• Biomolecules & Therapeutics
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• v.29 no.5
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• pp.551-561
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• 2021

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

• Journal of the Korea Society of Computer and Information
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• v.26 no.8
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• pp.197-207
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• 2021

Relationship between bone mineral density (BMD) and type 2 diabetes is still inconsistent. Recently, many epidemiologic data show that fracture risk is increased in type 2 diabetic patients regardless of BMD status. In this study, we used nation-wide data from 2008 to 2011 Korea National Health and Nutrition Examination Survey (KNHANES) to analyze the BMD status in patients with type 2 diabetes compared to non-diabetics. We included subjects aged 50 years or older in men (N=2,959, 2,430 without diabetes, 529 with type 2 diabetes) and postmenopausal women (N=2,902, 2,479 without diabetes, 423 with type 2 diabetes). Subjects with history of medication for osteoporosis or with illness or malignancy affecting bone metabolism were excluded. Data of anthropometric measurements and demographic characteristics were collected by trained examiner. Serum was separated from peripheral venous blood samples obtained after 8 hours of fasting. BMD was measured at lumbar spine and femur using dual-energy X-ray absorptiometry (DXA). There was a significant positive association between lumbar spine BMD and type 2 diabetes after adjusting age, gender, body mass index, monthly house income, education level, physical activity, daily calcium intake and vitamin D concentration by multiple regression analysis in all subjects. In the subgroup analysis by gender, this association was maintained both in male and female after adjusting those confounding factors. However, femur BMD was not different between type 2 diabetic and non-diabetic subjects. In conclusion, lumbar spine BMD was significantly higher in type 2 diabetic patients aged 50 years or more in men and postmenopausal women compared to non-diabetic subjects.

• Journal of the Korea Society of Computer and Information
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• v.26 no.8
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• pp.209-220
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• 2021

The effect of body composition such as lean mass and fat mass on bone mineral density (BMD) is complex and still controversial. In this study, we investigated the relationship between body composition and bone mineral density using nation-wide data from 2008 to 2011 Korea National Health and Nutrition Examination Survey (KNHANES) in 2,139 men and 2,193 postmenopausal women aged 50 years or older. Subjects with history of medication for osteoporosis or with diseases or malignancy affecting bone metabolism were excluded. Data of anthropometric measurements and demographic characteristics were collected by trained examiner. Fasting blood sample was obtained for blood chemistry analysis. BMD of the lumbar spine, total femur, and femoral neck, and body composition such as total lean mass (TLM), total fat mass (TFM), truncal fat mass (TrFM) were measured using dual-energy X-ray absorptiometry (DXA). There were significant positive correlations between body composition indices such as lean mass and fat mass with BMD. In multiple regression analysis, TLM was positively associated with BMD after adjusting age, body mass index, monthly house income, education level, physical activity, daily calcium intake and vitamin D concentration in both men and postmenopausal women. BMD at lumbar spine and femur in lowest quartile of TLM was significantly lower than other quartiles after adjusting those confounding factors in both gender. TrFM was negatively associated with total femur BMD in male and femur neck BMD in postmenopausal women after adjusting confounding factors. In conclusion, TLM is very important factor in maintaining BMD in subjects aged 50 years or older in men and postmenopausal women.

• Journal of Life Science
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• v.32 no.6
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• pp.468-475
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• 2022

The functional distinction between stem and progenitor cells is well established in several tissues, particularly in the blood. There, hematopoietic stem cells preserve their self-renewal potential and reconstitution ability in the bone marrow niche. Bone marrow represents a unique setting in which to examine how stroma influences tissue function. It was the setting in which the experimental definition of a niche was first provided in mammalian stem cell biology and where clear evidence for non-cell-autonomous oncogenesis was first defined. The relationship between bone and blood is ancient as all animals since the divergence of fish that have bones and blood, make blood in their bones. This long coevolution engendered complex interrelationships, including the first proposed and first experimentally defined niche for stem cells in mammals. Multiple bone marrow stromal cell types serve as regulators of hematopoiesis, and the dysfunction of some causes myelodysplasia and leukemia. However, no comprehensive atlas of stromal subpopulations exists. Therefore, we think these data point to something of importance, such as how the needs and challenges of the organism become translated down to distinct cell types that critically govern specific functions within tissues and do so at the level of a single molecule. We think this will be of broad interest to those focusing on systems biology and the physiology of organisms, particularly those seeking a molecular basis for understanding cell and tissue behavior. We summarized the current and emerging concepts of hematopoietic stem cells and bone marrow niche.

• Advances in nano research
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• v.12 no.6
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• pp.639-652
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• 2022

The prolyl 3-hydroxylase family member 4 (P3H4), is associated with post-translational modification of fibrillar collagens and aberrantly activated in cancer leading to tumor progression. However, its role in clear cell renal cell carcinoma (ccRCC) is still unknown. Here we reported that P3H4 was highly expressed in renal cancer tissues and significantly positive correlated with poor prognosis. Knockdown of P3H4 inhibited the proliferation, migration and metastasis of renal cancer cells in vitro and in vivo, and also, overexpression of it enhanced the oncogenic process. Mechanistically, P3H4 depletion decreased the levels of GDF15-MMP9 axis and repressed its downstream signaling. Further functional studies revealed that inhibition of GDF15 suppressed renal cancer cell growth and GDF15 recombinant human protein (rhGDF15) supplementation effectively rescued the inhibitory effect induced by P3H4 knockdown. Moreover, decreased levels of MMP9 caused by inhibition of P3H4-GDF15 signaling constrained the expression of PD-L1 and suppression of P3H4 accordingly promoted anti-tumor immunity via stimulating the infiltration of CD4+ and CD8+ T cells in syngeneic mice model. Taken together, our findings firstly demonstrated that P3H4 promotes ccRCC progression by activating GDF15-MMP9-PD-L1 axis and targeting P3H4-GDF15-MMP9 signaling pathway can be a novel strategy of controlling ccRCC malignancy.

• Archives of Plastic Surgery
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• v.49 no.4
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• pp.501-509
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• 2022

Background Acute facial nerve iatrogenic or traumatic injury warrants rapid management with the goal of reestablishing nerve continuity within 72 hours. However, reconstructive efforts should be performed up to 12 months from the time of injury since facial musculature may still be viable and thus facial tone and function may be salvaged. Methods Data of all patients who underwent facial nerve repair following iatrogenic or traumatic injury were retrospectively collected and assessed. Paralysis etiology, demographics, operative data, postoperative course, and outcome were examined. Results Twenty patients underwent facial nerve repair during the years 2004 to 2019. Data were available for 16 of them. Iatrogenic injury was the common category (n = 13, 81%) with parotidectomy due to primary parotid gland malignancy being the common surgery (n = 7, 44%). Nerve repair was most commonly performed during the first 72 hours of injury (n = 12, 75%) and most of the patients underwent nerve graft repair (n = 15, 94%). Outcome was available for 12 patients, all of which remained with some degree of facial paresis. Six patients suffered from complete facial paralysis (50%) and three underwent secondary facial reanimation (25%). There were no major operative or postoperative complications. Conclusion Iatrogenic and traumatic facial nerve injuries are common etiologies of acquired facial paralysis. In such cases, immediate repair should be performed. For patients presenting with facial paralysis following previous surgery or trauma, nerve repair should be considered up to at least 6 months of injury. Longstanding paralysis is best treated with standard facial reanimation procedures.

• Molecules and Cells
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• v.45 no.12
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• pp.886-895
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• 2022

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

• Journal of Digestive Cancer Research
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• v.6 no.1
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• pp.25-31
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• 2018

Background: In Korea, stomach cancer is the second most common malignancy and the third leading cause of cancer-related deaths. the time of diagnosis is very important for treatment so early detection and surgery are currently considered the mainstay of treatment, when diagnosed advanced with tumor extension through the gastric wall and direct extension into other organs, with metastatic involvement. Recently, new drugs, drug combinations, and multimodal approaches have been used to treat this disease and In cancers over expressing or amplifying HER2, the combination of cisplatin-fluoropyrimidine-trastuzumab is considered to be the treatment of reference. but At present, the choice of treatment schedule for HER2-negative tumors is based on the medical institution's preferences and adverse effects profile. The aim of this study was to evaluate the effectiveness and safety of using FOLFOX regimen as a first-line therapy or a salvage therapy in the patients with HER2-negative advanced or metastatic gastric cancer. Methods: We retrospective reviewed the patient medical record from March 2012 to July 2017. This study evaluated 113 patients. Sixty-eight patients were treated with the FOLFOX regimen for the first time (first-line group) and 45 patients were treated with the FOLFOX regimen as a second (35 patients) or third (10 patients) chemotherapy (salvage group). Results: In the first-line group, the response rate was 54.9%. In the salvage therapy group, the response rate was 24.4% and The difference was statistically significant (p=0.205). The median TTP of the first-line group was 10.7 months (95% confidence interval [95% CI], 7.8-13.7 months) and that of salvage line group was 6.1 months (95% CI, 3.8-8.4 months). The median OS of the first-line group was 15.8 months (95% CI, 12.7-18.9 months) and that of the salvage therapy group was 10.2 months (95% CI, 8.2-11.9 months). drug toxicity was similar andtolerable between two groups. Conclusion: In patients with unresctable metastatic gastric cancer, after failing to respond to first-line therapy, most patients have no alternative other than second-line therapy because the disease is highly progressive. if the performance status of the patient is good enough to be eligible to treatments beyond best supportive care. FOLFOX regimen can be a considerable therapeutic option for salvage treatment.

• Korean Journal of Radiology
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• v.22 no.7
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• pp.1185-1193
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• 2021

Objective: Clear cell sarcoma of the kidney (CCSK) is the second-most common but extremely rare primary renal malignancy in children after Wilms' tumor. The aims of this study were to evaluate the imaging features that could distinguish between CCSK and Wilms' tumor and to assess the features with diagnostic value for identifying CCSK. Materials and Methods: We reviewed the initial contrast-enhanced abdominal-pelvic CT scans of children with CCSK and Wilms' tumor between 2010 to 2019. Fifty-eight children (32 males and 26 females; age, 0.3-10 years), 7 with CCSK, and 51 with Wilms' tumor, were included. The maximum tumor diameter, presence of engorged perinephric vessels, maximum density of the tumor (Tmax) of the enhancing solid portion, paraspinal muscle, contralateral renal vein density, and density ratios (Tmax/muscle and Tmax/vein) were analyzed on the renal parenchymal phase of contrast-enhanced CT. Fisher's exact tests and Mann-Whitney U tests were conducted to analyze the categorical and continuous variables, respectively. Logistic regression and receiver operating characteristic curve analyses were also performed. Results: The age, sex, and tumor diameter did not differ between the two groups. Engorged perinephric vessels were more common in patients in the CCSK group (71% [5/7] vs. 16% [8/51], p = 0.005). Tmax (median, 148.0 vs. 111.0 Hounsfield unit, p = 0.004), Tmax/muscle (median, 2.64 vs. 1.67, p = 0.002), and Tmax/vein (median, 0.94 vs. 0.59, p = 0.002) were higher in the CCSK compared to the Wilms' group. Multiple logistic regression revealed that engorged vessels (odds ratio 13.615; 95% confidence interval [CI], 1.770-104.730) and Tmax/muscle (odds ratio 5.881; 95% CI, 1.337-25.871) were significant predictors of CCSK. The cutoff values of Tmax/muscle (86% sensitivity, 77% specificity) and Tmax/vein (71% sensitivity, 86% specificity) for the diagnosis of CCSK were 1.97 and 0.76, respectively. Conclusion: Perinephric vessel engorgement and greater tumor enhancement (Tmax/muscle > 1.97 or Tmax/vein > 0.76) are helpful for differentiating between CCSK and Wilms' tumor in children aged below 10 years.

• Korean Journal of Radiology
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• v.22 no.3
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• pp.344-353
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• 2021

Objective: The mitotic count of gastrointestinal stromal tumors (GIST) is closely associated with the risk of planting and metastasis. The purpose of this study was to develop a predictive model for the mitotic index of local primary GIST, based on deep learning algorithm. Materials and Methods: Abdominal contrast-enhanced CT images of 148 pathologically confirmed GIST cases were retrospectively collected for the development of a deep learning classification algorithm. The areas of GIST masses on the CT images were retrospectively labelled by an experienced radiologist. The postoperative pathological mitotic count was considered as the gold standard (high mitotic count, > 5/50 high-power fields [HPFs]; low mitotic count, ≤ 5/50 HPFs). A binary classification model was trained on the basis of the VGG16 convolutional neural network, using the CT images with the training set (n = 108), validation set (n = 20), and the test set (n = 20). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at both, the image level and the patient level. The receiver operating characteristic curves were generated on the basis of the model prediction results and the area under curves (AUCs) were calculated. The risk categories of the tumors were predicted according to the Armed Forces Institute of Pathology criteria. Results: At the image level, the classification prediction results of the mitotic counts in the test cohort were as follows: sensitivity 85.7% (95% confidence interval [CI]: 0.834-0.877), specificity 67.5% (95% CI: 0.636-0.712), PPV 82.1% (95% CI: 0.797-0.843), NPV 73.0% (95% CI: 0.691-0.766), and AUC 0.771 (95% CI: 0.750-0.791). At the patient level, the classification prediction results in the test cohort were as follows: sensitivity 90.0% (95% CI: 0.541-0.995), specificity 70.0% (95% CI: 0.354-0.919), PPV 75.0% (95% CI: 0.428-0.933), NPV 87.5% (95% CI: 0.467-0.993), and AUC 0.800 (95% CI: 0.563-0.943). Conclusion: We developed and preliminarily verified the GIST mitotic count binary prediction model, based on the VGG convolutional neural network. The model displayed a good predictive performance.