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1.
Int J Mol Sci ; 25(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38732054

RESUMO

This study investigates the efficacy of a thermo-responsive N-acetylcysteine (NAC) hydrogel on wound healing and oral ulcer recovery. Formulated by combining NAC with methylcellulose, the hydrogel's properties were assessed for temperature-induced gelation and cell viability using human fibroblast cells. In vivo experiments on Sprague Dawley rats compared the hydrogel's effects against saline, NAC solution, and a commercial NAC product. Results show that a 5% NAC and 1% methylcellulose solution exhibited optimal outcomes. While modest improvements in wound healing were observed, significant enhancements were noted in oral ulcer recovery, with histological analyses indicating fully regenerated mucosal tissue. The study concludes that modifying viscosity enhances NAC retention, facilitating tissue regeneration. These findings support previous research on the beneficial effects of antioxidant application on damaged tissues, suggesting the potential of NAC hydrogels in improving wound care and oral ulcer treatment.


Assuntos
Acetilcisteína , Hidrogéis , Úlceras Orais , Ratos Sprague-Dawley , Cicatrização , Cicatrização/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Ratos , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Úlceras Orais/tratamento farmacológico , Úlceras Orais/patologia , Regeneração/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Masculino , Temperatura , Sobrevivência Celular/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-38721636

RESUMO

Background: Malignant struma ovarii (MSO) is a very rare disease in which thyroid cancer originates from the ovary. Because it is rare for endocrinologists to encounter patients with MSO, endocrinologists may have a limited understanding of the disease. Therefore, we analyzed and introduced its incidence and clinical course in a tertiary hospital in Korea. Methods: We retrospectively investigated the clinical data of 170 patients who underwent surgery for struma ovarii at the Department of Obstetrics and Gynecology of Samsung Medical Center from 1994 to May 2023. Results: Among 170 patients with struma ovarii, 15 (8.8%) were diagnosed with MSO. The median age of patients with MSO was 48 years (range, 30 to 74), and the median tumor size was 3.3 cm (range, 0.5 to 11.0). Papillary thyroid carcinoma (46.7%) was the most common subtypes followed by follicular thyroid carcinoma (26.7%). All patients were diagnosed after surgery, with no predictions from preoperative imaging. The surgical extent of gynecological surgery was variable. Four patients (26.7%) underwent thyroidectomy for thyroid cancer, while one underwent total thyroidectomy and radioactive iodine therapy for MSO with peritoneal metastasis. Except for one patient who underwent hemithyroidectomy, thyroid stimulating hormone suppression therapy was performed in four patients. Only 53% of MSO patients were consulted by an endocrinologist. With a median follow-up period of 33 months (range, 4 to 156), 11 patients remained disease-free, one experienced progression with peritoneal seeding, and the remaining one was in treatment. There have been no recurrences or deaths due to MSO. Conclusion: An endocrinologist should be involved in establishing a therapeutic plan for MSO, for which the overall prognosis is generally favorable.

3.
J Occup Environ Med ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38708924

RESUMO

OBJECTIVES: Our study aimed to investigate the association between shift work and stroke and determine whether this association varies depending on the presence of insomnia. METHODS: Utilizing the KoGES prospective cohort data, our primary exposure variables were shift work and insomnia. The occurrence of stroke was the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction of shift work and insomnia on stroke incidence. RESULTS: In the interaction analysis, shift work was significantly associated with stroke incidence only in groups with insomnia and an HR of 2.49 (1.02-6.11). CONCLUSIONS: Our study demonstrated that shift work was associated with a higher risk of stroke among the population with insomnia.

4.
Clin Orthop Surg ; 16(2): 326-334, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38562638

RESUMO

Background: The use of electric scooters (e-scooters) continues to increase as a simple, inexpensive means of transport, resulting in a sharp increase in the incidence of scooter-related accidents. No study to date has closely examined the injury extent to the lower leg, joints, and extremities from e-scooter-related accidents. Here, we investigated the epidemiology and injury patterns of such accidents, focusing on injuries to the ankle and foot. Methods: Based on data from a single tertiary hospital's database, the demographics of 563 patients with scooter-associated injuries were analyzed retrospectively. Among the patients, 229 patients who were injured by e-scooter riding were further investigated. Based on the data, the general demographics of whole scooter-associated injuries and the injury characteristics and fracture cases of the lower leg, ankle, and foot were analyzed. Results: During the 4-year study period, the number of patients injured by e-scooters increased every year. Lower extremities were the most common injury site (67.2%) among riders, whereas injuries to the head and neck (64.3%) were more common in riders of non-electric scooters. Among the lower leg, ankle, and foot injuries of riders (52 cases), the ankle joint (53.8%) was the most commonly injured site, followed by the foot (40.4%) and lower leg (21.2%). The fracture group scored significantly higher on the Abbreviated Injury Scale than the non-fracture group (p < 0.001). Among the fracture group (20 cases), ankle fractures (9 cases) were most common, including pronation external rotation type 4 injuries (4 cases) and pilon fractures (2 cases). Five patients (25%) had open fractures, and 12 patients (60%) underwent surgical treatment. Conclusions: The ankle and foot are the most common injury sites in e-scooter-related accidents. Given the high frequency and severity of e-scooter-related ankle and foot injuries, we suggest that more attention be paid to preventing these types of injuries with greater public awareness of the dangers of using e-scooters.


Assuntos
Fraturas do Tornozelo , Traumatismos do Pé , Humanos , Tornozelo , Articulação do Tornozelo , Estudos Retrospectivos , Acidentes de Trânsito , Traumatismos do Pé/epidemiologia , Traumatismos do Pé/etiologia , Acidentes
5.
Stem Cell Res Ther ; 15(1): 103, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589946

RESUMO

BACKGROUND: Oral ulcers are a common side effect of chemotherapy and affect patients' quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its efficacy is limited as the stem cells tend to remain in the affected area for a short time. This study aims to develop a treatment for oral ulcers by using trimethyl chitosan (TMC) hydrogel with human tonsil-derived stem cells (hTMSCs) to increase the therapeutic effect of stem cells and investigate their effectiveness. METHODS: Animals were divided into four experimental groups: Control, TMC hydrogel, hTMSCs, and hTMSCs loaded in TMC hydrogel (Hydrogel + hTMSCs) (each n = 8). Oral ulcers were chemically induced by anesthetizing the rats followed by injection of dilute acetic acid in the right buccal mucosa. After confirming the presence of oral ulcers in the animals, a single subcutaneous injection of 100 µL of each treatment was applied to the ulcer area. Histological analyses were performed to measure inflammatory cells, oral mucosal thickness, and fibrosis levels. The expression level of inflammatory cytokines was also measured using RT-PCR to gauge therapeutic the effect. RESULTS: The ulcer size was significantly reduced in the TMC hydrogel + hTMSCs group compared to the control group. The stem cells in the tissue were only observed until Day 3 in the hTMSCs treated group, while the injected stem cells in the TMC Hydrogel + hTMSCs group were still present until day 7. Cytokine analysis related to the inflammatory response in the tissue confirmed that the TMC Hydrogel + hTMSCs treated group demonstrated superior wound healing compared to other experimental groups. CONCLUSION: This study has shown that the adhesion and viability of current stem cell therapies can be resolved by utilizing a hydrogel prepared with TMC and combining it with hTMSCs. The combined treatment can promote rapid healing of oral cavity wounds by enhancing anti-inflammatory effects and expediting wound healing. Therefore, hTMSC loaded in TMC hydrogel was the most effective wound-healing approach among all four treatment groups prolonging stem cell survival. However, further research is necessary to minimize the initial inflammatory response of biomaterials and assess the safety and long-term effects for potential clinical applications.


Assuntos
Quitosana , Células-Tronco Mesenquimais , Úlceras Orais , Humanos , Ratos , Animais , Úlceras Orais/terapia , Úlcera , Hidrogéis , Tonsila Palatina , Qualidade de Vida , Modelos Animais , Citocinas
6.
Proc Natl Acad Sci U S A ; 121(18): e2316819121, 2024 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-38657042

RESUMO

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.


Assuntos
Endocitose , Depressão Sináptica de Longo Prazo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Receptores de AMPA , Receptores de Glutamato Metabotrópico , Receptores de AMPA/metabolismo , Animais , Fosforilação , Endocitose/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Ratos , Tirosina/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Sinapses/metabolismo , Camundongos , Humanos , Neurônios/metabolismo
7.
Photobiomodul Photomed Laser Surg ; 42(2): 159-167, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38301211

RESUMO

Objective: The submandibular gland (SMG) produces the most saliva, and factors such as aging and chemotherapy can affect its structure and function. However, there are only temporary treatments available for salivary hypofunction. This study aimed to evaluate the effects of photobiomodulation (PBM) on the function of SMG by using a rat animal model and vismodegib, an antagonist of the sonic hedgehog (SHH) pathway. Methods: Vismodegib (10 mg/kg) drug was gavaged orally for 14 days in rats to significantly decrease the SHH signaling proteins [SHH, protein patched homolog 1 (PTCH1), smoothened protein (SMO), glioma-associated oncogene homolog 1 (GLI1)], induce damage in SMG tissue, and affect salivary functional markers AQP5 and Keratin5. After that, in conjunction with vismodegib administration, PBM was performed using an 850 nm high-power light-emitting diode (LED) device treated daily for 6 days at varying total energy densities of 60, 120, and 180 J/cm2 in at least 3 rats per group. The test results were confirmed by Western blot, immunofluorescence staining, and hematoxylin and eosin staining, and the statistics were t-test or one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests. Results: Significant decreases in the expression of SHH-related proteins (PTCH1, SMO, GLI1, p < 0.05) with damage of SMG ductal cells were observed with vismodegib administration. However, a significant increase in the expression levels of SHH-related proteins (SHH, SMO, GLI1, p < 0.05) and recovery of SMG ductal cells damaged after vismodegib administration were observed for PBM-treated groups. Salivary functional marker AQP5 also showed the same increase or decrease. Conclusions: This study found that vismodegib damages SMG ductal cells and decreases SHH-related proteins and associated salivary functional markers. Also, 850 nm high-power LED recovered the damaged structure of SMG and increased SHH-related proteins and salivary functional markers. The study results suggest that PBM can restore SMG structure and function through SHH signaling.


Assuntos
Anilidas , Terapia com Luz de Baixa Intensidade , Piridinas , Glândula Submandibular , Ratos , Animais , Glândula Submandibular/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/farmacologia , Transdução de Sinais
8.
Int J Mol Sci ; 25(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38396783

RESUMO

Wound management practices have made significant advancements, yet the search for improved antiseptics persists. In our pursuit of solutions that not only prevent infections but also address broader aspects of wound care, we investigated the impact of integrating trimethyl chitosan (TMC) into a widely used poly(vinylpyrrolidone)-iodine gel (PVP-I gel). Our study assessed the antimicrobial efficacy of the PVP gel with TMC against Escherichia coli, Staphylococcus aureus, multidrug-resistant S. aureus MRSA, and Candida albicans. Additionally, we compared hemostatic effects using a liver puncture bleeding model and evaluated wound healing through histological sections from full-thickness dermal wounds in rats. The results indicate that incorporating TMC into the commercially available PVP-I gel did not compromise its antimicrobial activity. The incorporation of TMC into the PVP-I gel markedly improves its hemostatic activity. The regular application of the PVP-I gel with TMC resulted in an increased blood vessel count in the wound bed and facilitated the development of thicker fibrous tissue with a regenerated epidermal layer. These findings suggest that TMC contributes not only to antimicrobial activity but also to the intricate processes of tissue regeneration. In conclusion, incorporating TMC proves beneficial, making it a valuable additive to commercially available antiseptic agents.


Assuntos
Anti-Infecciosos Locais , Anti-Infecciosos , Quitosana , Hemostáticos , Iodo , Staphylococcus aureus Resistente à Meticilina , Ratos , Animais , Anti-Infecciosos Locais/farmacologia , Povidona-Iodo/farmacologia , Quitosana/farmacologia , Hemostáticos/farmacologia , Anti-Infecciosos/farmacologia
9.
J Korean Med Sci ; 39(3): e31, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38258363

RESUMO

BACKGROUND: Postpartum depression (PPD) can negatively affect infant well-being and child development. Although the frequency and risk factors of PPD symptoms might vary depending on the country and culture, there is limited research on these risk factors among Korean women. This study aimed to elucidate the potential risk factors of PPD throughout pregnancy to help improve PPD screening and prevention in Korean women. METHODS: The pregnant women at 12 gestational weeks (GW) were enrolled from two obstetric specialized hospitals from March 2013 to November 2017. A questionnaire survey was administered at 12 GW, 24 GW, 36 GW, and 4 weeks postpartum. Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale, and PPD was defined as a score of ≥ 10. RESULTS: PPD was prevalent in 16.3% (410/2,512) of the participants. Depressive feeling at 12 GW and postpartum factors of stress, relationship with children, depressive feeling, fear, sadness, and neonatal intensive care unit admission of baby were significantly associated with a higher risk of PPD. Meanwhile, high postpartum quality of life and marital satisfaction at postpartum period were significantly associated with a lower risk of PPD. We developed a model for predicting PPD using factors as mentioned above and it had an area under the curve of 0.871. CONCLUSION: Depressive feeling at 12 GW and postpartum stress, fear, sadness, relationship with children, low quality of life, and low marital satisfaction increased the risk of PPD. A risk model that comprises significant factors can effectively predict PPD and can be helpful for its prevention and appropriate treatment.


Assuntos
Depressão Pós-Parto , Resultado da Gravidez , Lactente , Criança , Recém-Nascido , Gravidez , Feminino , Humanos , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Qualidade de Vida , Fatores de Risco , República da Coreia/epidemiologia
10.
Psychiatry Investig ; 21(1): 1-8, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38200636

RESUMO

OBJECTIVE: Our study hypothesizes that the interaction between depression, alcohol intake, and smoking status can significantly influence the risk of acute coronary syndrome (ACS). We aim to investigate the magnitude of the association between depression and ACS risk and explore how alcohol intake and smoking status affect this association. METHODS: We used data from the Korean Genome and Epidemiology Study. The primary exposure of interest was the presence of depression, as measured using the Beck Depression Inventory score at baseline. The primary outcome was the occurrence of ACS observed in the biennial follow-up surveys. We used Cox proportional regression analysis to estimate the effect of depression on ACS incidence. We conducted interaction and joint effect analyses to explore the interactions between depression and health-related habits including alcohol intake and smoking with regard to ACS incidence. RESULTS: During 16 years of follow-up among 3,254 individuals, we documented 88 cases of new-onset ACS (2.2 cases per 1,000 personyears). We found no association between depression and ACS risk; furthermore, the effect of depression on ACS risk by alcohol intake and smoking status did not differ significantly. In the analysis to observe the joint effect of smoking and depression, the multivariate hazard ratios of ACS were 1.26 (95% confidence interval [CI], 0.67-2.36) for non-smoking and depression, 1.52 (95% CI, 0.83-2.82) for smoking and non-depression, and 2.79 (95% CI, 1.21-6.41) for smoking and depression compared with non-smoking and non-depression. CONCLUSION: Our study reveals the combined effect of depression and smoking on ACS risk, highlighting the potential benefits of concurrent interventions for both depression and smoking for cardiovascular health.

11.
Endocrine ; 83(3): 671-680, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37814113

RESUMO

PURPOSE: Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis; however, some PTMCs exhibit poor outcomes. Cancer-specific death from PTMC has been rarely reported, so we aimed to evaluate mortality rates and causes of death in patients who died with PTMC. METHODS: We retrospectively reviewed 8969 PTMC patients treated at Samsung Medical Center from 1994 to 2017. Mortality rate and causes of death in PTMC patients were evaluated and compared with those of 7873 patients with papillary thyroid carcinoma (PTC) > 1 cm. In addition, we reviewed previous publications reporting cancer-specific deaths from PTMC. RESULTS: Among the 8969 PTMC patients, 107 (1.2%) patients died. Only two (0.02%) patients have died of PTMC, which was less than the cancer-specific deaths from PTC > 1 cm (0.71%). Among the deceased PTMC patients, 63 (58.9%) died of other malignancies, three (2.8%) died of cardiovascular diseases, and five (4.7%) died of other diseases. Compared with PTC > 1 cm, cancer-specific deaths was less (1.9% vs. 15.1%, P < 0.001), and deaths from other malignancies were higher in deceased PTMC patients (58.9% vs. 30.5%, P < 0.001). According to 18 studies, PTMC-specific mortality rates ranged from 0.05% to 14.3%, and 336 cancer-specific deaths (0.43%) occurred among 78,770 PTMC patients. CONCLUSION: The cancer-specific mortality rate of PTMC patients was extremely low (0.02%). More than half of deceased PTMC patients died of other malignancies, which was significantly more than those with PTC > 1 cm. These results support that active surveillance can be selected as a therapeutic option for PTMC.


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Tireoidectomia , Humanos , Estudos Retrospectivos , Causas de Morte , Neoplasias da Glândula Tireoide/patologia , Câncer Papilífero da Tireoide
12.
Sci Rep ; 13(1): 21341, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-38049526

RESUMO

Genetic, environment, and behaviour factors have a role in causing sudden cardiac arrest (SCA). We aimed to determine the strength of the association between various risk factors and SCA incidence. We conducted a multicentre case-control study at 17 hospitals in Korea from September 2017 to December 2020. The cases included out-of-hospital cardiac arrest aged 19-79 years with presumed cardiac aetiology. Community-based controls were recruited at a 1:1 ratio after matching for age, sex, and urban residence level. Multivariable conditional logistic regression analysis was conducted. Among the 1016 cases and 1731 controls, 948 cases and 948 controls were analysed. A parental history of SCA, low educational level, own heart disease, current smoking, and non-regular exercise were associated with SCA incidence (Adjusted odds ratio [95% confidence interval]: 2.51 [1.48-4.28] for parental history of SCA, 1.37 [1.38-2.25] for low edication level, 3.77 [2.38-5.90] for non-coronary artery heart disease, 4.47 [2.84-7.03] for coronary artery disease, 1.39 [1.08-1.79] for current smoking, and 4.06 [3.29-5.02] for non-regular exercise). Various risk factors related to genetics, environment, and behaviour were independently associated with the incidence of SCA. Establishing individualised SCA prevention strategies in addition to general prevention strategies is warranted.


Assuntos
Doença da Artéria Coronariana , Cardiopatias , Parada Cardíaca Extra-Hospitalar , Humanos , Estudos de Casos e Controles , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/complicações , Cardiopatias/complicações , Fatores de Risco , Parada Cardíaca Extra-Hospitalar/complicações , Comportamentos Relacionados com a Saúde , Fatores Socioeconômicos
13.
Int J Mol Sci ; 24(22)2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38003650

RESUMO

This study investigated the neuroprotective effects of Dendropanax morbifera leaves and stems (DMLS) water extract on scopolamine (SCO)-induced memory impairment in mice. First, we conducted experiments to determine the protective effect of DMLS on neuronal cells. Treatment with DMLS showed a significant protective effect against neurotoxicity induced by Aß(25-35) or H2O2. After confirming the neuroprotective effects of DMLS, we conducted animal studies. We administered DMLS orally at concentrations of 125, 250, and 375 mg/kg for 3 weeks. In the Y-maze test, SCO decreased spontaneous alternation, but treatment with DMLS or donepezil increased spontaneous alternation. In the Morris water-maze test, the SCO-treated group showed increased platform reach time and decreased swim time on the target platform. The passive avoidance task found that DMLS ingestion increased the recognition index in short-term memory. Furthermore, memory impairment induced by SCO reduced the ability to recognize novel objects. In the Novel Object Recognition test, recognition improved with DMLS or donepezil treatment. In the mouse brain, except for the cerebellum, acetylcholinesterase activity increased in the SCO group and decreased in the DMLS and donepezil groups. We measured catalase and malondialdehyde, which are indicators of antioxidant effectiveness, and found that oxidative stress increased with SCO but was mitigated by DMLS or donepezil treatment. Thus, our findings suggest that ingestion of DMLS restored memory impairment by protecting neuronal cells from Aß(25-35) or H2O2-induced neurotoxicity, and by reducing oxidative stress.


Assuntos
Fármacos Neuroprotetores , Escopolamina , Camundongos , Animais , Escopolamina/efeitos adversos , Fármacos Neuroprotetores/efeitos adversos , Peróxido de Hidrogênio/farmacologia , Água/farmacologia , Acetilcolinesterase/metabolismo , Donepezila/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo , Aprendizagem em Labirinto , Extratos Vegetais/efeitos adversos
14.
Cell Death Differ ; 30(12): 2491-2507, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37926711

RESUMO

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.


Assuntos
Neoplasias , Animais , Camundongos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fosforilação , Isoformas de Proteínas/genética
15.
ACS Med Chem Lett ; 14(9): 1198-1207, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37736180

RESUMO

Herein, we report the identification, structural optimization, and biological efficacy of thieno[2,3-b]pyridines as potent inhibitors of splice variants of the tyrosine kinase recepteur d'origine nantais (RON). Among synthesized compounds, compound 15f exhibited excellent in vitro kinase inhibition and antiproliferative activity, as well as in vivo antineoplastic efficacy against RON splice variant-expressing tumors. Moreover, compound 15f with excellent pharmacokinetics demonstrated significant activity with greater tumor growth inhibition (74.9% at 10 mg/kg) than compounds 2 and 4 in a patient-derived xenograft model. Collectively, 15f represents a promising, novel anticancer agent targeting RON splice variants.

16.
J Korean Med Sci ; 38(38): e300, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37750371

RESUMO

BACKGROUND: The purpose of this study was to evaluate the effect of vanishing twin (VT) on maternal serum marker concentrations and nuchal translucency (NT). METHODS: This is a secondary analysis of a multicenter prospective cohort study in 12 institutions. Serum concentrations of pregnancy-associated plasma protein-A in the first trimester and alpha-fetoprotein (AFP), total human chorionic gonadotrophin, unconjugated estriol, and inhibin A in the second trimester were measured, and NT was measured between 10 and 14 weeks of gestation. RESULTS: Among 6,793 pregnant women, 5,381 women were measured for serum markers in the first or second trimester, including 65 cases in the VT group and 5,316 cases in the normal singleton group. The cases in the VT group had a higher median multiple of the median value of AFP and inhibin A than the normal singleton group. The values of other serum markers and NT were not different between the two groups. After the permutation test with adjustment, AFP and inhibin A remained significant differences. The frequency of abnormally increased AFP was also higher in the VT group than in the normal singleton group. CONCLUSION: VT can be considered as an adjustment factor for risk assessment in the second-trimester serum screening test.


Assuntos
Medição da Translucência Nucal , alfa-Fetoproteínas , Gravidez , Humanos , Feminino , Segundo Trimestre da Gravidez , Estudos Prospectivos , Família
17.
Sci Rep ; 13(1): 15663, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37730953

RESUMO

Current guidelines recommend total thyroidectomy with central lymph node dissection (CND) for patients with medullary thyroid carcinoma (MTC). This study aimed to identify low-risk MTC patients who may be candidates for lobectomy. We retrospectively reviewed MTC patients who underwent primary surgery at a tertiary referral center from 1998 to 2019. Eighty-five MTC patients were enrolled, excluding patients with primary tumor size > 2.0 cm. Among them, one (1.2%) patient had bilateral tumors. During a median follow-up of 84 months, 12 of the 85 patients experienced structural recurrence. 13 patients had occult lymph node metastasis, and structural recurrence occurred in 2 patients. Factors that significantly affected disease-free survival were clinical N stage (cN0 vs. cN1, log-rank P < 0.001), pathological N stage (pN0 vs. pN1, P < 0.001), and preoperative calcitonin levels (≤ 250 vs. > 250 pg/mL, P = 0.017). After categorizing patients into four groups, patients with preoperative calcitonin levels > 250 pg/mL and cN1 or pN1 had a significantly worse prognosis. Patients with a primary tumor size of 2 cm or less, cN0, and preoperative calcitonin of 250 pg/mL or less can be classified as low-risk MTC patients. We used preoperative clinical information to identify low-risk MTC patients. Lobectomy with prophylactic CND may be a potential therapeutic approach.


Assuntos
Conservadores da Densidade Óssea , Neoplasias da Glândula Tireoide , Humanos , Calcitonina , Tireoidectomia , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/cirurgia , Hormônios e Agentes Reguladores de Cálcio
18.
Medicine (Baltimore) ; 102(34): e34560, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37653804

RESUMO

There are controversies about the effects of alcohol intake shortly before injury on prognosis of traumatic brain injury (TBI) patients. We investigated the association between alcohol intake and functional/survival outcomes in TBI patients, and whether this effect varied according to age and sex. This was a prospective international multicenter cohort study using the Pan-Asian trauma outcomes study registry in Asian-Pacific countries, conducted on adult patients with TBI who visited participating hospitals. The main exposure variable was alcohol intake before injury, and the main outcomes were poor functional recovery (modified Rankin Scale score, 4-6) and in-hospital mortality. Multivariable logistic regression analyses were conducted to estimate the effects of alcohol intake on study outcomes. Interaction analysis between alcohol intake and age/sex were also performed. Among the study population of 12,451, 3263 (26.2%) patients consumed alcohol before injury. In multivariable logistic regression analysis, alcohol intake was associated with lower odds for poor functional recovery [4.4% vs 6.6%, a odds ratio (95% confidence interval): 0.68 (0.56-0.83)] and in-hospital mortality (1.9% vs 3.1%, 0.64 [0.48-0.86]). The alcohol intake had interaction effects with sex for poor functional recovery: 0.59 (0.45-0.75) for male and 0.94 (0.60-1.49) for female (P for-interaction < .01), whereas there were no interaction between alcohol intake and age. In TBI patients, alcohol intake before injury was associated with lower odds of poor functional recovery and in-hospital mortality, and these effects were maintained in the male group in the interaction analyses.


Assuntos
Consumo de Bebidas Alcoólicas , Lesões Encefálicas Traumáticas , Adulto , Feminino , Humanos , Masculino , Consumo de Bebidas Alcoólicas/epidemiologia , Lesões Encefálicas Traumáticas/terapia , Estudos Prospectivos
19.
PLoS One ; 18(8): e0287915, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37594944

RESUMO

BACKGROUND: Insomnia and depression have been known to be risk factors of several diseases, including coronary heart disease. We hypothesized that insomnia affects the out-of-hospital cardiac arrest (OHCA) incidence, and these effects may vary depending on whether it is accompanied by depression. This study aimed to determine the association between insomnia and OHCA incidence and whether the effect of insomnia is influenced by depression. METHODS: This prospective multicenter case-control study was performed using Phase II Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiology Surveillance (CAPTURES-II) project database for OHCA cases and community-based controls in Korea. The main exposure was history of insomnia. We conducted conditional logistic regression analysis to estimate the effect of insomnia on the risk of OHCA incidence and performed interaction analysis between insomnia and depression. Finally, subgroup analysis was conducted in the patients with insomnia. RESULTS: Insomnia was not associated with increased OHCA risk (0.95 [0.64-1.40]). In the interaction analysis, insomnia interacted with depression on OHCA incidence in the young population. Insomnia was associated with significantly higher odds of OHCA incidence (3.65 [1.29-10.33]) in patients with depression than in those without depression (0.84 [0.59-1.17]). In the subgroup analysis, depression increased OHCA incidence only in patients who were not taking insomnia medication (3.66 [1.15-11.66]). CONCLUSION: Insomnia with depression is a risk factor for OHCA in the young population. This trend was maintained only in the population not consuming insomnia medication. Early and active medical intervention for patients with insomnia may contribute to lowering the risk of OHCA.


Assuntos
Parada Cardíaca Extra-Hospitalar , Humanos , Parada Cardíaca Extra-Hospitalar/complicações , Parada Cardíaca Extra-Hospitalar/epidemiologia , Estudos de Casos e Controles , Depressão/complicações , Depressão/epidemiologia , Estudos Prospectivos , Interpretação Estatística de Dados
20.
J Photochem Photobiol B ; 246: 112770, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37579650

RESUMO

In this study, the effect of photobiomodulation (PBM) treatment using 630 nm light emitting diode (LED) array (continuous wave type, 10 mW power) on tonsil-derived mesenchymal stem cells (TMSCs) and its interaction with RAW 264.7 macrophage cells via co-culture in vitro were investigated. PBM treatment was used as a priming method for TMSCs to improve therapeutic efficacy. TMSCs were subjected to multi-dose PBM treatments before co-culture with M1 activated (1 µg/mL lipopolysaccharide, LPS) macrophage cells with total energy doses of 0, 15, 30, and 60 J. Irradiation set at 15 J (1500 s treatment time) was performed once, twice for 30 J, and four times for 60 J in an incubator kept at 37 °C and 5% CO2. No significant anti-inflammatory response was observed for TMSCs co-cultured with macrophage cells without PBM. But PBM treatment of TMSCs with 630 nm LED array at 30 J reduced expression of inducible nitric oxide synthase, iNOS (M1) and increased expression of Arginase-1, Arg-1 (M2) phenotype macrophage markers. Anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) gene expression also increased significantly. Based on the results, PBM priming of TMSCs supports M2 macrophage polarization. PBM can be used to improve the therapeutic efficacy of TMSCs for potential applications in oral mucositis and wound healing.


Assuntos
Células-Tronco Mesenquimais , Tonsila Palatina , Camundongos , Animais , Tonsila Palatina/metabolismo , Macrófagos , Citocinas/metabolismo , Células RAW 264.7
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