ABSTRACT
Genomic analysis of structural variants(SVs) in breast cancer (BC) patients has been conducted, but the relationship between genomic alterations and BC prognosis remains unclear. We performed RNA sequencing of 297 early BC fresh-frozen tissues. We identified SVs using three tools (STAR.Arriba, STAR.fusion, and STAR.SEQR) with the COSMIC and Mitelman databases as guide references. We found a median of five to eight fusions per sample. In BC intrinsic subtypes, normal subtype had the fewest fusions (median: 1, interquartile range [IQR]: 0, 3) followed by luminal A (median: 5.5, IQR: 2.75, 10.25), luminal B (median: 9, IQR: 6, 16.5), HER2-enriched (median: 9, IQR: 6, 16.5) and basal (median 10, IQR: 6, 15.5) subtypes (p < 0.05). Intrachromosomal fusion was more frequent observed rather than interchromosomal fusion. In location, chromosome 17 had the most fusions followed by chromosome 1 and 11. When samples were divided into high and low fusion groups based on a cut-off value of 11 fusions, five-year event-free survival (5Y-EFS) was 68.1% in the high fusion group (n = 72) and 80.1% in the low fusion group (n = 125) (p = 0.024) while 75.6% among all patients (95% confidence interval: 0.699, 0.819). Among BC subtype, TNBCs with more fusions had shorter EFS compared to those with fewer fusions (5Y-EFS rate: 65.1% vs. 85.7%; p = 0.013) but no EFS differences were observed in other BC subtypes. ESTIMATE ImmuneScore was also associated with the number of fusions in TNBC (p < 0.005) and TNBCs with high ImmuneScore had better 5Y-EFS compared to those with low ImmuneScore (p = 0.041). In conclusion, diverse fusions were observed by BC subtype, and the number of fusions was associated with BC survival outcome and immune status in TNBC.
ABSTRACT
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of â¼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
Subject(s)
Haplotypes , Humans , Haplotypes/genetics , Comparative Genomic Hybridization , Genomic Structural Variation/genetics , Genome, Human/genetics , Gene Duplication/geneticsABSTRACT
Purpose: Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies. Materials and Methods: In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing. Results: By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor ß diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores. Conclusion: Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.
ABSTRACT
Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator PhenotypeHigh (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the thylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC. [BMB Reports 2024; 57(2): 110-115].
Subject(s)
Colorectal Neoplasms , DNA Methylation , Humans , DNA Methylation/genetics , Microsatellite Instability , Mutation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Republic of Korea , CpG Islands/genetics , PhenotypeABSTRACT
Background: The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions in cis . Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes. Results: Here we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the genomic DNA of 24 patients with neurodevelopmental disorders identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted SV haplotypes. Using a combination of short-read genome sequencing (GS), long- read GS, optical genome mapping and StrandSeq the haplotype structure was resolved in 18 samples. This approach refined the point of template switching between inverted LCRs in 4 samples revealing a DNA segment of â¼2.2-5.5 kb of 100% nucleotide similarity. A prediction model was developed to infer the LCR used to mediate the non-allelic homology repair. Conclusions: These data provide experimental evidence supporting the hypothesis that inverted LCRs act as a recombinant substrate in replication-based repair mechanisms. Such inverted repeats are particularly relevant for formation of copy-number associated inversions, including the DUP-TRP/INV-DUP structures. Moreover, this type of CGR can result in multiple conformers which contributes to generate diverse SV haplotypes in susceptible loci .
ABSTRACT
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Multiomics , Receptor, ErbB-2/genetics , Receptor, ErbB-2/analysis , Receptor, ErbB-2/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Receptors, Estrogen/genetics , Receptors, Estrogen/analysis , Receptors, Estrogen/therapeutic use , Estrogens/therapeutic useABSTRACT
OBJECTIVES: This systematic review aimed to identify the effects of normal saline instillation before endotracheal suctioning on clinical outcomes in critically ill patients on a mechanical ventilator. RESEARCH METHODOLOGY: This review was based on the guidelines of the National Evidence-based Healthcare Collaborating Agency in Korea and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Six electronic databases were searched for relevant literature. Other sources were also searched, including the reference lists of identified reports and previous systematic reviews. After the initial literature search, a two-step retrieval process was performed to select eligible studies. Then, data were collected using a newly developed form, and the risk of bias was assessed using the checklists of the Joanna Briggs Institute. Data were analyzed using both narrative syntheses and meta-analyses. RESULTS: In total, 16 studies: 13 randomized controlled trials and three quasi-experimental studies, were included. From the narrative syntheses, instilling normal saline before endotracheal suctioning was associated with a decrease in oxygen saturation, prolonged time for oxygen saturation to recover to baseline, decreased arterial pH, increased secretion amount, reduced incidence of ventilator-associated pneumonia, increased heart rate, and increased systolic blood pressure. Meta-analyses showed a significant difference in heart rate at five minutes after suctioning but no significant differences in oxygen saturation at two and five minutes after suctioning and heart rate at two minutes after suctioning. CONCLUSION: This systematic review indicated that instilling normal saline before performing endotracheal suctioning has more harmful effects than benefits. IMPLICATIONS FOR CLINICAL PRACTICE: As recommended in the current guidelines, it is necessary to refrain from routine normal saline instillation before endotracheal suctioning.
Subject(s)
Respiration, Artificial , Saline Solution , Humans , Adult , Saline Solution/adverse effects , Respiration, Artificial/adverse effects , Intubation, Intratracheal/adverse effects , Intensive Care Units , Heart RateABSTRACT
BACKGROUND & AIMS: Associations between hepatic fibrosis and mortality remain to be fully elucidated in large population-based studies. This study aimed to evaluate the associations of the fibrosis-4 index (FIB-4) with all-cause, cardiovascular, cancer, and liver-related mortality in the adult Korean population without viral hepatitis. METHODS: Baseline data were retrieved from the Korea National Health and Nutrition Examination Survey, and mortality data were retrieved from the Korean Cause of Death data registry. Adults (age, ≥19 y) without viral hepatitis B or C, liver cirrhosis, any cancer, stroke, myocardial infarction, angina pectoris, or renal failure at baseline were eligible. Presumed hepatic fibrosis was evaluated with FIB-4. Hazard ratios (HRs) and 95% CIs were calculated using multivariable Cox regression analysis, and Kaplan-Meier estimates of the cumulative mortality were evaluated. RESULTS: There were 46,456 individuals with a median follow-up period of 8.6 years (interquartile range, 6.3-10.6 y). Kaplan-Meier curves for cumulative mortality showed that participants with a FIB-4 of ≥2.67 (vs FIB-4, <2.67) had higher cumulative all-cause, cardiovascular, cancer, and liver-related mortality. In the fully adjusted model, Cox regression analysis revealed that presumed advanced hepatic fibrosis (FIB-4, ≥2.67) remained associated with all-cause mortality (HR, 1.64; 95% CI, 1.23-2.18), cardiovascular mortality (HR, 2.96; 95% CI, 1.60-5.46), and liver-related mortality (HR, 10.50; 95% CI, 4.70-23.44), but not cancer mortality, after adjusting for confounders including central obesity and insulin resistance. Excluding participants with an estimated alcohol intake of 30 grams or more for men and 20 grams or more for women did not affect the results. CONCLUSIONS: At the population level, liver fibrosis estimated by FIB-4 was associated with increased cumulative all-cause, cardiovascular, and liver-related mortality.
Subject(s)
Hepatitis, Viral, Human , Neoplasms , Non-alcoholic Fatty Liver Disease , Male , Adult , Humans , Female , Nutrition Surveys , Liver Cirrhosis/diagnosis , Republic of Korea/epidemiologySubject(s)
Hemophilia A , Humans , Hemophilia A/genetics , Factor VIII/genetics , Chromosome Inversion , Chromosome Mapping , Mutation , IntronsABSTRACT
Obesity in children and adolescents is a serious global problem. In Korea, approximately 35% of students' daily nutrient intake is from school lunch (SL), and all schools provide SL. However, the association between SL and obesity remains controversial. This study examined this association and the daily nutrient intake according to lunch type in Korean children and adolescents. We analyzed 1736 individuals aged 7-18 from the Korea National Health and Nutrition Examination Survey (2017-2019), a cross-sectional study, using logistic regression analysis with odds ratios and 95% confidence intervals. The SL group had higher energy and greater phosphorus, potassium, vitamin A, carotene, vitamin B1, and niacin intake than the non-school lunch (NSL) and skipping lunch (SKL) groups. Protein intake was also higher in the SL group than in the NSL group. The SKL group had higher saturated fatty acid intake, and was thereby 2.5, 1.9, and 2.5 times more likely to have obesity, overweight and obesity, and central obesity (p = 0.0071, 0.0459, 0.0092), respectively, than the SL group. Therefore, the SL group consumed more appropriate nutrients than the NSL and SKL groups, and was less likely to become obese than the SKL group. More in-depth prospective studies are needed to elucidate the causal relationship between SL and obesity.
Subject(s)
Food Services , Pediatric Obesity , Humans , Child , Adolescent , Diet , Nutrition Surveys , Cross-Sectional Studies , Energy Intake , Pediatric Obesity/epidemiology , Pediatric Obesity/etiology , Lunch , Republic of Korea/epidemiologyABSTRACT
Although the combination of radiotherapy and immunotherapy has proven to be effective in lung cancer treatment, it may not be sufficient to fully activate the antitumor immune response. Here, we investigated whether entinostat, a histone deacetylase inhibitor, could improve the efficacy of radiotherapy and anti-PD-1 in a murine syngeneic LL/2 tumor model. A total of 12 Gy of X-rays administered in two fractions significantly delayed tumor growth in mice, which was further enhanced by oral entinostat administration. Flow cytometry-aided immune cell profiling revealed that entinostat increased radiation-induced infiltration of myeloid-derived suppressor cells and CD8+ T cells with decreased regulatory T-cells (Tregs). Transcriptomics-based immune phenotype prediction showed that entinostat potentiated radiation-activated pathways, such as JAK/STAT3/interferon-gamma (IFN-γ) and PD-1/PD-L1 signaling. Entinostat augmented the antitumor efficacy of radiation and anti-PD-1, which may be related to an increase in IFN-γ-producing CD8+ T-cells with a decrease in Treg cells. Comparative transcriptomic profiling predicted that entinostat increased the number of dendritic cells, B cells, and T cells in tumors treated with radiation and anti-PD-1 by inducing MHC-II genes. In conclusion, our findings provided insights into how entinostat improves the efficacy of ionizing radiation plus anti-PD-1 therapy and offered clues for developing new strategies for clinical trials.
Subject(s)
Carcinoma, Lewis Lung , Histone Deacetylase Inhibitors , Animals , Mice , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , CD8-Positive T-Lymphocytes , Carcinoma, Lewis Lung/drug therapy , Immunomodulation , Immunity , Interferon-gamma/pharmacology , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
PURPOSE: ω-5 gliadin is the major allergen that causes wheat-dependent exercise-induced anaphylaxis (WDEIA). Recently, a missing mutant wheat cultivar at 1B chromosome Glu-B3 and closely linked Gli-B1 loci was bred. This cultivar (ω5D) has a deficiency in ω-5 and γ-gliadins as well as some low-molecular-weight glutenins. We evaluated specific immunoglobulin E (sIgE) reactivity of the ω5D in WDEIA patients compared to wild-type cultivar. METHODS: Serum samples from 14 WDEIA and 7 classic wheat allergy patients were used to compare the allergenicity of ω5D and wild-type cultivars using immunoglobulin E immunoblotting, enzyme-linked immunosorbent assay (ELISA), and ImmunoCAP inhibition assays. RESULTS: Immunoblotting revealed that ω5D extracts had less sIgE binding to gliadins and glutenins in WDEIA sera than wild-type extracts. Immunoblot inhibition assay for gliadin sIgE reactivity also showed that ω5D gliadins had less allergenicity than wild-type gliadins. ELISA inhibition assay showed stronger allergenicity of gliadins than glutenins, although they had cross-reactivity. This assay also showed that the 50% inhibitory concentrations (IC50) of ω5D extracts against gliadin- or glutenin-sIgE reactivity were approximately 4-fold higher in WDEIA patients than those of wild-type extracts. The inhibition capacity of ω5D gliadins against recombinant ω-5 gliadin-sIgE reactivity was also lower in WDEIA patients than that of wild-type. CONCLUSIONS: The allergenicity of the ω5D cultivar is markedly lower for WDEIA patients in the sIgE inhibition tests. These results suggest that the ω5D cultivar may be a safe alternative for WDEIA patients.
ABSTRACT
BACKGROUND: The etiology of small for gestational age (SGA) is multifactorial and includes maternal/uterine-placental factors, fetal epigenetics, and genetic abnormalities. We evaluated the genetic causes and diagnostic effectiveness of targeted-panel sequencing (TES) or whole-exome sequencing (WES) in SGA infants without a known cause. METHODS: A prospective study was conducted on newborn infants born with a birth weight of less than the 10th percentile for gestational age between January 2019 and December 2020 at the Pusan National University Hospital. We excluded infants with known causes of SGA, including maternal causes or major congenital anomalies or infections. SGA infants without a known etiology underwent genetic evaluation, including karyotyping, chromosomal microarray (CMA), and TES/WES. RESULTS: During the study period, 82 SGA infants were born at our hospital. Among them, 61 patients were excluded. A total of 21 patients underwent karyotyping and chromosomal CMA, and aberrations were detected in two patients, including one chromosomal anomaly and one copy number variation. Nineteen patients with normal karyotype and CMA findings underwent TES or WES, which identified three pathogenic or likely pathogenic single-gene mutations, namely LHX3, TLK2, and MED13L. CONCLUSIONS: In SGA infants without known risk factors, the prevalence of genetic causes was 22% (5/21). The diagnostic yield of TES or WES in SGA infants with normal karyotype and CMA was 15.7% (3/19). TES or WES was quite helpful in identifying the etiology in SGA infants without a known cause.
ABSTRACT
Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1, a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing (n = 60) and whole transcriptomic sequencing (WTS) (n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.
ABSTRACT
BACKGROUND: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. PATIENTS AND METHODS: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. RESULTS: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS <6 month. CONCLUSION: Of palbociclib plus ET, luminal type showed better prognosis and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy and resistance.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , DNA Copy Number Variations , Female , Hormones/therapeutic use , Humans , Piperazines , Pyridines , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolismABSTRACT
BACKGROUND: nosocomial sepsis remains a significant source of morbidity and mortality in extremely low birth weight (ELBW) infants. Early and accurate diagnosis is very important, but it is difficult due to the similarities in clinical manifestation between the causative microorganisms. We tried to identify the differences between causative microorganisms in clinical and laboratory findings and to help choose antibiotics, when sepsis was suspected in ELBW infants. METHODS: a retrospective study was conducted on preterm infants, born at less than 28 weeks of gestation, with a birth weight of less than 1000 g between January 2009 and December 2019. Clinical and laboratory findings of suspected sepsis, after the first 72 h of life, were assessed. We classified them into four groups according to blood culture results (gram positive, gram negative, fungal, and negative culture groups) and compared them. RESULTS: a total of 158 patients were included after using the exclusion criteria, with 45 (29%) in the gram positive group, 35 (22%) in the gram negative group, 27 (17%) in the fungal group, and 51 (32%) in the negative culture group. There were no significant differences in mean gestational age, birth weight, and neonatal morbidities, except for the age of onset, which was earlier in the fungal group than other groups. White blood cell (WBC) counts were the highest in the gram negative group and the lowest in the fungal group. The mean platelet counts were the lowest in the fungal group. C-reactive protein (CRP) levels were the highest in the gram negative group, while glucose was the highest in the fungal group. CONCLUSIONS: in conclusion, we showed that there are some differences in laboratory findings, according to causative microorganisms in the nosocomial sepsis of ELBW infants. Increased WBC and CRP were associated with gram negative infection, while decreased platelet and glucose level were associated with fungal infection. These data may be helpful for choosing empirical antibiotics when sepsis is suspected.
ABSTRACT
This study compared the effects of a real-world multidisciplinary intervention with additional exercise or nutritional elements and investigated the effectiveness of a booster intervention after weight regain. A total of 242 children and adolescents (age- and sex-specific body mass index [BMI] ≥ 85th percentile, mean age: 10.82 years, 60% male) were allocated to three groups: usual care, exercise, or nutrition. Six-month active treatment with 1:1 session and a maintenance stage with group activities were repeated twice to comprise a 24-month intervention. The primary outcome was change % of the BMI z-score (zBMI). A total of 110 (45.4%) participants completed the 24-month intervention. A mixed-effects model analysis indicated no significant interaction effect of the intervention group and treatment phase on the zBMI change % (p = 0.976). However, there was a significant main effect of the treatment phase on zBMI change % at 6 months (ß = -2.98, [95% CI, -5.69-0.27]), 18 months (ß = -3.99, [95% CI, -6.76-1.22]), and 24 months (ß = -3.23, [95% CI, -5.94-0.52]; p = 0.042). The improvements in zBMI, body fat %, and cardiometabolic markers were observed only among males. Whereas the additive effect of intensive exercise or nutritional feedback was not detected in the long term, a booster intervention with 1:1 counseling was effective even after weight regain during the maintenance period. It may be useful to combine individualized counseling with a less intensive form of group care for long-term maintenance in a real-world setting.
Subject(s)
Exercise , Nutrition Therapy , Pediatric Obesity/therapy , Behavior Therapy , Body Composition , Body Mass Index , Cardiometabolic Risk Factors , Child , Counseling , Female , Formative Feedback , Humans , Life Style , Male , Recurrence , Treatment Outcome , Weight LossABSTRACT
Trimethylamine N-oxide (TMAO) and its precursors, including choline, betaine, and L-carnitine, are gut microbiota-related metabolites associated with the risk of obesity. We aimed (1) to comprehensively examine whether the changes in plasma TMAO and its precursors induced by lifestyle intervention are associated with the improvements in plasma metabolic parameters; and (2) to identify the fecal microbiome profiles and nutrient intakes associated with these metabolites and metabolic index. Data from 40 participants (obese children and adolescents) having the plasma metabolites data related to the changes in BMI z-scores after 6-month lifestyle intervention were analyzed. In this study, we observed that choline and the betaine-to-choline ratio (B/C) showed different patterns depending on the changes in BMI z-scores by the response to lifestyle intervention. During the 6 months, an increase in choline and a decrease in B/C were observed in non-responders. We also found that changes in choline and B/C were associated with the improvements in plasma lipid levels. Individuals who showed reduced choline or increased B/C from the baseline to 6 months had a significant decrease in LDL-cholesterol over 6 months compared to those with increased choline or decreased B/C, respectively. In addition, the increase in choline or decrease in B/C was associated with the increase in plasma triglycerides. The distribution of gut microbiota belonging to the Firmicutes, such as Clostridia, Clostridiales, Peptostreptococcaceae, Romboutsia, and Romboutsia timonensis was altered to be lower during the 6 months both as choline decreased and B/C increased. Moreover, the decrease in choline and the increase in B/C were associated with reduced fat intake and increased fiber intake after the 6-month intervention. Finally, lower abundance of Romboutsia showed the association with lower LDL-cholesterol and higher intake of fiber. In summary, we demonstrated that reduced choline and increased B/C by lifestyle intervention were associated with the improvements of LDL-cholesterol and triglycerides, low-fat and high-fiber intakes, and low abundance of Firmicutes. These indicate that changes to circulating choline and B/C could predict individuals' changes in metabolic compositions in response to the lifestyle intervention.
Subject(s)
Betaine/blood , Choline/blood , Gastrointestinal Microbiome/physiology , Life Style , Lipid Metabolism , Lipids/blood , Adolescent , Bacteria/classification , Betaine/metabolism , Carnitine/blood , Child , Choline/metabolism , Clostridiales , Eating , Feces/microbiology , Firmicutes , Gastrointestinal Microbiome/genetics , Humans , Methylamines , Nutrients , Pediatric Obesity , RNA, Ribosomal, 16S/geneticsABSTRACT
Childhood obesity has increased worldwide, and many clinical and public interventions have attempted to reduce morbidity. We aimed to determine the metabolomic signatures associated with weight control interventions in children with obesity. Forty children from the "Intervention for Children and Adolescent Obesity via Activity and Nutrition (ICAAN)" cohort were selected according to intervention responses. Based on changes in body mass index z-scores, 20 were responders and the remaining non-responders. Their serum metabolites were quantitatively analyzed using capillary electrophoresis time-of-flight mass spectrometry at baseline and after 6 and 18 months of intervention. After 18 months of intervention, the metabolite cluster changes in the responders and non-responders showed a difference on the heatmap, but significant metabolites were not clear. However, regardless of the responses, 13 and 49 metabolites were significant in the group of children with obesity intervention at 6 months and 18 months post-intervention compared to baseline. In addition, the top five metabolic pathways (D-glutamine and D-glutamate metabolism; arginine biosynthesis; alanine, aspartate, and glutamate metabolism; TCA cycle (tricarboxylic acid cycle); valine, leucine, and isoleucine biosynthesis) including several amino acids in the metabolites of obese children after 18 months were significantly changed. Our study showed significantly different metabolomic profiles based on time post obesity-related intervention. Through this study, we can better understand and predict childhood obesity through metabolite analysis and monitoring.
ABSTRACT
BACKGROUND: MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification. METHODS: Fifty-eight whole exome sequencing (WES) and forty-eight whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. RESULTS: In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients. CONCLUSIONS: This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.