• Genomics & Informatics
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• v.19 no.1
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• pp.2.1-2.10
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• 2021

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

• Archives of Pharmacal Research
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• v.25 no.4
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• pp.522-527
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• 2002

The antimetastatic effect of BCG-CWS, which was emulsified in an oil-in-water form with either Drakeol 6VR mineral oil (BCG-CWS/DK) or squalane (BCG-CWS/SQA), on lung metastasis produced by highly metastatic murine tumor cells, Colon26-M3.1 carcinoma cells and B16-BL6 melanoma cells, was investigated in syngeneic mice. An intravenous (i.v.) administration of BCG-CWS (100 mg/mouse) 1 day after tumor inoculation significantly inhibited tumor metastasis of both Colon26-M3.1 carcinoma and B16-BL6 melanoma cells in experimental lung metastasis models. No differences in the antitumor activity of the two oil-based formulations (BCG-CWS/DK and BCG-CWS/SQA) were obverved. However, BCG-CWS/SQA administered through subcutaneous (s.c.) route was shown to be effective only when it was consecutively injected (3 times) after tumor inoculation. An in vivo analysis for tumor-induced angiogenesis shwed that a single i.v. administration of BCG-CWS/SQA inhibited the number of tumor-induced blood vessels and suppressed tumor growth. Furthermore, the multiple administration of BCG-CWS/SQA given at on week intervals led to a significant reduction in spontaneous lung metastasis of B16-BL6 melanoma cells in a spontaneous metastasis model. These results suggest that BCG-CWS emulsified with squalane is a potent inhibitory agent of lung metastasis, and that the anti metastatic effect of BCG-CWS is related to the suppression of tumor growth and the inhibition of tumor-induced angiogenesis.

• Advances in Traditional Medicine
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• v.1 no.2
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• pp.36-44
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• 2000

The polysaccharide fractions were isolated and purified from Phellodendron chinese SCHNEID, and antitumor activities using the melanoma B-16-derived metastatic tumors were examined at dosages of 2, 5 and 10 mg/100 g. F-7 and F-8 showed the highest tumor metastatic inhibitory activities (inhibition ratio 60 and 80% in 2 mg/100 g), and in dose of 5 mg/100 g, the inhibitory ratios were 85 and 70%, respectively. Furthermore, 10 mg/100 g of intraperitoneal (i.p.) injection gave 90 and 95% of inhibition. When the effects of polysaccharides on hypersensitivity were examined, the inhibitory activities were not markedly observed in oral administration, indicating that the polysaccharides are directly acting to immune system. Also, the polysaccharides increased the number of circulating blood leukocytes and total peritoneal exudate cells. Although implantation of tumor cells greatly decreased the productivity of antibody (antibody-mediated) and T lymphocyte reactivity (delayed-type) as 6.3 from 9.3 and 5.9 from 7.7, represented by the increase of footpad thickness, respectively. the polysaccharides elevated the reactivity of T lymphocyte in tumor-bearing mice, which were rapidly recovered by discontinuance of sample treatments. Especially, F-2, F-5, F-7 and F-8 remarkably recovered the decreased sensitivity. These results clearly indicated that the i.p. injection is much effective to suppress tumor growth than oral administration.

• KSBB Journal
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• v.10 no.5
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• pp.525-532
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• 1995

Chitosan derivative, of a sulfated N-acetyl chitosan was synthesized, and the inhibitory effects of this compound on the experimental and spontaneous lung metastallc B16/BL6 melanoma bearing mice were investigated. Position of substitution with sulfate in water-soluble sulfated derivatives of chitosan were analysed by 13C-nmr. The structure of N-acetyl chitosan 3,6 0-disulfate were confirmed. The tumor growth inhibition of B16/BL6 melanoma cells has been shown at the highest level of 77.6% when sulfated N-acetyl chitosan were administered at the dose of 100mg/kg. In the lung metastasls, the sulfated N-atetyl chitosan was administered to C57BL/6B mice bearing B16/BL6 melanoma cells by I.V. injection and the number of metastasis foci of melanoma were decreased by the dose dependent manner ranging from 20 to 100mg/kg. In the spontaneous metastasis, I.V. administrations of sulfated N-acetyl chitosan after tumor inoculation resulted in marked reduction of metastatic colonies. A sulfated N-acetyl chitosan was able to partially inhibit the tumor cell adhesion by migration to laminin. These results suggested that chitosan derivative, a sulfated N-acetyl chitoasn was able to inhibit to the experimental and spontaneous metastasis models as well as cell adhesion ability.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5709-5714
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• 2015

Aim: To assess the treatment outcome in patients with malignant skin melanoma and prognostic factors for distant metastases (DM), disease-free survival (DFS) and overall survival (OS). Materials and Methods: A retrospective analysis was conducted on 113 patients with malignant skin melanoma (60 females, 53 males, average age-55 years) who were treated surgically. Primary treatment consisted of local excision. In 12 cases, it was accompanied by lymph node excision. In 93 (82%) cases, radicalization was necessary, which was either local only (19 cases) or accompanied by lymph node surgery/biopsy (74 cases). Possible prognostic factors such as Clark's stage and Breslow's depth of invasion, ulceration, average tumor dimensions, lymph nodes metastases (pN+), gender, tumor location and primary excision margins were considered. Results: In 51 (45%) cases, treatment failure occurred. The 5-year DM rate was 47%, the 5-year DFS was 38%, and the 5-year OS was 56%. In the univariate analysis, the important factors with respect to at least one endpoint included Clark's stage, Breslow's depth of invasion, ulceration, average tumor dimensions, lymph nodes metastases, gender and primary tumor localization. The presence of metastasic nodes was the most important prognostic factor, with a 5-year DM rates of 30% for pN(-) and 76% for pN(+) and a 5-year DFS and OS of 56% and 76% for pN(-) and 13% and 24% for pN(+), respectively. The average tumor dimension was independently significant for DFS and OS, with 5-year rates of 69% and 80% for ${\leq}1cm$, 28% and 53% for 1-2 cm, and 18% and 30% for >2 cm, respectively. Tumor location was also significant for DM and OS, with 5-year rates of 69% vs 33% and 41% vs 66% for trunk vs other locations, respectively. Conclusions: The natural course of a malignant skin melanoma treated radically is disadvantageous, with unsuccessful outcome in nearly half of the cases. Common clinical factors, such as Clark's tumor stage, Breslow's depth of invasion and the presence of metastatic nodes, have high prognostic significance. The size and location of the primary lesion may be considered independent prognostic factors. The most important negative prognostic factor is the presence of metastatic regional lymph nodes. Only one quarter of patients with metastases in lymph nodes survive 5 years from primary surgery.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6681-6684
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• 2015

Background: Metastatic cancer with invasion of skin, soft tissue and skeletal muscle is not common. Examples presenting as soft tissue masses could sometimes lead to misdiagnosis with delayed or inappropriate management. The purpose of current study was to investigate clinical characteristics in the involvement of metastatic cancer. Materials and Methods: A total of 1,097 patients complaining of skin or soft tissue masses and/or lesions were retrospectively reviewed from January 2012 to June 2013. Tumors involving skin, soft tissue and skeletal muscle of head and neck, chest wall, abdominal wall, pelvic region, back, upper and lower extremities were included in the study. Results: Fifty-seven (5.2%) patients were recognized as having malignancies on histopathological examination. The most common involvement of malignancy was basal cell carcinoma, followed by cutaneous squamous cell carcinoma, sarcoma and melanoma. The most common anatomical location in skin and soft tissue malignancies was head and neck (52.6% of the malignancies). Four (0.36%) of the malignant group were identified as metastatic cancer with the primary cancer source from lung, liver and tonsil and the most common site was upper extremities. One of them unexpectedly expired during the operation of metastatic tumor excision at the scalp. Conclusions: Discrimination between benign and malignant soft tissue tumors is crucial. Performance of imaging study could assist in the differential diagnosis and the pre-operative risk evaluation of metastatic tumors involving skin, soft tissue and skeletal muscle.

• CELLMED
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• v.13 no.12
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• pp.44.1-44.7
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• 2023

Objective: A case of reducing adverse effects associated with imatinib using Cyaplex F. Methods: The 52-year-old female with past medical history of stage 1 triple-positive breast cancer 10 years ago, and current metastatic melanoma has been complaining adverse effects after imatinib was started. Results: After OCNT was initiated, the patient's headache and muscle pain have been much tolerable and her AST/CPK levels were returned close to her baseline. Conclusion: OCNT may reduce side effects caused by Imatinib and help patient to stay with the current chemotherapy regimen.

• The Korean Journal of Cytopathology
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• v.3 no.2
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• pp.82-89
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• 1992

Electron microscopy (EM) can provide a valuable contribution to light microscopy (LM) In the Interpretation of fine needle aspiration cytology (FNAC) specimen, especially in the diagnosis of the tumor. However, considerable care in processing the specimen is mandatory to recover the cells and avoid altering the fine structures. We experienced a case of malignant melanoma in 33-yrs-old female, diagnosed by EM study of FNAC specimen from the axillary mass, who was initially thought as disseminated carcinomatosis on LM study. The technique of EM study on FNAC specimen consisted of washing the needle and syringe in 2.5% glutaraldehyde after a rapid stain (Diff-Quik), which was used to obtain a preliminary diagnostic impression and to assure the adequacy of the EM specimen. After centrifugation in the steps of fixation and dehydration, the sediment was made into an epon block and examined. The whole processing time of EM study can be shortened within 7 or 8 hours, and results can be available within 48 to 72 hours. Our experience suggests the EM study on FNAC can be a useful diagnostic method in the diagnosis of difficult FNAC cases.

• Interdisciplinary Bio Central
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• v.3 no.1
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• pp.5.1-5.5
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• 2011

Introduction: Many signal transduction pathways mediate cell's behavior by regulating expression level of involved genes. Abnormal behavior indicates loss of regulatory potential of pathways, and this can be attributed to loss of expression regulation of downstream genes. Therefore, function of pathways should be assessed by activity of a pathway itself and relative activity between a pathway and downstream genes, simultaneously. Results and Discussion: In this study, we suggested a new method to assess pathway's function by introducing concept of 'responsiveness'. The responsiveness was defined as a relative activity between a pathway itself and its downstream genes. The expression level of a downstream gene as a function of an upstream pathway activation characterizes disease status. In this aspect, by using the responsiveness we predicted potential progress in cancer development. We applied our method to predict primary and metastatic status of melanoma cancer. The result shows that the responsiveness-based approach achieves better performance than using gene or pathway information alone. The mean of ROC scores in the responsiveness-based approach was 0.90 for GSE7553 data set, increased more than 40% compared to a gene-based method. Moreover, identifying the abnormal regulatory patterns between pathway and its downstream genes provided more biologically interpretable information compared to gene or pathway based approaches.

• International Journal of Oral Biology
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• v.42 no.3
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• pp.107-115
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• 2017

Human malignant melanoma is an aggressive skin cancer which has been rising at a greater rate than any other cancers. Although various new therapeutic methods have been developed in previous studies, this disease has properties of high proliferation and metastasis rate which remain obstacles that have lead to a poor prognosis in patients. It has been reported that a specific Lactobacillus extract has anti-cancer and -metastasis effect in vitro and in vivo. However, previous research has not specified precisely what effect the Lactobacillus rhamnosus GG (LGG) extract has had on human malignant melanomas. In this study, we showed that the LGG extract has anti-cancer and -metastasis effects on the human malignant melanoma cell lines, A375P and A375SM. At first, it was found that, while the LGG extract affects human neonatal dermal fibroblasts slightly, it induced the dose-dependent anti-cancer effect on A375P and A375SM by a WST-1 proliferation assay. As a result of a real-time PCR analysis, the expression patterns of several genes related to cell cycle, proliferation, and apoptosis were modulating in a manner that inhibited the growth of both malignant melanoma cell lines after the treatment of the LGG extract. Furthermore, genes related to the epithelial-mesenchymal transition were down-regulated, and migration rates were also decreased significantly by the LGG extract. Our study showed that the LGG extract could be used as a potential therapeutic source.