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We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.
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Sinalização do Cálcio , Reparo do DNA , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Mesotelioma , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Humanos , Reparo do DNA/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Mesotelioma/genética , Sinalização do Cálcio/genética , Feminino , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Apoptose/genética , Fibroblastos/metabolismo , Amianto/toxicidade , Instabilidade GenômicaRESUMO
Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.
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Amianto , Proteína HMGB1 , Mesotelioma Maligno , Mesotelioma , Animais , Camundongos , Fator de Necrose Tumoral alfa/genética , Proteína HMGB1/genética , Mesotelioma/induzido quimicamente , Mesotelioma/genética , Amianto/toxicidade , Inflamação , Microambiente TumoralRESUMO
BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1ß forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.
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Subunidade alfa do Fator 1 Induzível por Hipóxia , Mesotelioma Maligno , Mesotelioma , Ubiquitina Tiolesterase , Humanos , Heterozigoto , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma Maligno/genética , Mesotelioma Maligno/complicações , Mutação , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.
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OBJECTIVE: Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence. METHODS: Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS). RESULTS: A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001). CONCLUSION: WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.
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Adenocarcinoma , Adenoma , Neoplasias do Colo do Útero , Feminino , Humanos , Estudos Retrospectivos , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Prognóstico , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Adenocarcinoma/cirurgia , Adenoma/patologiaRESUMO
BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.
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PURPOSE: DNA methylation is a major epigenetic phenomenon through which diet affects health and disease. This study aimed to determine the epigenetic influence of the traditional Korean diet (K-diet) on global DNA methylation via one-carbon metabolism. METHODS: A crossover study was conducted on 52 women. Two diets, a K-diet, high in plant foods and low in calories and animal fat, and a control diet, similar to the diet currently consumed in Korea, were provided to all subjects alternately for 4 weeks with a 4-week washout period. Clinical parameters were measured before and after each dietary intervention. Nutrient intake was calculated by using a computer-aided nutritional analysis program. One-carbon metabolites in the serum and global DNA methylation in peripheral mononuclear cells were determined using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: The K-diet group consumed more folate (669.9 ± 6.7 µg vs. 502.7 ± 3.0, p < 0.001), B6, B12, serine, and choline, and less methionine (992.6 ± 63 vs. 1048.3 mg ± 34.1, p < 0.0001) than the control group did. In the K-diet group, the increment of plasma 5-methyltetrahydrofolate (0.08 µg/mL ± 0.11 vs 0.02 ± 0.10, p < 0.009) and decrement of L-homocysteine (- 70.7 ± 85.0 vs - 39.3 ± 69.4, p < 0.0168) were greater than those of the control group. Global DNA methylation was significantly increased in the K-diet group (6.70 ± 3.02% to 9.45 ± 3.69, p < 0.0001) but not in the control group. CONCLUSIONS: A K-diet high in one-carbon nutrients can enhance the global DNA methylation status, suggesting an epigenetic mechanism by which the K-diet conveys health effects. Trial registration Korean Clinical Trial Registry (trial number: KCT0005340, 24/08/2020, retrospectively registered).
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BACKGROUND: We aimed to identify the ideal chest compression site for cardiopulmonary resuscitation (CPR) in patients with a single ventricle with dextrocardia corrected by Fontan surgery. METHODS: The most recent stored chest computed tomography images of all patients with a single ventricle who underwent Fontan surgery were retrospectively analysed. We reported that the ideal chest compression site is the largest part of the compressed single ventricle. To identify the ideal chest compression site, we measured the distance from the midline of the sternum to the point of the maximum sagittal area of the single ventricle as a deviation and calculated the area fraction of the compressed structures. RESULTS: 58 patients (67.2% male) were analysed. The mean right deviation from the midline of the sternum to the ideal compression site was similar to the mean sternum width (32.85 ± 15.61 vs. 31.05 ± 6.75 mm). When chest compression was performed at the ideal site, the area fraction of the single ventricle significantly increased by 7%, which was greater than that of conventional compression (0.15 ± 0.10 vs. 0.22 ± 0.11, P < 0.05). CONCLUSIONS: When performing CPR on a patient with Fontan circulation with dextrocardia, right-sided chest compression may be better than the conventional location.
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Reanimação Cardiopulmonar , Dextrocardia , Técnica de Fontan , Humanos , Masculino , Feminino , Reanimação Cardiopulmonar/efeitos adversos , Técnica de Fontan/efeitos adversos , Estudos Retrospectivos , Esterno , Dextrocardia/diagnóstico por imagemRESUMO
BACKGROUND: Inter-hospital transfers of severely injured patients are inevitable due to limited resources. We investigated the association between inter-hospital transfer and the prognosis of pediatric injury using the Korean multi-institutional injury registry. METHODS: This retrospective observational study was conducted from January 2013 to December 2017; data for hospitalized subjects aged < 18 years were extracted from the Emergency Department-based Injury in Depth Surveillance database, in which 22 hospitals are participating as of 2022. The survival rates of the direct transfer group and the inter-hospital transfer group were compared, and risk factors affecting 30-day mortality and 72- hour mortality were analyzed. RESULTS: The total number of study subjects was 18,518, and the transfer rate between hospitals was 14.5%. The overall mortality rate was 2.3% (n = 422), the 72-hour mortality was 1.7% (n = 315) and the 30-day mortality rate was 2.2% (n = 407). The Kaplan-Meier survival curve revealed a lower survival rate in the inter-hospital transfer group than in the direct visit group (log-rank, P < 0.001). Cox proportional hazards regression analysis showed that inter-hospital transfer group had a higher 30-day mortality rate and 72-hour mortality (hazard ratio [HR], 1.681; 95% confidence interval [CI], 1.232-2.294 and HR, 1.951; 95% CI, 1.299-2.930) than direct visit group when adjusting for age, sex, injury severity, and head injury. CONCLUSION: Among the pediatric injured patients requiring hospitalization, inter-hospital transfer in the emergency department was associated with the 30-day mortality rate and 72-hour mortality rate in Korea.
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Hospitais , Traumatismo Múltiplo , Criança , Humanos , Serviço Hospitalar de Emergência , Instalações de Saúde , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Although the reporting rate of child abuse is increasing every year, the child abuse detection rate is 3.81% as of 2019 in Korea, which is significantly lower than that of developed countries for child rights. OBJECTIVE: We investigated the associated factors with barriers that emergency physicians face in recognizing and reporting cases of child abuse. METHODS: From May to July 2022, 240 emergency physicians working in the 15 emergency department were asked to participate in the survey via email. The questionnaire included the respondent's basic information, treatment experience for child abuse, reasons for reporting or not reporting, and opinions on measures to increase the reporting rate. We conducted a logistic regression analysis to discern the factors contributing to underreporting. RESULTS: Seventy-one individuals were included in the analysis, after excluding those who had never encountered suspected cases of child abuse. A multivariable logistic regression was performed with the above variables, and although it was not statistically significant, there was a tendency for workers to report well when working at a pediatric emergency department (odds ratio [95% confidence interval], 3.97 [0.98-16.09]). The primary reason for reporting suspected abuse was the pattern of damage suspected of abuse. The first reason for not reporting suspected abuse was because they were not sure it was child abuse. Respondents answered that to report better, a quick and appropriate response from the police and confidentiality of the reporter were needed. CONCLUSIONS: Physicians in pediatric emergency departments demonstrated a tendency for more proactive reporting suspected cases of child abuse.
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PURPOSE: This systematic review and meta-analysis aimed to investigate the postoperative analgesic efficacy and safety of the modified thoracoabdominal nerve block through the perichondral approach (M-TAPA) in abdominal surgeries. DESIGN: Systematic review and meta-analysis. METHODS: We searched electronic databases to identify relevant studies comparing M-TAPA with conventional analgesic techniques. The primary outcome was the requirement for rescue analgesia at 12 and 24 hours postsurgery. Secondary outcomes included the 11-point numerical rating scale pain scores at 0, 1, 2, 4, 6, 8, 12, and 24 hours following surgery, global quality of recovery scores, and postoperative adverse events. FINDINGS: Five randomized controlled trials involving 308 patients were analyzed. M-TAPA showed no significant difference in the requirement for rescue analgesia at 12 hours (relative risk [RR]: 0.87; 95% confidence interval [CI]: 0.62, 1.22; P = .424; I2 = 40.7%; Ph = .185) and 24 hours (RR: 0.67; 95% CI: 0.22, 1.99; P = .252; I2 = 90.3%; Ph < .001) postsurgery compared to non-M-TAPA. No significant differences in numerical rating scale pain scores or global quality of recovery scores were found between the two groups (all P < .05). However, M-TAPA was associated with a lower occurrence of nausea (RR: 0.37; 95% CI: 0.22, 0.68; P < .001; I2 = 0%; Ph = .834), vomiting (RR: 0.32; 95% CI: 0.17, 0.62; P < .001; I2 = 0%; Ph = .884), and itching (RR: 0.38; 95% CI: 0.21, 0.70; P = .002; I2 = 0%; Ph = .826). CONCLUSIONS: There was no significant difference in analgesic efficacy and safety between M-TAPA and non-M-TAPA techniques.
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PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.
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Neoplasias Encefálicas , Neoplasias da Mama , Radiocirurgia , Humanos , Feminino , Neoplasias da Mama/patologia , Irradiação Craniana , Neoplasias Encefálicas/secundário , Encéfalo/patologia , Terapia de Salvação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Currently there is no Food and Drug Administration-approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut-liver axis in their pathogenesis, we investigated the therapeutic effect of a long-acting dual agonist of glucagon-like peptide (GLP)-1 and GLP-2 receptors in mice with NAFLD/NASH. APPROACH AND RESULTS: C57BL/6J mice were fed a choline-deficient high-fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1-Fc, GLP2-Fc, or GLP1/2-Fc fusion (GLP1/2-Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well-developed NASH phenotypes. GLP1/2-Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2-Fc were found in in vitro cell systems. GLP1/2-Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2-Fc-mediated protection. We confirmed that FMT exerted an additive effect on GLP1-Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis. CONCLUSIONS: A long-acting dual agonist of GLP-1 and GLP-2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.
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Microbiota , Hepatopatia Gordurosa não Alcoólica , Animais , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Inflamação/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
Several studies have been conducted among South Korean to investigate effects of high blood mercury (Hg) levels. In this study fetal body burden of Hg in 344 pregnant women were estimated using a physiologically-based pharmacokinetic model (PBPK) and its associative effects on the growth of infants were analyzed. The association between cord blood Hg and growth variables at birth was analyzed based on parameters such as the sex of the newborn, living area, maternal age group, gestation day, maternal body mass index . We investigated the effects of Hg on infant growth through follow-ups, using a non-linear mixed model. The mean Hg levels in maternal and cord blood were 4.47 µg/L and 7.35 µg/L, respectively. Among the subjects, the corresponding fetal body burden for Methylmercury ranged between 26.3-86.9 mg. Cord blood Hg levels positively correlated with length at birth. Furthermore, the high cord blood group showed greater growth rates compared to the low cord blood group. Therefore, we suggest that pregnant women should make efforts to mitigate exposures to Hg, specifically from diet. Further research is suggested to investigate the relationship between the follow-up growth of the infants and Hg levels, considering fish consumption, diet information, and other environmental pollutants.
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Mercúrio , Compostos de Metilmercúrio , Animais , Gravidez , Feminino , Humanos , Carga Corporal (Radioterapia) , Mercúrio/análise , Compostos de Metilmercúrio/toxicidade , Parto , Gestantes , Sangue Fetal/química , Exposição MaternaRESUMO
PURPOSE OF REVIEW: Postoperative adhesions remain a clinical challenge to both patients and providers, as they are associated with significant complications and a high economic burden. This article provides a clinical review of currently available antiadhesive agents and promising new therapies that have advanced past animal studies. RECENT FINDINGS: Several agents have been investigated on their ability to reduce adhesion formation; however, there is no widely acceptable option. The few available interventions are barrier agents and while low-quality evidence suggests that they may be more effective than no treatment, there is no general agreement on their overall efficacy. There is an abundance of research on new solutions; however, their clinical efficacy is yet to be determined. SUMMARY: Although a wide range of therapeutics have been investigated, majority are halted in animal models with only a select few being studied in humans and ultimately available in the market. Many agents have shown effectiveness in reducing adhesion formation, however, that has not been translated to improvement in clinically relevant outcomes; hence the need for high-quality large randomized trials.
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Procedimentos Cirúrgicos em Ginecologia , Animais , Feminino , Humanos , Modelos AnimaisRESUMO
Button mushrooms (Agaricus bisporus), are one of the most widely consumed mushrooms in the world. However, changes within its microbial community as it relates to the use of different raw materials and cultivation methods, as well as potential points of microbial contamination throughout the production process have not been investigated extensively. In the present study, button mushroom cultivation was investigated in each of the four stages (raw materials, composting (phase I, â ¡, and â ¢), casing, and harvesting), and samples (n = 186) from mushrooms and their related environments were collected from four distinct mushroom-growing farms (A-D) in Korea. Shifts within the bacterial consortium during mushroom production were characterized with 16 S rRNA amplicon sequencing. The succession of bacterial communities on each farm was dependent on the raw material incorporated, aeration, and the farm environment. The dominant phyla of the compost stack at the four farms were Pseudomonadota (56.7%) in farm A, Pseudomonadota (43.3%) in farm B, Bacteroidota (46.0%) in farm C, and Bacillota (62.8%) in farm D. During the Phase â , highly heat-resistant microbes, such as those from the phylum Deinococcota (0.6-65.5%) and the families Bacillaceae (1.7-36.3%), Thermaceae (0.1-65.5%), and Limnochordaceae (0.3-30.5%) greatly proliferated. The microbial diversity within compost samples exhibited a marked decline as a result of the proliferation of thermophilic bacteria. In the spawning step, there were considerable increases in Xanthomonadaceae in the pasteurized composts of farms C and D - both of which employed an aeration system. In the harvesting phase, beta diversity correlated strongly between the casing soil layer and pre-harvest mushrooms, as well as between gloves and packaged mushrooms. The results suggest that gloves may be a major source of cross-contamination for packaged mushrooms, highlighting the need for enhanced hygienic practices during the harvesting phase to ensure product safety. These findings contribute to the current understanding of the influence of environmental and adjacent microbiomes on mushroom products to benefit the mushroom industry and relevant stakeholders by ensuring quality production.
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Agaricus , Microbiota , Humanos , Agaricus/genética , Microbiota/genética , Bactérias/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1ß, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.
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Asbestose/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Mesotelioma/genética , RecQ Helicases/genética , Adulto , Idoso , Animais , Asbesto Crocidolita , Família , Feminino , Instabilidade Genômica , Heterozigoto , Humanos , Incidência , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Abdominal pain, which is a common cause of children presenting to the paediatric emergency department (PED), is often evaluated by ultrasonography (US). However, uncertainty in US reports may necessitate additional imaging. OBJECTIVE: In this study, we evaluated factors contributing to uncertainty in paediatric abdominal US reports in the PED. MATERIALS AND METHODS: This retrospective cohort study included children younger than 18 years of age who underwent abdominal US in the PED of the study hospital between January 2017 and December 2019. After exclusion, the researchers manually reviewed and classified all US reports as 'certain' or 'uncertain'. Univariate and multivariate logistic regression analyses were performed to identify the factors contributing to uncertain reports. RESULTS: In total, 1006 patients were included in the final analysis., 796 patients were tagged as having certain reports, and 210 as having uncertain reports. Children with uncertain reports had a significantly higher rate of undergoing an additional computed tomography (CT) scan (31.0% vs. 2.5%, p < 0.001) and a longer PED median length of stay (321.0 (Interquartile range (IQR); 211.3-441.5) minutes vs. 284.5 (IQR; 191.8-439.5) minutes, p = 0.042). After logistic regression, US performed by a radiology resident (odds ratio, 5.01; 95% confidence interval, 3.63-7.15) was the most significant factor contributing to uncertainty in paediatric abdominal US reports followed by obesity and age. CONCLUSION: Several factors contribute to uncertainty in paediatric abdominal US reports. Uncertain radiological reports increase the likelihood of additional CT scans. Measures to improve the clarity of radiological reports must be considered to improve the quality of care for children visiting the PED.
Assuntos
Dor Abdominal , Serviço Hospitalar de Emergência , Criança , Humanos , Estudos Retrospectivos , Incerteza , Dor Abdominal/diagnóstico por imagem , UltrassonografiaRESUMO
FJH-KO obtained from Antarctic krill, especially Euphausia superba, has been reported to contain high amounts of omega-3 polyunsaturated fatty acids (n-3 PUFA) and to exhibit anticancer and anti-inflammatory properties. However, its antithrombotic effects have not yet been reported. This study aimed to investigate the antithrombotic effects of FJH-KO in carrageenan-induced thrombosis mouse models and human endothelial cells. Thrombosis was induced by carrageenan injection, whereas the mice received FJH-KO pretreatment. FJH-KO attenuated carrageenan-induced thrombus formation in mouse tissue vessels and prolonged tail bleeding. The inhibitory effect of FJH-KO was associated with decreased plasma levels of thromboxane B2, P-selectin, endothelin-1, ß-thromboglobulin, platelet factor 4, serotonin, TNF-α, IL-1ß, and IL-6. Meanwhile, FJH-KO induced plasma levels of prostacyclin I2 and plasminogen. In vitro, FJH-KO decreased the adhesion of THP-1 monocytes to human endothelial cells stimulated by TNF-α via eNOS activation and NO production. Furthermore, FJH-KO inhibited the expression of TNF-α-induced adhesion molecules such as ICAM-1 and VCAM-1 by suppressing the NF-κB signaling pathway. Taken together, our study demonstrates that FJH-KO protects against carrageenan-induced thrombosis by regulating endothelial cell activation and has potential as an antithrombotic agent.
Assuntos
Euphausiacea , Ácidos Graxos Ômega-3 , Trombose , Humanos , Animais , Camundongos , Carragenina/efeitos adversos , Células Endoteliais/metabolismo , Fibrinolíticos/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Ácidos Graxos Ômega-3/efeitos adversosRESUMO
OBJECTIVES: This cross-sectional study was to determine the coronavirus disease 2019 (COVID-19) vaccination intention of clinical dental hygienists in South Korea and the factors that influence vaccination intention. METHODS: COVID-19 vaccination intention of the 500 participants was confirmed through a survey including the following options: 'I will vaccinate (VAC)', 'I will not vaccinate (NoVAC)' and 'I do not know if I should get vaccinated (UNK)'. A Chi-square test was performed to determine whether there were differences in COVID-19 vaccination intention according to the general characteristics of the participants, degree of infection control knowledge (Score-K) and practice (Score-P) in response to COVID-19, fears over COVID-19 (Fear-C) and the level of anxiety before (GADBefore ) and after (GADAfter ) the COVID-19 pandemic. Multiple logistic regression was performed to identify factors affecting VAC and NoVAC by setting the base category as UNK. The p-values of <0.05 were considered statistically significant. RESULTS: According to the analysis, 44.8%, 18.8% and 36.4% of participants selected VAC, NoVAC and UNK respectively. There were significant differences in vaccination intention according to age, monthly income, residential area, symptoms related to COVID-19, Score-K, Fear-C and GADBefore . Compared to UNK, < $2000 monthly income, Score-K and Fear-C variables significantly influenced the opinion of VAC. Compared to the answer UNK, monthly incomes of $2000 to $2360 and $2360 to $2730 in residential areas significantly influenced the opinion of NoVAC. CONCLUSIONS: The variables influencing vaccination intention were monthly income, residential area, Score-K and Fear-C.