RESUMO
BACKGROUND: Variants in COL7A1 cause an extremely rare and clinically heterogeneous syndrome known as dystrophic epidermolysis bullosa pruriginosa (DEB-Pr). Duplilumab, a fully humanized anti-IL-4Ra monoclonal antibody, can inhibit IL-4 and IL-13-driven signaling. METHODS: Ethical Compliance: Following our Institutional Review Board, genetic testing has been made available after completing a signed informed consent form. This article presents the case study of a DEB-Pr patient who received dupilumab therapy. Genomic DNA was extracted from the peripheral blood of the patient. RESULTS: The findings showed that a unique COL7A1 mutation was discovered in the patient who underwent genetic testing. As a result of the patient receiving dupilumab treatment, the individual reported experiencing significantly less itching and considerably improved erythema, less severe scales, crusts, and flattening of plaques. CONCLUSION: In conclusion, the current investigation showed that to the best of our knowledge, this is the first DEB-Pr patient with heterozygous COL7A1 (NM_000094.3:c.8110G>A [p. Gly2704Arg]) who responded positively to dupilumab treatment without experiencing any serious side effects.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Humanos , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/genética , MutaçãoRESUMO
Background: The purpose of the current research was to investigate the biological roles of LINC00467 in inducing melanoma deterioration. Methods: Differential level of LINC00467 in melanoma tissues and its prognostic value were analyzed in GEPIA, which were further confirmed in clinical samples we collected. Regulatory effects of LINC00467 on proliferation, migration and invasion capacities of A375 and SKMEL1 cell lines were examined by a series of functional experiments. Potential downstream targets of LINC00467 were identified through dual-luciferase reporter assay, and their synergistic role in melanoma process was finally explored by rescue experiments. Results: LINC00467 was up-regulated in melanoma samples, but it did not have a prognostic potential in melanoma. LINC00467 has the capacities to stimulate proliferation, migration and invasion of A375 and SKMEL1 cell lines. The feedback loop LINC00467/miR-485-5p/PAK1 was identified, which was responsible for inducing melanoma deterioration. Conclusions: LINC00467 stimulates proliferation, migration and invasion capacities of melanoma via targeting miR-485-5p to upregulate PAK1, which provides potential targets for treatment of melanoma.
RESUMO
Hedgehog (Hh) signaling has been proved to be closely associated with the occurrence of melanoma. Wogonin is one of the active components of flavonoids that extracts from Scutellariae radix. Previous studies showed that wogonin could inhibit the invasion and migration of B16F10 cells, and suppress the synthesis of melanin in A375 melanoma cells. However, the regulatory effects of Hh signaling in wogonin against melanoma and its potential mechanisms remain largely unknown. The present study aimed to investigate the effect of wogonin on the growth of HT144 melanoma, and to elucidate the role of Hh signaling in wogonin-induced antitumor effects by focusing on inflammation and glycolysis regulation. Wogonin inhibited the proliferation, colony formation and tumor growth of HT144 melanoma cells. Wogonin showed strong anti-inflammatory effect in HT144 melanoma, as shown by the decreased levels of pro-inflammatory factors, the increased level of anti-inflammatory factor and the decreased expression of inflammatory cytokines. Wogonin decreased the glucose consumption and the production of lactic acid and ATP, and decreased the activities of hexokinase (HK), phosphofructokinase(PFK) and pyruvate kinase (PK), and further inhibited the expression of monocarboxylate transporter 1 (MCT-1), MCT-4 and glucosecotransporter-1 (GLUT1), showing potent anti-glycolysis effect against HT144 melanoma. Wogonin inhibited the patched and Smo expression while increased Hhip expression in HT144 cells, suggesting that wogonin blocked the Hh signaling in HT144 cells. The Hh signaling inhibitor cyclopamine, like wogonin, inhibited the colony formation of HT144 cells, however, the inhibitory effect of wogonin on colony formation of HT144 cells was abrogated by the Hh signaling agonist SAG. In addition, SAG abrogated the inhibitory effect of wogonin on the secretion of inflammatory factors and the expression of inflammatory cytokines. Furthermore, SAG abrogated the inhibitory effect of wogonin on several key molecules controlling glycolysis. Overall, these findings suggested that the anti-tumor effect of wogonin can be attributed to the inhibition of Hh signaling-mediated regulation of inflammation and glycolysis in HT144 melanoma.
Assuntos
Flavanonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Inflamação/tratamento farmacológico , Queratinócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Glicólise , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Approximately 60% of patients with melanoma harbor BRAF mutation and targeting BRAF offers enormous advance in the treatment of those patients. Unfortunately, the efficacy of the BRAF inhibitors is usually restricted by the onset of drug resistance. Therefore, better understanding of the adaptive drug resistance mechanisms is essential for the development of alternative therapeutic strategies, and offers more promising measures to promote the short duration of response to BRAF inhibitors. METHODS: The levels of tumor suppressive long noncoding RNA on chromosome 8p12 (TSLNC8) were evaluated by qPCR. The MTT assay, colony formation assay, apoptosis assay, and in vivo xenograft tumor model were performed to assess the functions of TSLNC8 on drug resistance. Western blotting, RNA pull-down, and RNA immunoprecipitation (RIP) assays were applied to investigate the mechanisms of TSLNC8 in melanoma. RESULTS: Herein, our findings demonstrate that TSLNC8 is significantly downregulated in BRAF inhibitor-resistant melanoma tissues and cells. Moreover, downregulation of TSLNC8 in BRAF inhibitor sensitive cells reduces the toxicity response to BRAF inhibitor PLX4720, and inhibits apoptosis of melanoma cells-treated with PLX4720. Further assay elucidates that TSLNC8 can bind with the catalytic subunit of protein phosphatase 1α (PP1α) to regulate its distribution, and Downregulation of TSLNC8 results in PP1α cytoplasmic accumulation, thus re-activating the MAPK signaling. Eventually, the overexpression of TSLNC8 in BRAF inhibitor PLX4720-resistant melanoma cells restores the sensitive to BRAF inhibitor. CONCLUSION: Collectively, our research provides a compelling rationale for resistance to BRAF inhibitor in melanoma, and the patient might benefit from the combinatorial therapy of BRAF inhibitors and lncRNA TSLNC8.
Assuntos
Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Proteína Fosfatase 1/metabolismo , RNA Longo não Codificante/metabolismo , Sulfonamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA Longo não Codificante/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Acquired reactive perforating collagenosis is a rare skin disease characterized by the discharge of collagen fibers through the epidermis. There is no standard treatment for this disease currently. Here, we report a case of ARPC that has been successfully treated and cured. CASE DESCRIPTION: A 32-year-old man developed severe itching papules on his torso and limbs for 3 months. Skin lesions were keratotic papules scattered on the limbs and trunk, with a diameter of 3 to 12 mm. Some lesions had umbilical recesses and the shape of a crater with positive isomorphic reactions. The patient scratched his severe itching lesions which merged into large ones. This patient had histories of hypertension and dilated cardiomyopathy with mild congestive heart failure. The clinical presentation and histopathology of skin lesions met Faver's diagnostic criteria for ARPC. TREATMENT: Oral Doxycycline 100mg/d, NB-UVB phototherapy 3 times a week with initial dose 400mJ/cm2, gradually increased to 1200mJ/cm2(total cumulative dose 16700J/cm2). OUTCOMES: After a week of treatment, the patient's itching symptoms were significantly reduced and stopped presenting any new skin lesions. Most of the lesions healed in 6 weeks of treatment. LESSONS: Doxycycline combined with NB-UVB may be an effective treatment for ARPC.
RESUMO
BACKGROUND: Glucocorticoids, such as dexamethasone, are widely used for prevent vomiting and allergic reactions associated with cancer immunotherapy and chemotherapy. Although such use is reported to reduce the immunotherapy's efficacy, nevertheless, how dexamethasone associates with specific immune cells, particularly inside the tumor microenvironment, still remains unclear. METHODS: We integrate multi-omics data, including transcriptome, mutation, copy number variation (CNV), and methylation, to explore the dexamethasone responsive genes. RESULTS: We surprisingly found that dexamethasone responsive genes are transcriptionally down-regulated in general, where heterozygous deletion underlie such dysregulation. We further perform the pathway analysis and demonstrate that such dysregulation associates with cancer hallmarks such as epithelial-to-mesenchymal transformation (EMT) activation. Next, by performing the drug sensitivity analysis, we generate a list of drugs whose efficacy potentially associates with dexamethasone response, including Methotrexate and Navitoclax. Unexpectedly, in the cancer microenvironment, dexamethasone response score positively correlates with a subset of innate immune cells. This indicates that dexamethasone potentially correlated with anti-cancer immunity in the cancer microenvironment which may be on the contrary to its systemic effect. CONCLUSIONS: Our systems-level analysis define the landscape of dexamethasone responsive genes in cancers and may serve as a useful resource for understanding the roles of dexamethasone in cancer.
RESUMO
Melanoma is a highly malignant skin cancer with limited treatment options, the mechanism of the occurrence and development of melanoma is still unclear till now. Receptor for activated C kinase 1 (RACK1) is a scaffolding protein that mediates multiple signaling pathways; it interconnects distinct signaling pathways to control essential cellular processes. RACK1 was reported as an oncogene in human tumorigenesis, but little is known about its role in melanoma. This study aimed to investigate the expression of RACK1 in patients with melanoma and to reveal its possible functions in melanoma cells. The expression profiles of RACK1 detected in tumor tissues from melanoma patients showed that RACK1 was higher in tumor tissues, and its expression level was well associated with the clinical progression of melanoma (TNM stage, P=0.009). Furthermore, RNA interfering (RNAi) knockdown of RACK1 could efficiently suppress the proliferation, migration and invasion of A375 and A875 cells and promote their apoptosis. Taken together, these results suggest that RACK1 may be a poor prognostic factor in human melanoma, and it may be a new therapeutic target for melanoma treatment.
RESUMO
BACKGROUND: miRNAs are small noncoding RNAs that function as posttranscriptional regulators during development and disease. Aberrant expression of miRNAs has been associated with various types of malignant tumors. Decreased levels of miR-124 have been observed in human cancers. RACK1 is a scaffold protein that acts as an oncogene in various human cancers. The association between miR-124 and RACK1 in melanoma has not been characterized. MATERIALS AND METHODS: Real-time quantitative PCR was used to analyze RACK1 and miR-124 expression in melanoma tissue and cell lines. Dual-Luciferase reporter assay was performed to evaluate the effect of miR-124 inhibition on RACK1 expression. The effects of miR-124 on RACK1 in melanoma cell lines were evaluated using Western blot analysis and immunocytochemical staining. Wound-healing, transwell, and MTT assays, and annexin V-fluorescein isothiocyanate/propidium iodide followed by flow cytometry were used to evaluate the effects of miR-124 on RACK1-mediated proliferation, migration, invasion, and apoptosis of melanoma cells. RESULTS: The expression of miR-124 in melanoma tissue was lower than that in normal skin tissue, and the expression of RACK1 was higher in melanoma tissue than that in normal skin tissue. Analysis using Dual-Luciferase reporter assay showed that RACK1 was a direct target of miR-124. Western blot and immunocytochemical staining showed that the expression of RACK1 was significantly inhibited by miR-124 in both A375 and A875 melanoma cells. Furthermore, the results of functional experiments showed that degradation of RACK1 by miR-124 inhibited proliferation, migration, and invasion of melanoma cells, and promoted melanoma cell apoptosis. CONCLUSION: The results suggested that miR-124 affected melanoma cells by directly targeting RACK1. miR-124 and RACK1 may be biomarkers for clinical diagnosis, and prognostic factors of human melanoma. Furthermore, miR-124 and RACK1 may be targets for the treatment of melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Eritema Multiforme/induzido quimicamente , Hipersensibilidade Tardia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Anti-Inflamatórios/uso terapêutico , Eritema Multiforme/tratamento farmacológico , Humanos , Hipersensibilidade Tardia/tratamento farmacológico , Metilprednisolona/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , PrognósticoRESUMO
It has been demonstrated that numerous types of metastatic cancer overexpress vacuolar-type H+ (V)-ATPases. It may be possible to inhibit the growth and metastasis of human cancer cells by inhibiting V-ATPases. It was previously reported that diphyllin, a novel V-ATPase inhibitor, can inhibit the migration and invasion of SGC7901 human gastric cancer cells; however, the effects of cleistanthin A (CA), a diphyllin glycoside, on melanoma cells has not been demonstrated. The present study aimed to investigate the effect of CA as a V-ATPase inhibitor and its effects on the invasion and metastasis of A375 cells. The results of an MTT assay in the present study indicated that the growth inhibition of A375 cells by CA was induced in a dose- and time-dependent manner; however, A375 cell viability was not significantly affected by low concentrations (0.03, 0.1 and 0.3 µM) after 24 h. Similar results were obtained by viable cell counting with trypan blue. Therefore, these concentrations of CA were selected for the treatment of A375 cells in further experiments. It was demonstrated that CA inhibited the expression of V-ATPases in a dose-dependent manner and decreased the internal pH level of A375 cells. Alterations to the lysosomal pH were associated with the CA concentration. Furthermore, CA treatment induced a significant decrease in cell migration and invasion, as demonstrated with wound-healing and Transwell assays. Gelatin zymography and western blot analysis demonstrated that the expression levels of matrix metallopeptidase (MMP)-2 and -9 decreased following CA treatment. Therefore, CA can be characterized as a novel V-ATPase inhibitor for the treatment of melanoma that may inhibit invasion and metastasis by downregulating the expression of MMP-2 and -9.
RESUMO
Research on examinees' response changes on multiple-choice tests over the past 80 years has yielded some consistent findings, including that most examinees make score gains by changing answers. This study expands the research on response changes by focusing on a high-stakes admissions test-the Verbal Reasoning and Quantitative Reasoning measures of the GRE revised General Test. We analyzed data from 8,538 examinees for Quantitative and 9,140 for Verbal sections who took the GRE revised General Test in 12 countries. The analyses yielded findings consistent with prior research. In addition, as examinees' ability increases, the benefit of response changing increases. The study yielded significant implications for both test agencies and test takers. Computer adaptive tests often do not allow the test takers to review and revise. Findings from this study confirm the benefit of such features.