporal sulcus (STS) and right inferior frontal gyrus (IFG) than TDC group when fearful faces were shown. Activation of left insular cortex and right IFG in response to happy faces was less in the ASD group. Similar findings were also found in left superior insular gyrus and right insula in case of neutral stimulation.
These findings suggest that children with ASD have different processing of social and emotional experience at the neural level. In other words, the deficit of social cognition in ASD could be explained by the deterioration of the capacity for visual analysis of emotional faces, the subsequent inner imitation through mirror neuron system (MNS), and the ability to transmit it to the limbic system and to process the transmitted emotion.
PMCID: PMC4310919
Autism spectrum disorder; Social brain network; Social cognition; fMRI
19.  Validation of the Korean version of the European Community Respiratory Health Survey screening questionnaire for use in epidemiologic studies for adult asthma 
Asia Pacific Allergy  2015;5(1):25-31.
Standardized questionnaire is one of key instruments for general population surveys.
The present study aimed to develop and validate the Korean version of the European Community Respiratory Health Survey (ECRHS) screening questionnaire for adult asthma surveys.
The ECRHS screening questionnaire was translated into Korean language according to the international criteria. Study participants were prospectively recruited from six referral hospitals and one health check-up center. Comprehensibility of the translation was tested in a pilot study of 10 patients. The reliability was evaluated by internal consistency and test-retest repeatability. Validity was assess with regard to physician-diagnosed asthma.
A total of 100 adult asthma patients and 134 volunteers were recruited. Reliability was examined for 10 items in 100 asthmatics; Cronbach α coefficients were 0.84, and test-retest repeatability was good (Cohen κ coefficient, 0.71-1.00). Validity was assessed for 8 items in 234 participants; in particular, 'recent wheeze' showed a high sensitivity (0.89) for physician-diagnosed asthma. 'Recent asthma attack' and 'current asthma medication' showed high specificity (0.96-0.98).
The present study demonstrated that the Korean version of the ECRHS screening questionnaire was comprehensible, reliable and valid. We suggest the questionnaire to be utilized in further epidemiological studies for asthma in Korean adult populations.
PMCID: PMC4313752  PMID: 25653917
Asthma; Epidemiology; Questionnaires
20.  Time to dig deep into the plant proteome: a hunt for low-abundance proteins 
PMCID: PMC4311630
low-abundance proteins; high-abundance proteins; two-dimensional gel electrophoresis; RuBisCO; post-translational modifications
21.  Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1 
eLife  null;3:e05151.
Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.
eLife digest
Neurofibromatosis type 1 is a condition characterized by the growth of tumors along the nerves of the body. It is caused by mutations in a gene called NF1, which codes for a protein that normally works to inhibit the activity of another protein called Ras. In healthy cells, Ras is needed to stimulate the cells to grow and divide. However, if the Ras protein is not turned off at the right time or if it is activated at the wrong time, it can force cells to keep growing and dividing; this leads to the growth of tumors.
Along with being prone to developing cancer, individuals with neurofibromatosis type 1 also develop a range of neurodevelopmental disorders that alter their learning, motor skills and social interactions. Some also exhibit behaviors that are associated with autism. This led Kim, Wang et al. to investigate whether a region of the brain—called the cerebellum—that has recently been associated with autism is also affected in a mouse model of neurofibromatosis type 1.
The cerebellum is best known for its role in coordinating movement, although it also has functions in cognition, behavior and other processes. Ras is involved in the development of the cerebellum; and so Kim, Wang et al. asked whether the loss of the Nf1 gene from cells in the mouse cerebellum might cause the neurodevelopmental defects associated with neurofibromatosis type 1.
Loss of Nf1 during early (but not in late) development of the cerebellum disrupted the normal organization of the nerve cells (or neurons) into specific cell layers. These defects were caused, in part, by the over-growth of a type of supporting cell—called glia cells—at a specific developmental stage—that would normally form a scaffold to help neurons migrate to their correct position. Nf1 also controls the generation of the correct types of neurons in the right time and at right location during the early development of the cerebellum.
Next, Kim, Wang et al. treated newborn mice with a compound that inhibits Ras signaling via their mother's milk for 3 weeks. In mice with an inactive Nf1 gene, the treatment helped to prevent some defects in the cerebellum and the mice had improved motor coordination several months later. Whether this could form the basis of a preventative treatment for neurodevelopmental disorders associated with neurofibromatosis type 1 in humans remains a question for future work.
PMCID: PMC4297949  PMID: 25535838
neurofibromatosis type 1; cerebellum; bergmann glial cells; granule cells; unipolar brush cells; tumor suppressor gene; mouse
22.  Is elective inguinal radiotherapy necessary for locally advanced rectal adenocarcinoma invading anal canal? 
We investigated whether routine elective irradiation of a clinically negative inguinal node (IGN) is necessary for patients with locally advanced distal rectal cancer and anal canal invasion (ACI).
We reviewed retrospectively 1,246 patients with locally advanced rectal adenocarcinoma managed using preoperative or postoperative chemoradiotherapy and radical surgery between 2001 and 2011. The patients’ IGN was clinically negative at presentation and IGN irradiation was not performed. ACI was defined as the lower edge of the tumor being within 3 cm of the anal verge. Patients were divided into two groups, those with ACI (n = 189, 15.2%) and without ACI (n = 1,057, 84.8%).
The follow-up period was a median of 66 months (range, 3–142 months). Among the 1,246 patients, 10 developed IGN recurrence; 7 with ACI and 3 without ACI. The actuarial IGN recurrence rate at 5 years was 0.7%; 3.5% and 0.2% in patients with and without ACI, respectively (p < 0.001). Isolated IGN recurrence occurred in three patients, all of whom had ACI tumors. These three patients received curative intent local treatments, and one was alive with no evidence of disease 10 years after IGN recurrence. Salvage treatments in the other two patients controlled successfully the IGN recurrence for >5 years, but they developed second malignancy or pelvic and distant recurrences. Seven patients with non-isolated IGN recurrence died of disease at 5–22 months after IGN recurrence.
The low IGN recurrence rate even with ACI and the feasibility of salvage of isolated IGN recurrence indicated that routine elective IGN irradiation is not necessary for rectal cancer with ACI.
PMCID: PMC4299686  PMID: 25533887
Rectal cancer; Radiotherapy; Inguinal lymph node; Anal canal invasion
23.  Prognostic Value of Glioma Cancer Stem Cell Isolation in Survival of Primary Glioblastoma Patients 
Stem Cells International  2014;2014:838950.
Cancer stem cells (CSCs) have been reported to be critical in the initiation, maintenance, and progression of cancers. The expression of stem cell markers, such as podoplanin (PDPN), CD133, and nestin, may have been correlated with malignant progression. However, the effects of CSCs and stem cell markers on clinical outcomes in cancer patients remain unclear. In this study, we assessed the prognostic roles of glioma CSCs (gCSCs) isolation and stem cell markers in patients with primary glioblastoma (pGBM). A cohort of 39 patients with pGBM was separated into two groups, those positive or negative for gCSCs, and the correlation between gCSC and patient survival was evaluated. We observed significantly different cumulative survival (P = 0.045) when comparing patients positive for gCSCs patients and negative for gCSC. Among the patients positive for gCSCs, we observed no significant differences in survival between those whose gCSCs were each positive or negative for PDPN, CD133, or nestin. This study strongly supports the prognostic value of gCSCs isolation on the survival of patients with pGBM.
PMCID: PMC4279114  PMID: 25580136
24.  Autophagosome-Mediated EGFR Down-Regulation Induced by the CK2 Inhibitor Enhances the Efficacy of EGFR-TKI on EGFR-Mutant Lung Cancer Cells with Resistance by T790M 
PLoS ONE  2014;9(12):e114000.
Protein kinase CK2 has diverse functions promoting and maintaining cancer phenotypes. We investigated the effect of CK2 inhibition in lung cancer cells with T790M-mediated resistance to the EGFR-TK inhibitor. Resistant sublines of PC-9 to gefitinib (PC-9/GR) and erlotinib (PC-9/ER) were established by previous study, and T790M secondary mutation was found in both resistant sublines. A decrease of EGFR by siRNA treatment effectively controlled the growth of resistant cells, thus suggesting that they still have EGFR-dependency. CX-4945, a potent and selective CK2 inhibitor, induced autophagy in PC-9/GR and PC-9/ER, and which was supported by the induction of autophagic vacuoles and microtubule-associated protein 1 light chain 3 (LC3) expression, and the increase of punctate fluorescent signals in resistant cells pre-transfected with green fluorescent protein (GFP)-tagged LC3. However, the withdrawal of CX-4945 led to the recovery of cancer cells with autophagy. We found that the induction of autophagy by CX-4945 in both resistant cells was CK2 dependent by using small interfering RNA against CK2. The treatment with CX-4945 alone induced a minimal growth inhibition in resistant cells. However, combined treatment of CX-4945 and EGFR-TKI effectively inhibited cancer-cell proliferation and induced apoptosis. CX-4945 increased the translocation of EGFR from the cell surface into the autophagosome, subsequently leading to the decrease of EGFR while inhibition of autophagy by 3MA or Atg7-targeted siRNA pretreatment reduced the decrease of EGFR by CX-4945. Accordingly, apoptosis by a combination of CX-4945 and EGFR-TKI was suppressed by 3MA or Atg7-targeted siRNA pretreatment, thus suggesting that autophagosome-mediated EGFR down-regulation would have an important role regarding apoptotic cell death by EGFR-TKI. Combined treatment of the CK2 inhibitor and EGFR-TKI may be a promising strategy for overcoming T790M-mediated resistance.
PMCID: PMC4259313  PMID: 25486409
25.  HIV Antiretroviral Resistance Mutations Among Antiretroviral Treatment-Naive and -Experienced Patients in South Korea 
AIDS Research and Human Retroviruses  2013;29(12):1617-1620.
The purpose of this study was to assess the prevalence and characteristics of HIV drug resistance mutations among antiretroviral therapy (ART)-naive and ART-experienced patients in South Korea. A total of 50 ART-naive and 34 ART-experienced Korean HIV-1-infected patients who visited an urban hospital from February 2007 to March 2011 were included. Most patients (86.9%) were infected with clade B HIV-1. Six (12%) ART-naive and 22 (64.7%) ART-experienced patients had HIV strains with resistance mutations. Among ART-naive patients, V179D was the most common mutation, being found in five ART-naive patients. Among ART-experienced patients, M184V was the most common mutation. Eight of 34 ART-experienced patients had thymidine analogue mutations (TAMs). The prevalence of drug-resistant HIV-1 in ART-naive patients was higher than in previous reports, and 50% of patients with virologic failure harbored strains with multiple resistance mutations. HIV drug resistance testing should be recommended to guide therapy of ART-naive patients in South Korea.
PMCID: PMC3848436  PMID: 23952717

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