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BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) manifests as a diverse hematological malignancy. Although it was categorized into a favorable subtype, 30-40% of patients experience relapse. The objective of this research was to devise a nomogram for the accurate anticipation of both overall survival (OS) and cancer-specific survival (CSS) in t(8;21) AML. METHODS: From the Surveillance, Epidemiology, and End Results (SEER) database, individuals diagnosed with t(8;21) AML from 2000 to 2018 were selected. Prognostic factors for t(8;21) AML were identified using Cox regression analysis and Akaike Information Criterion (AIC), forming the basis for constructing prognostic nomograms. RESULTS: Key variables, including first primary tumor, age group, race, and chemotherapy, were identified and integrated into the nomogram. The C-index values for the nomograms predicting OS and CSS were 0.753 (validation: 0.765) and 0.764 (validation: 0.757), respectively. Ultimately, based on nomogram scores, patients were stratified into high-risk and low-risk groups, revealing significant disparities in both OS and CSS between these groups (P < 0.001). CONCLUSION: This study innovatively crafted nomograms, incorporating clinical and therapeutic variables, to forecast the 1-, 3-, and 5-year survival rates for individuals with t(8;21) AML.
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Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda , Nomogramas , Programa de VERF , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 21/genética , Translocación Genética , Pronóstico , Adolescente , Anciano , Adulto JovenRESUMEN
Background and purpose: Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disorders that is characterized by core features in social communication impairment and restricted, repetitive sensory-motor behaviors. This study aimed to further investigate the utilization of fecal microbiota transplantation (FMT) in children with ASD, both with and without gastrointestinal (GI) symptoms, evaluate the effect of FMT and analyze the alterations in bacterial and fungal composition within the gut microbiota. Methods: A total of 38 children diagnosed with ASD participated in the study and underwent oral lyophilized FMT treatment. The dosage of the FMT treatment was determined based on a ratio of 1â g of donor stool per 1â kg of recipient body weight, with a frequency of once every 4 weeks for a total of 12 weeks. In addition, 30 healthy controls (HC) were included in the analysis. The clinical efficacy of FMT was evaluated, while the composition of fecal bacteria and fungi was determined using 16S rRNA and ITS gene sequencing methods. Results: Median age of the 38 children with ASD was 7 years. Among these children, 84.2% (32 of 38) were boys and 81.6% (31 of 38) exhibited GI symptoms, with indigestion, constipation and diarrhea being the most common symptoms. Sample collections and assessments were conducted at baseline (week 0), post-treatment (week 12) and follow-up (week 20). At the end of the follow-up phase after FMT treatment, the autism behavior checklist (ABC) scores decreased by 23% from baseline, and there was a 10% reduction in scores on the childhood autism rating scale (CARS), a 6% reduction in scores on the social responsiveness scale (SRS) and a 10% reduction in scores on the sleep disturbance scale for children (SDSC). In addition, short-term adverse events observed included vomiting and fever in 2 participants, which were self-limiting and resolved within 24â h, and no long-term adverse events were observed. Although there was no significant difference in alpha and beta diversity in children with ASD before and after FMT therapy, the FMT treatment resulted in alterations in the relative abundances of various bacterial and fungal genera in the samples of ASD patients. Comparisons between children with ASD and healthy controls (HC) revealed statistically significant differences in microbial abundance before and after FMT. Blautia, Sellimonas, Saccharomycopsis and Cystobasidium were more abundant in children with ASD than in HC, while Dorea were less abundant. After FMT treatment, levels of Blautia, Sellimonas, Saccharomycopsis and Cystobasidium decreased, while levels of Dorea increased. Moreover, the increased abundances of Fusicatenibacter, Erysipelotrichaceae_UCG-003, Saccharomyces, Rhodotorula, Cutaneotrichosporon and Zygosaccharomyces were negatively correlated with the scores of ASD core symptoms. Conclusions: Oral lyophilized FMT could improve GI and ASD related symptoms, as well as sleep disturbances, and alter the gut bacterial and fungal microbiota composition in children with ASD. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR2200055943. Registered 28 January 2022, www.chictr.org.cn.
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This retrospective study aimed to analyze the treatment effect and prognostic factors of pediatric acute myeloid leukemia (AML) patients with t(8;21). A total of 268 newly diagnosed pediatric AML (pAML) enrolled from 1 January 2005 to 31 December 2022 were retrospectively reviewed, and 50 (18.7%) patients harbored t(8;21) translocation. CR rate, OS, EFS, and RFS were assessed by multivariate Logistic and Cox regression models in these patients. Of the 50 patients, 2 patients abandoned treatment during the first induction course. Of the remaining 48 patients who received double-induction therapy and were included in the final analyses, CR1 and CR2 were 75.0% (36/48) and 95.8% (46/48), respectively. The overall three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0-85.1), 64.2% (95% CI, 50.7-81.4), and 65.5% (95% CI, 51.9-82.8), respectively. The presence of loss of sex chromosome (LOS) at diagnosis (n = 21) was associated with a better 3-year OS [87.5% (95% CI, 72.7-100) vs. 52.7% (95% CI, 35.1-79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7-100) vs. 49.7% (95% CI, 32.4-76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7-100) vs. 51.7% (95% CI, 33.9-78.9), p = 0.036] than those without LOS (n = 27), and it was also an independent good prognostic factor of OS (HR, 0.08 [95% CI, 0.01-0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05-0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05-0.90], p = 0.035). However, extramedullary leukemia (EML) featured the independent risk factors of inferior OS (HR, 10.99 [95% CI, 2.08-58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10-20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40-30.63], p = 0.017) in pediatric individuals with t(8;21) AML. Further analysis of combining LOS with EML indicated that the EML+LOS- subgroup had significantly inferior OS (92.9%, [95% CI, 80.3-100]), EFS (86.2%, [95% CI, 70.0-100]), and RFS (86.2%, [95% CI, 80.3-100]) compared to the other three subgroups (all p < 0.001). LOS and EML are independent prognostic factors of OS, EFS, and RFS with t(8;21) pAML patients. LOS combined with EML may help improve risk stratification.
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Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.
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Alcaloides , Fosfatidilinositol 3-Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , Benzofenantridinas/farmacología , Alcaloides/metabolismo , Isoquinolinas/farmacologíaRESUMEN
Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated from the leaves of Ochrosia elliptica Labill. Ellipticine and its derivatives are characterized by multiple biological activities. The purpose of this review was to provide a critical and systematic assessment of ellipticine and its derivatives as bioactive molecules over the last 60â years. Publications focused mainly on the total synthesis of alkaloids of this type without any evaluation of bioactivity have been excluded. We have reviewed papers dealing with the synthesis, bioactivity evaluation and mechanism of action of ellipticine and its derivatives. It was found that ellipticine and its derivatives showed cytotoxicity, antimicrobial ability, and anti-inflammatory activity, among which cytotoxicity toward cancer cell lines was the most investigated aspect. The inhibition of DNA topoisomerase II was the most relevant mechanism for cytotoxicity. The PI3K/AKT pathway, p53 pathway, and MAPK pathway were also closely related to the antiproliferative ability of these compounds. In addition, the structure-activity relationship was deduced, and future prospects were outlined. We are confident that these findings will lay a scientific foundation for ellipticine-based drug development, especially for anticancer agents.
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Elipticinas , Elipticinas/farmacología , Elipticinas/química , Humanos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinfecciosos/farmacología , Antiinfecciosos/química , Estructura Molecular , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificaciónRESUMEN
PURPOSE: To investigate the prevalence of Y chromosome polymorphisms in Chinese men and analyze their associations with male infertility and female adverse pregnancy outcomes. METHODS: The clinical data of 32,055 Chinese men who underwent karyotype analysis from October 2014 to September 2019 were collected. Fisher's exact test, chi-square test, or Kruskal-Wallis test was used to analyze the effects of Y chromosome polymorphism on semen parameters, azoospermia factor (AZF) microdeletions, and female adverse pregnancy outcomes. RESULTS: The incidence of Y chromosome polymorphic variants was 1.19% (381/32,055) in Chinese men. The incidence of non-obstructive azoospermia (NOA) was significantly higher in men with the Yqh- variant than that in men with normal karyotype and other Y chromosome polymorphic variants (p < 0.050). The incidence of AZF microdeletions was significantly different among the normal karyotype and different Y chromosome polymorphic variant groups (p < 0.001). The detection rate of AZF microdeletions was 28.92% (24/83) in the Yqh- group and 2.50% (3/120) in the Y ≤ 21 group. The AZFb + c region was the most common AZF microdeletion (78.57%, 22/28), followed by AZFc microdeletion (7.14%,2/28) in NOA patients with Yqh- variants. There was no significant difference in the distribution of female adverse pregnancy outcomes among the normal karyotype and different Y chromosome polymorphic variant groups (p = 0.528). CONCLUSIONS: Patients with 46,XYqh- variant have a higher incidence of NOA and AZF microdeletions than patients with normal karyotype and other Y chromosome polymorphic variants. Y chromosome polymorphic variants do not affect female adverse pregnancy outcomes.
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Azoospermia , Infertilidad Masculina , Oligospermia , Humanos , Masculino , Femenino , Azoospermia/epidemiología , Azoospermia/genética , Estudios Retrospectivos , Deleción Cromosómica , Infertilidad Masculina/genética , Cromosomas Humanos Y/genética , China/epidemiología , Oligospermia/genéticaRESUMEN
PURPOSE: To establish a medically valuable normal reference interval of follicle-stimulating hormone (FSH) levels in males with normal semen and to assess the predictive value of FSH in males exhibiting semen abnormalities. METHODS: The study involved male patients who underwent their initial serum sex hormone test and semen test between October 2013 and June 2023. The reference interval was identified as the 95% confidence interval (CI) of FSH values in the patients with normal semen parameters. Then, in the total study population, receiver operating characteristic (ROC) curves were performed to evaluate the discriminatory ability of FSH for oligozoospermia and non-obstructive azoospermia (NOA). Besides, multivariable logistic regression was performed to investigate the association of FSH with oligozoospermia and NOA adjusted by age. RESULTS: A total of 11,929 patients were finally enrolled in the study. The normal reference interval of FSH ranged from 1.70 IU/L to 7.60 IU/L (median: 3.98 IU/L) based on 4595 patients with normal semen routine parameters. In the total patients, ROC curves showed FSH to have a "fair" discriminatory ability for oligozoospermia (area under receiver operating characteristic curve (AUC) 0.747, threshold 7.32 IU/L, accuracy 0.734, positive predictive value (PPV) 0.754, negative predictive value (NPV) 0.726), while ROC curves showed FSH to have a "excellent" discriminatory ability for NOA (AUC: 0.921, threshold 10.18 IU/L, accuracy 0.903, PPV 0.593, NPV 0.972). Besides, multivariable logistic regression showed that FSH ≥ 7.32 IU/L was associated with a 8.51-fold increase in the risk of oligozoospermia adjusted by age, while FSH ≥ 10.18 IU/L was associated with a 38.93-fold increase in the risk of NOA. CONCLUSIONS: Our findings indicated that the reference interval for FSH in males with normal semen was 1.70-7.60 IU/L and found that FSH was capable of effectively discerning oligospermia and NOA.
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Azoospermia , Oligospermia , Análisis de Semen , Humanos , Masculino , Estudios Retrospectivos , Hormona Folículo Estimulante , Testosterona , Semen , ChinaRESUMEN
Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.
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Lignanos , Adenosina Trifosfatasas , Antiinflamatorios/farmacología , Lactonas , Lignanos/farmacología , Lignanos/químicaRESUMEN
BACKGROUND: Post-transplant bone disease (PTBD) is a common complication in kidney transplant recipients. This systematic review and meta-analysis evaluates the efficiency and safety of denosumab for the treatment of PTBD in kidney transplant recipients. METHODS: Comprehensive search of PubMed Central, SCOPUS, EMBASE, MEDLINE, Cochrane trial registry, Google Scholar, and Clinicaltrials.gov databases was done for studies, published until April 2023. Primary outcomes included changes in bone mineral density (BMD) and T-scores. Secondary outcomes included incidence of fractures, alterations in bone turnover markers, and the incidence of adverse events. RESULTS: Eleven studies with a total of 511 participants that underwent kidney transplant were included. Denosumab treatment resulted in a significant improvement in lumbar spine BMD (SMD: -0.31, 95% CI: -0.56 to -0.06) and T-score (SMD: -1.07, 95% CI: -1.51 to -0.64), while no differences were detected in hip/femoral neck BMD and the T-score. There was no marked change in the fracture incidence (OR: 0.42, 95% CI: 0.06 to 3.07). However, patients who received denosumab treatment had an increased incidence rate of hypocalcemia (OR: 9.98, 95% CI: 1.72 to 57.88). CONCLUSIONS: Denosumab treatment may improve lumbar spine BMD and T-scores in patients with PTBD. However, it does not significantly affect fracture incidence and may increase the risk of hypocalcemia. These findings underline the necessity for well-powered, randomized controlled trials to further clarify the role of denosumab in managing PTBD.
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Conservadores de la Densidad Ósea , Hipocalcemia , Trasplante de Riñón , Humanos , Densidad Ósea , Denosumab/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Hipocalcemia/etiología , Trasplante de Riñón/efectos adversosRESUMEN
Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.
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Antineoplásicos , Compuestos Heterocíclicos , Pirazinas/farmacología , Pirazinas/química , Compuestos Heterocíclicos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , NitrógenoRESUMEN
PURPOSE: We tested the role of age and sex in surgery following pediatric TBI hospitalization. METHODS: Records of 1745 children hospitalized at a pediatric neurotrauma center in China included age, sex, cause of injury, diagnosis of injury, days of hospitalization, in-house rehabilitation, Glasgow Coma Scale score, mortality, 6-month post-discharge Glasgow Outcome Scale score, and surgery intervention. The children were 0-13 years (M= 3.56 years; SD = 3.06), with 47.4% 0-2 years of age. RESULTS: The mortality rate was 1.49%. Logistic regression on 1027 children with epidural hematoma, subdural hematoma, intracerebral hemorrhage, and intraventricular hemorrhage showed that controlling for other variables, the odds for younger children to receive surgery was statistically lower for epidural hematomas (OR = 0.75; 95% CI = 0.68-0.82), subdural hematomas (OR = 0.59; 95% CI = 0.47-0.74), and intraventricular hemorrhage (OR = 0.52; 95% CI = 0.28-0.98). CONCLUSIONS: While severity of TBI and type of TBI were expected predictors for surgery, a younger age also predicted a significantly lower likelihood of surgery in our sample. Sex of the child was unrelated to surgical intervention.
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Lesiones Traumáticas del Encéfalo , Hematoma Epidural Craneal , Niño , Humanos , Cuidados Posteriores , Pueblos del Este de Asia , Alta del Paciente , Hematoma Epidural Craneal/cirugía , Hematoma Epidural Craneal/etiología , Hematoma Subdural/complicaciones , Hemorragia Cerebral/complicaciones , Escala de Coma de Glasgow , Hospitales , Estudios Retrospectivos , Lesiones Traumáticas del Encéfalo/complicacionesRESUMEN
Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.
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Alcaloides , Antineoplásicos , Compuestos Heterocíclicos de Anillo en Puente , Neoplasias , Humanos , Antineoplásicos/farmacología , Azepinas/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Lactonas/farmacología , Apoptosis , Alcaloides/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular TumoralRESUMEN
BACKGROUND AND AIMS: There are currently no clear conclusions about whether major depression (MD) and bipolar disorder (BD) increase the risk of erectile dysfunction (ED). In our study, we used a Mendelian randomization (MR) analysis to discover the causal associations between MD, BD and ED. METHODS: We got single-nucleotide polymorphisms (SNPs) related to MD, BD and ED from the MRC IEU Open genome-wide association study (GWAS) datasets. After a series of selection, SNPs left were selected as instrumental variables (IVs) of MD and BD for the following MR test to evaluate the relationship of genetically predicted MD or BD with the incidence of ED. Among them, we used the random-effects inverse-variance weighted (IVW) method as the main analysis. Finally, sensitivity analyses were further performed using Cochran's Q test, funnel plots, MR-Egger regression, Leave-one-out method and MR- pleiotropy residual sum and outlier (PRESSO). RESULTS: Genetically-predicted MD was causally related to the incidence of ED in the IVW methods (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.19-1.96; p = 0.001), while no causal impact of BD on the risk of ED (OR = 0.95, 95% CI 0.87-1.04; p = 0.306). The results of sensitivity analyses supported our conclusion, and no directional pleiotropy were found. CONCLUSION: The findings of this research found evidence of a causal relationship between MD and ED. However, we did not find a causal relationship between BD and ED in European populations.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Disfunción Eréctil , Masculino , Humanos , Trastorno Depresivo Mayor/genética , Trastorno Bipolar/genética , Disfunción Eréctil/genética , Depresión , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Gut microbiota alterations have been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19). This study aimed to explore gut microbiota changes in a prospective cohort of COVID-19 children and their asymptomatic caregivers infected with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Omicron variant. METHODS: A total of 186 participants, including 59 COVID-19 children, 50 asymptomatic adult caregivers, 52 healthy children (HC), and 25 healthy adults (HA), were recruited between 15 April and 31 May 2022. The gut microbiota composition was determined by 16S rRNA gene sequencing in fecal samples collected from the participants. Gut microbiota functional profiling was performed by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) software. RESULTS: The gut microbiota analysis of beta diversity revealed that the fecal microbial community of COVID-19 children remained far distantly related to HC. The relative abundances of the phyla Actinobacteria and Firmicutes were decreased, whereas Bacteroidetes, Proteobacteria, and Verrucomicrobiota were increased in COVID-19 children. Feces from COVID-19 children exhibited notably lower abundances of the genera Blautia, Bifidobacterium, Fusicatenibacter, Streptococcus, and Romboutsia and higher abundances of the genera Prevotella, Lachnoclostridium, Escherichia-Shigella, and Bacteroides than those from HC. The enterotype distributions of COVID-19 children were characterized by a high prevalence of enterotype Bacteroides. Similar changes in gut microbiota compositions were observed in asymptomatic caregivers. Furthermore, the microbial metabolic activities of KEGG (Kyoto Encyclopedia of Genes and Genomes) and COG (cluster of orthologous groups of proteins) pathways were perturbed in feces from subjects infected with the SARS-CoV-2 Omicron variant. CONCLUSION: Our data reveal altered gut microbiota compositions in both COVID-19 children and their asymptomatic caregivers infected with the SARS-CoV-2 Omicron variant, which further implicates the critical role of gut microbiota in COVID-19 pathogenesis.
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COVID-19 , Microbioma Gastrointestinal , Adulto , Humanos , Niño , SARS-CoV-2 , Cuidadores , Estudios Prospectivos , ARN Ribosómico 16S/genética , Filogenia , Heces/microbiologíaRESUMEN
Exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn's disease (CD). This study aims to depict EEN's modification of bile acid (BA) metabolism in pediatric CD and explores the effect of the EEN-enriched BA in inhibiting the inflammatory response. The twelve enrolled pediatric CD patients showed BA dysmetabolism, represented by decreased levels of fecal secondary and unconjugated BAs as determined by UPLC-TQMS, which were accompanied by gut microbiota dysbiosis and reduced BA-metabolizing bacteria including Eubacterium and Ruminococcus genera, assessed by shotgun metagenomic sequencing. EEN treatment induced remission in these patients at eight weeks, and nine patients remained in stable remission for longer than 48 weeks. EEN improved BA dysmetabolism, with some enriched BAs, including hyocholic acid (HCA), α-muricholic acid (αMCA), strongly associated with decreased severity of CD symptoms. These BAs were significantly correlated with the increased abundance of certain bacteria, including Clostridium innocuum and Hungatella hathewayi, which express 3ß-hydroxysteroid dehydrogenase and 5ß-reductase. HCA could suppress TNF-α production by CD4+ T cells in the peripheral blood mononuclear cells (PBMCs) of CD patients. Moreover, intraperitoneal injection of HCA could attenuate dextran sulfate sodium (DSS)-induced mouse colitis. Our data suggests that BA modification may contribute to the EEN-induced remission of pediatric CD.
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Nutrición Enteral , Microbiota , Ratones , Animales , Inducción de Remisión , Leucocitos Mononucleares , Bacterias , Antiinflamatorios , Ácidos y Sales BiliaresRESUMEN
BACKGROUND: Mitochondrial encephalomyopathy (ME) is a multisystem metabolic disease that primarily affects the central nervous system and skeletal muscle. It is caused by mutations in mitochondrial or nuclear DNA, resulting in abnormal mitochondrial structure and function and insufficient ATP synthesis. The most common subtype is mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. In recent years, reports of MELAS syndrome have increased but familial cases are rare. CASE SUMMARY: We report a case of familial MELAS syndrome. Cases 2 and 3 are sisters and case 1 is their nephew. All are short in stature and showed stroke-like episodes with rapid onset and no obvious symptoms such as paroxysmal headache, aphasia, or blurred vision. After admission, blood lactate levels were significantly higher than normal. The patients underwent magnetic resonance imaging of the head. Cases 1 and 2 were considered to have ME, whereas case 3 was considered to have a space-occupying lesion in the left temporal lobe. Pathological evaluation showed no obvious tumor cells in the brain lesions of case 3. Muscle biopsy or genetic test results were consistent with ME. The patients were diagnosed with MELAS syndrome and their symptoms improved with intravenous infusions of coenzyme Q10, coenzyme A, vitamin B, and vitamin C. At the 6 mo follow-up, there was no recurrence or progression. CONCLUSION: When a patient has MELAS syndrome, familial MELAS syndrome should be considered if related family members have similar symptoms.
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OBJECTIVE: To evaluate the efficacy and safety of fecal microbiota transplantation (FMT) in functional gastrointestinal disorders (FGIDs) in children with abdominal bloating and changes in their gut microbiome and metabolome. METHODS: Twelve pediatric FGID patients with predominant abdominal bloating who underwent FMT were enrolled in the study. Fourteen healthy controls and four stool donors were included for analysis. Clinical responses were assessed at 8 weeks after FMT. Fecal bacterial composition was determined by 16S rRNA gene sequencing. The fecal metabolome was measured by targeted metabolomics analysis. RESULTS: Median age of the 12 children with FGIDs was 6 years, and nine were boys. Abdominal bloating was relieved in all patients by FMT at 8 weeks. Meanwhile, FMT significantly improved abdominal pain and diarrhea. The a diversity was significantly lower in the FGID patients, while the fecal microbial community (ß diversity) separated from that of healthy control (HCs). The relative abundances of multiple bacterial genera were significantly changed in the feces of the pediatric FGID patients. The levels of several short-chain fatty acids were lower, and lactic acid level was higher in FGID patients than in HCs. Altered bacterial composition was correlated with changes in the fecal metabolite profile and clinical symptoms in FGID patients. FMT modulated fecal microbiome and metabolome in FGID children toward a healthy state. CONCLUSIONS: FMT relieves abdominal bloating and modulates fecal microbiome and metabolome toward a healthy state in children with FGIDs. FMT may provide an alternative therapy for children with FGIDs and abdominal bloating.
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Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Masculino , Humanos , Niño , Femenino , Trasplante de Microbiota Fecal , ARN Ribosómico 16S/genética , Heces/microbiología , Enfermedades Gastrointestinales/terapia , Metaboloma , Bacterias , Resultado del TratamientoRESUMEN
Pediatric acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) characterized by abnormal megakaryoblasts, and it is divided into the AMKL patients with Down syndrome (DS-AMKL) and AMKL patients without DS (non-DS-AMKL). Pediatric non-DS-AMKL is a heterogeneous disease with extremely poor outcome. We performed single-cell RNA sequencing (scRNA-seq) of the bone marrow from two CBFA2T3-GLIS2 fusion-positive and one RBM15-MKL1 fusion-positive non-DS-AMKL children. Meanwhile, we downloaded the scRNA-seq data of normal megakaryocyte (MK) cells of the fetal liver and bone marrow from healthy donors as normal controls. We conducted cell clustering, cell-type identification, inferCNV analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Monocle2 analysis to investigate the intratumoral heterogeneity of AMKL. Using canonical markers, we identified and characterized the abnormal blasts and other normal immune cells from three AMKL samples. We found intratumoral heterogeneity of AMKL in various cell-type proportions, malignant cells' diverse copy number variations (CNVs), maturities, significant genes expressions, and enriched pathways. We also identified potential markers for pediatric AMKL, namely, RACK1, ELOB, TRIR, NOP53, SELENOH, and CD81. Our work offered insight into the heterogeneity of pediatric acute megakaryoblastic leukemia and established the single-cell transcriptomic landscape of AMKL for the first time.
RESUMEN
Cyclosporine (CsA) is a component of the first-line treatment for acquired aplastic anemia (acquired AA) in pediatric patients. This study aimed to develop a population pharmacokinetic (PK) model of CsA in Chinese pediatric patients with acquired AA to inform individual dosage regimens. A total of 681 CsA whole blood concentrations and laboratory data of 157 pediatric patients with acquired AA were retrospectively collected from two hospitals in Shanghai. A nonlinear mixed-effect model approach was used to build the population PK model. Potential covariate effects of age, body weight, and biochemical measurements (renal and liver functions) on CsA PK disposition were evaluated. Model fit was assessed using the basic goodness of fit and a visual predictive check. The CsA concentration data were accurately described using a two-compartment disposition model with first-order absorption and elimination. Body weight value was implemented as a fixed allometric function on all clearance and volume of distribution parameters. Total bilirubin level was identified as a significant covariate on apparent clearance (CL/F), with a 1.07% reduction per 1 nmol/L rise in total bilirubin level. The final estimates for CL/F and central volume (Vc/F) were 29.1 L/h and 325 L, respectively, for a typical 28 kg child. Other covariates (e.g., gender, age, albumin, hemoglobin, hematocrit, serum creatinine, and concomitant medication) did not significantly affect the PK properties of CsA. This population PK model, along with a maximum a posteriori Bayesian approach, could estimate individual PK parameters in pediatric patients with acquired AA to conduct individual CsA therapy.
RESUMEN
PURPOSE: Testicular sperm aspiration (TESA) is widely used to retrieve sperm from testis. Diagnostic testicular biopsy should not be routinely performed for azoospermia. Therefore, a good predictive model is needed before TESA. METHODS: A total of 1972 azoospermia patients constituted the modelling set, and 260 azoospermia patients from two other centres constituted the validation set. An integrated predictive model was built using logistic regression. Receiver operating characteristic (ROC), calibration and decision curve analyses were performed to evaluate the performance of follicle-stimulating hormone (FSH), semen volume, testicular volume and the integrated model. RESULTS: The FSH level was the best univariate predictor for successful sperm retrieval (SSR) and was better than semen volume and testicular volume alone (p<0.001, threshold 6.17 IU/L, modelling set area under receiver operating characteristic curve (AUC) 0.80, accuracy 0.79; validation set AUC 0.87, accuracy 0.78). The integrated predictive model had excellent accuracy for predicting SSR (modelling set: AUC 0.93, accuracy 0.89; validation set: AUC 0.96, accuracy: 0.89). Calibration curve analysis indicated that the integrated model calibration was good and better than that of FSH, semen volume and testicular volume alone. Decision curve analysis indicated with a threshold probability between 0.05 and 0.98, the integrated model added more benefit than treating either all or no patients. CONCLUSIONS: The integrated model has excellent discrimination and good calibration. It can help azoospermic men make better decisions before TESA. It should be noted that TESA is not the first-line treatment for non-obstructive azoospermia because of a low sperm retrieval rate.