RESUMO
BACKGROUND: The optimal duration of regimens for tailored therapy based on genotypic resistance for clarithromycin has yet to be established. AIM: This study was a nationwide, multicenter, randomized trial comparing empirical therapy with tailored therapy based on genotypic resistance for first-line eradication of Helicobacter pylori. We also compared the eradication rates of 7- and 14-day regimens for each group. PATIENTS AND METHODS: Patients with H. pylori infection were first randomized to receive empirical or tailored therapy. Patients in each group were further randomized into 7- or 14-day regimens. Empirical therapy consisted of a triple therapy (TT) regimen (twice-daily doses of pantoprazole 40 mg, amoxicillin 1 g, and clarithromycin 500 mg) for 7 or 14 days. Tailored therapy consisted of TT of 7 or 14 days in patients without genotypic resistance. Patients with genotypic resistance were treated with bismuth quadruple therapy (BQT) regimens (twice-daily doses of pantoprazole 40 mg, three daily doses of metronidazole 500 mg, and four times daily doses of bismuth 300 mg and tetracycline 500 mg) for 7 or 14 days. A 13C-urea breath test assessed eradication rates. The primary outcome was eradication rates of each group. RESULTS: A total of 593 patients were included in the study. The eradication rates were 65.7% (201/306) in the empirical therapy group and 81.9% (235/287) in the tailored therapy group for intention-to-treat analysis (p < 0.001). In the per-protocol analysis, the eradication rates of the empirical therapy and tailored groups were 70.3% (201/286) and 85.5% (235/274) (p < 0.001), respectively. There was no difference in compliance between the two groups. The rate of adverse events was higher in the tailored group compared to the empirical group (p < 0.001). DISCUSSION: Our study confirmed that tailored therapy based on genotypic resistance was more effective than empirical therapy for H. pylori eradication in Korea. However, no significant difference was found between 7- and 14-day regimens for each group. Future studies are needed to determine the optimal duration of therapy for empirical and tailored therapy regimens.
Assuntos
Antibacterianos , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Humanos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Masculino , Feminino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , República da Coreia , Adulto , Idoso , Resultado do Tratamento , Farmacorresistência Bacteriana , Amoxicilina/uso terapêutico , Amoxicilina/administração & dosagem , Claritromicina/uso terapêutico , Metronidazol/uso terapêutico , Pantoprazol/uso terapêutico , Genótipo , Adulto JovemRESUMO
BACKGROUND: Differences in clinical efficacy based on the fluence of fractional picosecond laser treatment for acne scars are unknown. OBJECTIVE: To compare the efficacy and safety of low-fluence versus high-fluence fractional picosecond Nd:YAG 1064-nm laser treatment in acne scar patients. METHODS: In this 12-week, investigator-blinded, randomized, split-face study, 25 patients with moderate-to-severe acne scars received three sessions of high-fluence laser treatment (1.0 J/cm2 ) on one side of their face and low-fluence (0.3 J/cm2 ) on the other side every 4 weeks. Patients were assessed using acne scar counts, the scar global assessment (SGA), and the ECCA scar grading scale every 4 weeks. The histological analysis compared the acne scars obtained before and 4 weeks after treatment. RESULTS: At their last visit, 88.00% and 92.00% of the subjects achieved >30% reduction in scar counts on the low- and high-fluence sides, respectively, without a significant difference between the two sides. On both sides, the scar counts, SGA, and ECCA score significantly improved 4 weeks after the last treatment. Although the high-fluence side showed a greater reduction in scar counts (-66.73%) than the low-fluence side (-62.13%), the two sides had no significant difference in the grading scores. The high-fluence side showed significantly more severe pain and higher side-effect scores immediately and 4 weeks after treatment. Histological analysis revealed a significantly increased collagen, elastin, and vimentin expression after treatment on the low-fluence side. CONCLUSIONS: The low-fluence setting demonstrated comparable efficacy and superior safety in treating acne scars compared with the high-fluence setting.
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Acne Vulgar , Lasers de Estado Sólido , Humanos , Cicatriz/etiologia , Cicatriz/radioterapia , Acne Vulgar/complicações , Acne Vulgar/radioterapia , Resultado do Tratamento , Lasers de Estado Sólido/efeitos adversos , ElastinaRESUMO
BACKGROUND: Photoprotection is crucial in preventing the development and progression of various skin diseases. However, patients with skin disease have limited awareness of photoprotection. We evaluated the knowledge and behavioral patterns of photoprotection among Koreans with skin diseases. METHODS: A cross-sectional study was conducted in 11 general hospitals across South Korea. The study population consisted of patients aged 19 years or older who visited dermatologic clinics for their skin diseases. A self-administered questionnaire was used to collect patient demographics, knowledge of photoprotection, and photoprotective habits. RESULTS: In this study, 1173 patients with skin cancer, hyperpigmentary disorders, hypopigmentary disorders, or other skin diseases participated. Females scored significantly higher in knowledge of photoprotection compared to males (mean score 8.4 vs. 7.8; p < .001), and younger patients (<50 years) scored higher than older patients (mean score 8.7 vs. 7.5; p < .001). Males also reported longer sun exposure times and lower usage of photoprotective measures (both p < .001). Patients with skin cancer had the lowest mean knowledge score (7.1 ± 2.6) and were less likely to use photoprotective measures compared to other groups (p < .001). In contrast, patients with hyperpigmentation actively avoided sun exposure compared with other groups (p < 0.001). CONCLUSIONS: Knowledge of photoprotection among Korean patients with skin diseases varied depending on the gender, age, and type of skin disease. Their photoprotective behaviors were inadequate, especially among males and those with skin cancer. These findings emphasize the importance of educating and tailoring photoprotection strategies for patients with skin diseases.
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Hiperpigmentação , Neoplasias Cutâneas , Masculino , Feminino , Humanos , Raios Ultravioleta/efeitos adversos , Protetores Solares/uso terapêutico , Estudos Transversais , Neoplasias Cutâneas/tratamento farmacológico , Hábitos , Hiperpigmentação/tratamento farmacológicoRESUMO
Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for their application in research. However, traditional methods such as morphological evaluation and immunohistochemical analysis have limitations due to their lack of precision and invasiveness, respectively. This study aims to identify non-invasive biomarkers for RO differentiation quality using exosomal microRNAs (miRNAs), which are known to reflect cell-specific functions and development in the retina. We differentiated ROs from human induced pluripotent stem cells (hiPSCs) and classified them into 'superior' and 'inferior' groups based on morphological and immunohistochemical criteria. Exosomes from the conditioned media were isolated and analyzed for miRNA content. Our findings revealed distinct miRNA profiles between superior and inferior ROs, with superior ROs exhibiting higher miRNA diversity and specifically up- or down-regulated miRNAs. Gene ontology and pathway enrichment analyses indicated that the target genes of these miRNAs are involved in neuron proliferation and differentiation. The study suggests the potential of exosomal hsa-miR-654-3p and hsa-miR-451a as non-invasive biomarkers for real-time monitoring of RO quality, facilitating the development of standardized, efficient, and cost-effective culture methods.
Assuntos
Biomarcadores , Diferenciação Celular , Exossomos , Células-Tronco Pluripotentes Induzidas , MicroRNAs , Organoides , Retina , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Organoides/metabolismo , Organoides/citologia , Diferenciação Celular/genética , Retina/citologia , Retina/metabolismo , Biomarcadores/metabolismo , Exossomos/metabolismo , Exossomos/genética , Células CultivadasRESUMO
BACKGROUND: Proton-pump inhibitors (PPIs) are the most effective drugs for treating acid-related disorders. However, once-daily dosing with conventional PPIs fail to fully control acid secretion over 24 h. This study aimed to compare the efficacy and safety of HIP1601 (dual delayed-release esomeprazole) and HGP1705 (delayed-release esomeprazole) in patients with erosive esophagitis (EE). METHODS: We enrolled 213 patients with EE randomized in a 1:1 ratio to receive 40 mg HIP1601 (n = 107) or HGP1705 (n = 106) once daily for 4 or 8 weeks. The primary endpoint was the EE healing rate, confirmed by endoscopy up to week 8. GERD-related symptoms and treatment-emergent adverse events were compared between both groups. RESULTS: By week 8, the estimated healing rates of EE were 97.8% and 96.8% in the HIP1601 and HGP1705 groups, respectively, with a 95% confidence interval of -4.7 to 7.2. After 4 or 8 weeks of treatment, the EE healing rate at week 4, complete resolution rate of symptoms, time to sustained resolution of symptoms, and number of rescue medications used were similar in both groups. The proportion of heartburn- and acid regurgitation-free nights by week 4 were higher in the HIP1601 group compared to the HGP1705 group, but the difference did not reach clinical significance (87.7% vs. 85.8%, P = 0.514, 87.5% vs. 85.8%, P = 0.774). The number of adverse events did not differ significantly between the two groups. CONCLUSIONS: The efficacy and safety of HIP1601 40 mg were comparable to those of HGP1705 40 mg for the treatment of EE and symptomatic improvement of GERD. TRIAL REGISTRATION: NCT04080726 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT04080726 ), registration date: 25/10/2018.
Assuntos
Esofagite Péptica , Esofagite , Refluxo Gastroesofágico , Úlcera Péptica , Humanos , Método Duplo-Cego , Esomeprazol/efeitos adversos , Esofagite Péptica/tratamento farmacológico , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/diagnóstico , Inibidores da Bomba de Prótons/efeitos adversos , Resultado do TratamentoRESUMO
Keloids are skin tumours caused by aberrant growth of dermal fibroblasts. Cellular senescence contributes to aging and various pathological conditions, including cancer, atherosclerosis, and fibrotic diseases. However, the effects of cellular senescence and senolytic drugs on keloids remain largely unknown. This study investigated senescent fibroblasts in keloids and assessed the effects of dasatinib on these cells. Tissues acquired from keloid removal surgery were analysed for senescence-associated ß-galactosidase-positive cells, p16 expression, and the effects of dasatinib treatment on keloids. Keloid tissue was xenotransplanted into mice, and the effect of intralesional dasatinib injection on keloid growth was observed. The results showed that the numbers of ß-galactosidase-positive and p16-expressing cells were higher in the keloids compared with in the controls. Dasatinib induced selective clearance of senescent cells and decreased procollagen expression in cultured keloid fibroblasts. In this xenotransplant keloid mouse model, intralesional injection of dasatinib reduced gross keloid tissue weight and the expression of both procollagen and p16. In addition, dasatinib-treated keloid fibroblasts conditioned medium reduced procollagen and p16 expression in cultured keloid fibroblasts. In conclusion, these results suggest that an increased number of senescent fibroblasts may play an important role in the pathogenesis of keloids. Therefore, dasatinib could be an alternative treatment for patients with keloids.
Assuntos
Queloide , Animais , Camundongos , Queloide/tratamento farmacológico , Queloide/metabolismo , Queloide/patologia , Pró-Colágeno/metabolismo , Pró-Colágeno/farmacologia , Dasatinibe/metabolismo , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Senescência Celular , Fibroblastos/metabolismo , Fibroblastos/patologia , Células CultivadasRESUMO
BACKGROUND: To discuss the first case of mitomycin C (MMC) toxicity after XEN® gel stent implantation in a glaucoma patient, conducted using the XEN "air" technique with an ophthalmic viscosurgical device (OVD). CASE PRESENTATION: A 44-year-old Asian male presented with increased intraocular pressure (IOP; 52 mmHg) accompanied by keratic precipitates and an edematous cornea. He was diagnosed with uveitic glaucoma in the left eye, and the IOP was controlled with a topical anti-glaucoma agent. However, glaucoma progression was revealed by Humphrey visual field (HVF) and optical coherence tomography (OCT) examinations. The patient underwent uneventful XEN gel stent implantation using the XEN air technique and an MMC (0.02%, 0.1 mL) injection, with subconjunctival air and OVD injection provided prior to XEN implantation in the left eye. The patient exhibited a decreased IOP (11 mmHg), elevated bleb, and extensive subconjunctival hemorrhage on postoperative day 1. On postoperative day 18, diffuse conjunctival injection and a large avascular bleb was noticed around the XEN gel stent. The patient complained of severe eye pain and discomfort, suggestive of MMC toxicity, and the IOP was 12 mmHg. The patient was treated with a topical steroid and antibiotics tapered over a 6-month period. Finally, the toxicity was successfully controlled, with the IOP stabilizing at around 15 mmHg. CONCLUSIONS: Although significantly greater lowering of the IOP can be expected with the use of subconjunctival OVD injection and MMC during XEN gel stent implantation, a cautious approach and a longer monitoring period are required.
Assuntos
Implantes para Drenagem de Glaucoma , Glaucoma de Ângulo Aberto , Glaucoma , Humanos , Masculino , Adulto , Mitomicina/efeitos adversos , Pressão Intraocular , Glaucoma de Ângulo Aberto/cirurgia , Implantes para Drenagem de Glaucoma/efeitos adversos , Resultado do Tratamento , Glaucoma/cirurgia , Stents/efeitos adversosRESUMO
BACKGROUND: Pigmented contact dermatitis (PCD), a rare variant of non-eczematous contact dermatitis, is clinically characterized by sudden-onset brown or grey pigmentation on the face and neck. It is hypothesized to be caused by repeated contact with low levels of allergens. OBJECTIVES: This study evaluated the risk of using hair dyes in patients with PCD in Korea. METHODS: A total of 1033 PCD patients and 1366 controls from 31 university hospitals were retrospectively recruited. We collected and analysed the data from the patient group, diagnosed through typical clinical findings of PCD and the control group, which comprised age/sex-matched patients who visited the participating hospitals with pre-existing skin diseases other than current allergic disease or PCD. RESULTS: Melasma and photosensitivity were significantly more common in the control group, and a history of contact dermatitis was more common in the PCD group. There were significantly more Fitzpatrick skin type V participants in the PCD group than in the control group. There was no significant difference in sunscreen use between the groups. Using dermatologic medical history, Fitzpatrick skin type and sunscreen use as covariates, we showed that hair dye use carried a higher PCD risk (odds ratio [OR] before adjustment: 2.06, confidence interval [CI]: 1.60-2.65; OR after adjustment: 2.74, CI: 1.88-4.00). Moreover, henna users had a higher risk of PCD (OR before adjustment: 5.51, CI: 4.07-7.47; OR after adjustment: 7.02, CI: 4.59-10.74), indicating a significant increase in the risk of PCD with henna dye use. Contact dermatitis history was more prevalent in henna users than in those using other hair dyes in the PCD group (17.23% vs. 11.55%). CONCLUSION: Hair dye use is a risk factor for PCD. The risk significantly increased when henna hair dye was used by those with a history of contact dermatitis.
Assuntos
Dermatite Alérgica de Contato , Tinturas para Cabelo , Humanos , Tinturas para Cabelo/efeitos adversos , Estudos Retrospectivos , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/epidemiologia , Dermatite Alérgica de Contato/etiologia , Protetores Solares , República da Coreia/epidemiologiaRESUMO
Solar lentigo (SL) commonly occurs as hyperpigmented macules in areas exposed to ultraviolet radiation. It typically shows an increased number of melanocytes in the basal cell layer of the skin, with or without elongated rete ridges. This retrospective study aimed to evaluate the characteristic dermoscopic patterns, reflecting different histopathological features, which might be valuable in predicting the possibility of postinflammatory hyperpigmentation (PIH) occurring after laser treatment. In total, 88 Korean patients diagnosed with biopsy-proven SL (a total of 90 lesions were diagnosed) between January, 2016 and December, 2021 were included. Histopathological patterns were classified into six categories. Dermoscopic features were classified into six categories. Pseudonetwork pattern and rete ridge elongation showed a statistically significant negative correlation. This means that a flatter epidermis is likely to manifest as a pseudonetwork pattern. The erythema pattern showed a significant positive correlation with interface changes and inflammatory infiltration. Bluish-gray granules (peppering), a characteristic dermoscopic finding, showed significant positive correlations with interface changes, inflammatory infiltration, and dermal melanophages. Clinicians considering laser treatment for patients with SL should perform dermoscopic tests before treatment. The pseudonetwork relates to flattened epidermis and fewer Langerhans cells; thus, a lower remission of PIH after laser treatment might be expected. If bluish-gray granules or erythema are observed, inflammatory conditions are likely to be involved. In such cases, regression of the inflammatory response through drug therapy, such as topical corticosteroids, should be a priority option before laser treatment.
Assuntos
Hiperpigmentação , Lentigo , Humanos , Estudos Retrospectivos , Raios Ultravioleta , Lentigo/etiologia , Hiperpigmentação/etiologia , Lasers , DermoscopiaRESUMO
Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.
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Exossomos , Células-Tronco Pluripotentes Induzidas , MicroRNAs , Degeneração Retiniana , Cirurgiões , Ratos , Humanos , Animais , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/metabolismo , Proteínas Quinases Ativadas por Mitógeno , Exossomos/metabolismo , Espécies Reativas de Oxigênio , Células-Tronco Pluripotentes Induzidas/metabolismoRESUMO
BACKGROUND: Large studies on the clinical features and natural course of pediatric longitudinal melanonychia (LM) are lacking. OBJECTIVE: To investigate the clinical features and natural course of pediatric LM. METHODS: Retrospective cohort analysis of pediatric patients (age ≤ 18 years) with LM. RESULTS: We examined 703 LM lesions in 381 children. Single, narrow, and homogeneously pigmented fingernail lesions were most frequently observed. Our results suggested that within 3, 4.5, and 9.5 years after onset, approximately 3%, 5%, and 10% of LM lesions, respectively, will completely regress and that single, left-sided, and homogeneously pigmented lesions are more likely to disappear completely. The age of onset, sex, finger/toe position, Hutchinson's sign, and nail dystrophy were not associated with complete regression. During follow-up, most cases demonstrated no change in color or width between the first and last visit, and early darkening/widening before stabilization or lightening/narrowing was common. The lightning of pigmentation was associated with complete regression, whereas change in width was not. LIMITATIONS: Retrospective study at a tertiary center. CONCLUSION: Our results suggest that clinicians ought to follow pediatric patients with LM without intervention for several years even if lesions grow darker or wider. Single, left-sided, and homogeneously colored lesions are more likely to regress.
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Melanoma , Doenças da Unha , Neoplasias Cutâneas , Adolescente , Criança , Estudos de Coortes , Humanos , Melanoma/patologia , Doenças da Unha/diagnóstico , Doenças da Unha/epidemiologia , Doenças da Unha/patologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.
Assuntos
Inibidores de Calcineurina/efeitos adversos , Linfoma/epidemiologia , Fototerapia/efeitos adversos , Neoplasias Cutâneas/epidemiologia , Vitiligo/terapia , Administração Cutânea , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores de Calcineurina/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Pele/patologia , Neoplasias Cutâneas/etiologia , Fatores de Tempo , Adulto JovemRESUMO
The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Melanoma/metabolismo , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Actinas , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Melanoma/genética , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas B-raf/genética , RNA/genética , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Vemurafenib , Proteínas de Sinalização YAPRESUMO
Keloids, benign cutaneous overgrowths of dermal fibroblasts, are caused by pathologic scarring of wounds during healing. Current surgical and therapeutic modalities are unsatisfactory. Although adiponectin has shown an antifibrotic effect, its large size and insolubility limit its potential use in keloid treatment. We investigated the effect of a smaller and more stable adiponectin-based peptide (ADP355) on transforming growth factor ß1 (TGF-ß1)-induced fibrosis in a primary culture of keloid fibroblasts prepared from clinically obtained keloid samples. Xenograft of keloid tissues on athymic nude mice was used to investigate the effect of intralesional injection of ADP355. ADP355 significantly attenuated the TGF-ß1-induced expression of procollagen type 1 in keloid fibroblasts (p < 0.05). Moreover, it inhibited the TGF-ß1-induced phosphorylation of SMAD3 and ERK, while amplifying the phosphorylation of AMP-activated protein kinase (p < 0.05). Knockdown of adiponectin receptor 1 reversed the attenuation of procollagen expression in ADP355-treated TGF-ß1-induced fibrosis (p < 0.05). ADP355 also significantly reduced the gross weight and procollagen expression of keloid tissues in xenograft mice compared to control animals. These results demonstrate the therapeutic potential of the adiponectin peptide ADP355 for keloids.
Assuntos
Fibroblastos/metabolismo , Queloide/tratamento farmacológico , Queloide/metabolismo , Oligopeptídeos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Adiponectina/farmacologia , Adiponectina/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cicatriz/tratamento farmacológico , Cicatriz/metabolismo , Colágeno Tipo I/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose , Técnicas de Silenciamento de Genes , Humanos , Injeções Intralesionais , Camundongos , Camundongos Nus , Oligopeptídeos/administração & dosagem , Fosforilação , Proteínas Quinases/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad3/metabolismo , Transplante HeterólogoRESUMO
Microtubule-based motors contribute to the efficiency and selectivity of Golgi exit and post-Golgi transport of membrane proteins that are targeted to distinct compartments. Cytoplasmic dynein moves post-Golgi vesicles that carry rhodopsin toward the base of the connecting cilium in photoreceptor cells; however, the identity of the motors that are involved in the vesicular trafficking of ciliary membrane proteins in nonphotoreceptor cells remains unclear. Here, we demonstrate that the minus end-directed kinesin KIFC1 (kinesin family member C1) is required for both ciliary membrane protein transport and serum starvation-induced ciliogenesis in retinal pigmented epithelial 1 cells. Although KIFC1 is known as a mitotic motor that is sequestered in the nucleus during interphase, KIFC1 immunoreactivity appeared in the Golgi region after serum starvation. Knockdown of KIFC1 inhibited the export of ciliary receptors from the Golgi complex. KIFC1 overexpression affected the Golgi localization of GMAP210 (Golgi microtubule-associated protein 210) and IFT20 (intraflagellar transport 20), which are involved in membrane protein transport to cilia. Moreover, KIFC1 physically interacted with ASAP1 (ADP-ribosylation factor GTPase-activating protein with SH3 domain, ankyrin repeat and PH domain 1), which regulates the budding of rhodopsin transport carriers from the Golgi complex, and KIFC1 depletion caused Golgi accumulation of ASAP1. A decrease in the centrosomal levels of IFT20 and TTBK2 (τ-tubulin kinase 2) was associated with ciliogenesis defects in KIFC1-depleted cells. Our results suggest that KIFC1 plays roles in the Golgi exit of ciliary receptors and in the recruitment of ciliogenesis regulators.-Lee, S.-H., Joo, K., Jung, E. J., Hong, H., Seo, J., Kim, J. Export of membrane proteins from the Golgi complex to the primary cilium requires the kinesin motor, KIFC1.
Assuntos
Complexo de Golgi/metabolismo , Cinesinas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Cílios/genética , Cílios/metabolismo , Proteínas do Citoesqueleto , Complexo de Golgi/genética , Cinesinas/genética , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transporte Proteico/fisiologiaRESUMO
INTRODUCTION: The eradication rates for Helicobacter pylori have decreased in Korea although the prevalence of this bacterium has also decreased. Antibiotic resistance is likely to be a crucial factor in H. pylori eradication success, and we therefore mapped these resistance patterns nationwide in Korea. MATERIALS AND METHODS: Five hundred and ninety adult subjects were prospectively enrolled from 2017 to 2018 from 15 centers across six geographic areas of Korea. A total of 580 biopsy tissues had been sampled from these patients during an upper endoscopy and were frozen at -80°C and delivered to a central laboratory. The agar dilution method was used to determine the minimum inhibitory concentration of amoxicillin, clarithromycin, metronidazole, tetracycline, ciprofloxacin, and levofloxacin for each H. pylori isolate. RESULTS: The culture success rate was 60.2% (349/580). Resistance rates against clarithromycin, metronidazole, amoxicillin, tetracycline, levofloxacin, and ciprofloxacin were 17.8%, 29.5%, 9.5%, 0%, 37.0%, and 37.0%, respectively. The geographic distribution of metronidazole and quinolone resistance was highly variable. Some subjects had multiple H. pylori strains in the antrum and body of the stomach and showed a heterogeneous resistance profile between these anatomic areas. The H. pylori multidrug resistance (MDR) rate was 25.2% (88/349) among amoxicillin, clarithromycin, metronidazole, tetracycline, and quinolone and 11.2% (39/349) among four of these major antibiotics except for quinolone. The Seoul and Chungcheong areas showed a relatively lower MDR rate. CONCLUSION: The antibiotic resistance of H. pylori differs by drug and geographic area in Korea. Detailed nationwide antibiotic resistance mapping is needed to develop an effective H. pylori eradication strategy.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/farmacologia , Claritromicina/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/fisiologia , Humanos , Levofloxacino/farmacologia , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia , Tetraciclina/farmacologia , Adulto JovemRESUMO
BACKGROUND: Although various laser treatments have been tried for congenital melanocytic nevi (CMNs), only small retrospective studies with short-term follow-up had been done to assess outcomes. OBJECTIVE: We analyzed the long-term outcomes of laser treatment for CMN and compared these outcomes with those of a combination treatment including partial excision and lasers. METHODS: Patients with CMN treated with lasers were retrospectively reviewed, and patients with >3 years of follow-up were grouped as the long-term follow-up group. RESULTS: A total of 67 cases of CMN were reviewed. Among 20 patients (20/52, 38.5%) with near total clearance during laser-only treatment, 11 patients were in the long-term follow-up group, and 5 of 11 showed repigmentation. In total, 15 patients showed repigmentation regardless of clearance, and the mean period until repigmentation was 3.93 years from the initial treatment. Patients with partial excision and laser combination treatment showed higher Investigator's Global Assessment scores, fewer laser treatments, and shorter treatment periods compared with patients with laser-only treatment. LIMITATIONS: This is a retrospective study, and various laser devices were used. CONCLUSION: More than 4 years of follow-up is required to evaluate the efficacy of lasers in CMN, and partial excision and laser combination treatment might be an effective treatment option.
Assuntos
Terapia a Laser/métodos , Nevo Pigmentado/congênito , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/cirurgia , Adolescente , Criança , Estudos de Coortes , Terapia Combinada , Estética , Feminino , Humanos , Masculino , Cirurgia de Mohs/métodos , Recidiva , República da Coreia , Estudos Retrospectivos , Medição de Risco , Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: For small to medium sized congenital melanocytic nevi (CMN), the treatment of choice is staged surgical excision. Ablative lasers or pigment-specific lasers have also been recommended for lesions difficult for surgical removal or to avoid surgery. In this study, we retrospectively analyzed the results of several treatment options for CMN to find out the optimal treatment method. METHODS: Patients with small to medium sized CMN were retrospectively reviewed. Treatment options were categorized into four groups: (i) Excision only; (ii) Excision followed by scar laser; (iii) Excision followed by pigment-specific laser; and (iv) Laser only. Treatment response was assessed by investigator's global assessment (IGA) score on a seven-point scale. RESULTS: A total of 119 cases were included. Lesions were most commonly located on the face (59/119, 49.6%), measured 2 â¼ 10 cm in size (72/119, 60.5%), and treated with excision only (50/119, 42.0%). Among treatment options, excision followed by scar laser showed the highest IGA score of 6.38. Options including surgical methods showed higher IGA scores compared to laser-only treatment (P < 0.01). Staged excisions and single excisions showed no difference in IGA scores. Patient satisfaction scores increased after scar laser treatment of the staged excision scar. CONCLUSIONS: For the treatment of small to medium sized CMN, treatment strategies including surgical methods are cosmetically superior to laser-only treatment. Also, the combination of surgical excision with scar laser has the potential for better clinical outcomes and patient satisfaction. Lasers Surg. Med. 51:62-67, 2019. © 2018 Wiley Periodicals, Inc.
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Procedimentos Cirúrgicos Dermatológicos/métodos , Terapia a Laser/métodos , Nevo Pigmentado/radioterapia , Nevo Pigmentado/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos RetrospectivosRESUMO
To investigate the role of Wnt/ß-catenin signaling pathway in the restoration of induced pluripotent stem cell-derived retinal pigment epithelium (hiPSC-RPE) after laser photocoagulation. After differentiation of RPE cells from hiPSCs, laser photocoagulation was performed. Activation of Wnt/ß-catenin signaling at days 1 and 5 after laser photocoagulation was evaluated by expression of ß-catenin. Cell proliferation and alteration in cell-to-cell contact at day 5 after laser photocoagulation with or without Dickkopf-1 (Dkk-1) treatment were studied using ethynyl-2'-deoxyuridine (EdU) assay and zonula occludens-1 (ZO-1) expression analysis, respectively. The mRNA levels of Wnt genes at day 5 after laser photocoagulation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Activation of Wnt/ß-catenin signaling at days 1 and 5 after laser photocoagulation was confirmed by ß-catenin accumulation in the cytoplasm and nucleus of hiPSC-RPE. Many EdU-positive cells also expressed ß-catenin, and the number of EdU-positive cells was decreased at day 5 after laser photocoagulation after Dkk-1 treatment, indicating that Wnt/ß-catenin signaling mediated hiPSC-RPE proliferation. ZO-1 expression was not decreased with Dkk-1 treatment at day 5 after laser photocoagulation, indicating that Wnt/ß-catenin signaling mediated hiPSC-RPE restoration. At day 5, after laser photocoagulation, mRNA levels of Wnt2b, Wnt3, Wnt5a, Wnt7a, and Wnt10b were increased. Wnt/ß-catenin signaling has a crucial role in restoration of hiPSC-RPE proliferation after laser photocoagulation. Manipulation of Wnt/ß-catenin signaling while elucidating the underlying mechanisms of RPE restoration might have a therapeutic potential in retinal degenerative diseases.
Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Fotocoagulação a Laser , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos da radiação , Via de Sinalização Wnt , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Forma Celular/efeitos da radiação , Fluorescência , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Fatores de Tempo , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/efeitos da radiação , Proteína da Zônula de Oclusão-1/metabolismo , beta Catenina/metabolismoRESUMO
KEY POINTS: Interstitial cells of Cajal (ICC) from murine colonic muscles express genes encoding inwardly rectifying K+ channels. Transcripts of Kcnj2 (Kir2.1), Kcnj4 (Kir2.3), Kcnj14 (Kir2.4), Kcnj5 (Kir3.4), Kcnj8 (Kir 6.1) and Kcnj11 (Kir6.2) were found in colonic ICC. A conductance with properties consistent with Kir2 channels was observed in ICC but not in smooth muscle cells (SMC). Despite expression of gene transcripts, G-protein gated K+ channel (Kir3) and KATP (Kir6) currents were not resolved in ICC. KATP is a conductance prominent in SMC. Kir2 antagonist caused depolarization of freshly dispersed ICC and colonic smooth muscles, suggesting that this conductance is active under resting conditions in colonic muscles. The conclusion of the present study is that ICC express the Ba2+ -sensitive, inwardly rectifying K+ conductance in colonic muscles. This conductance is most probably a result of heterotetramers of Kir2 gene products, with this regulating resting potentials and the excitability of colonic muscles. ABSTRACT: Membrane potentials of gastrointestinal muscles are important because voltage-dependent Ca2+ channels in smooth muscle cells (SMC) provide the Ca2+ that triggers contraction. Regulation of membrane potential is complicated because SMC are electrically coupled to interstitial cells of Cajal (ICC) and PDGFRα+ cells. Activation of conductances in any of these cells affects the excitability of the syncytium. We explored the role of inward rectifier K+ conductances in colonic ICC that might contribute to regulation of membrane potential. ICC expressed Kcnj2 (Kir2.1), Kcnj4 (Kir2.3), Kcnj14 (Kir2.4), Kcnj5 (Kir3.4), Kcnj8 (Kir 6.1) and Kcnj11 (Kir6.2). Voltage clamp experiments showed activation of inward current when extracellular K+ ([K+ ]o ) was increased. The current was inwardly rectifying and inhibited by Ba2+ (10 µm) and ML-133 (10 µm). A similar current was not available in SMC. The current activated in ICC by elevated [K+ ]o was not affected by Tertiapin-Q. Gßγ, when dialysed into cells, failed to activate a unique, Tertiapin-Q-sensitive conductance. Freshly dispersed ICC showed no evidence of functional KATP . Pinacidil failed to activate current and the inward current activated by elevated [K+ ]o was insensitive to glibenclamide. Under current clamp, ML-133 caused the depolarization of isolated ICC and also that of cells impaled with microelectrodes in intact muscle strips. These findings show that ICC, when isolated freshly from colonic muscles, expressed a Ba2+ -sensitive, inwardly rectifying K+ conductance. This conductance is most probably a result of the expression of multiple Kir2 family paralogues, and the inwardly rectifying conductance contributes to the regulation of resting potentials and excitability of colonic muscles.