Copy number variants (CNVs), defined as genome sequences of ≥50 bp that differ in copy number from that in a reference genome, are a common form of structural variation. Germline CNVs account for ...some of the missing heritability that single nucleotide polymorphisms could not account for. Recent technological advances have had a huge impact on CNV research. Microarray technology enables relatively low-cost, high-throughput, genome-wide measurements, and short-read sequencing technology enables the detection of short CNVs that cannot be detected by microarrays. As a result, large-scale genetic studies have been able to identify a variety of common and rare germline CNVs and their associations with diseases. Rare germline CNVs have been reported to be associated with neuropsychiatric disorders. In this review, we focused on germline CNVs and briefly described their functional characteristics, formation mechanisms, detection methods, related databases, and the latest findings. Finally, we introduced recent large-scale genetic studies to assess associations of CNVs with diseases, especially psychiatric disorders, and discussed the use of CNV-based animal models to investigate the molecular and cellular mechanisms underlying these disorders. The development and implementation of improved detection methods, such as long-read single-molecule sequencing, are expected to provide additional insight into the molecular basis of psychiatric disorders and other complex diseases, thus facilitating basic and clinical research on CNVs.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We explored risk indicators likely to result in older adults needing certified long-term care in Japan and ascertained whether this relationship forms a U-shaped link. We analyzed a community-based ...cohort of residents in Kitanagoya City, Aichi Prefecture, Japan. Participants were 3718 individuals aged 65 years and above who underwent health examinations between April 1, 2011 and March 31, 2012. For continuous clinical variables, we applied a time-dependent Cox regression model. Two types of models were applied-a linear and nonlinear model with restricted cubic splines-to assess the U-shaped association. Statistical significance (set at 0.05) for the nonlinearity was tested by comparing the spline and linear models. Among the participants, 701 were certified as needing Level 1 care or higher during a follow-up. Among the continuous clinical variables, the nonlinear model for body mass index, systolic blood pressure, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase revealed significant U-shaped associations as compared with the linear model in which the outcome was a certification of the need for nursing care. These results provide an important insight into the usefulness of nonlinear models for predicting the risk of such certification.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Developing a personalized risk prediction model of death is fundamental for improving patient care and touches on the realm of personalized medicine. The increasing availability of genomic ...information and large-scale meta-analytic data sets for clinicians has motivated the extension of traditional survival prediction based on the Cox proportional hazards model. The aim of our paper is to develop a personalized risk prediction formula for death according to genetic factors and dynamic tumour progression status based on meta-analytic data. To this end, we extend the existing joint frailty-copula model to a model allowing for high-dimensional genetic factors. In addition, we propose a dynamic prediction formula to predict death given tumour progression events possibly occurring after treatment or surgery. For clinical use, we implement the computation software of the prediction formula in the joint.Cox R package. We also develop a tool to validate the performance of the prediction formula by assessing the prediction error. We illustrate the method with the meta-analysis of individual patient data on ovarian cancer patients.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in ...Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks' gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio OR, 1.31; 95% confidence interval, 1.04-1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53-0.87) and periventricular leukomalacia (0.60; 0.48-0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47-0.80), severe intraventricular haemorrhage (0.47; 0.35-0.63), periventricular leukomalacia (0.59; 0.45-0.78), neonatal seizures (0.40; 0.28-0.57) and cerebral palsy (0.70; 0.52-0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22-27 gestational weeks and 28-31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and ...the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology. Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement. This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), ...which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Thyroid transcription factor‐1 (TTF‐1), also known as NKX2‐1, plays a role as a lineage‐survival oncogene in lung adenocarcinoma that possesses double‐edged sword characteristics. Although evidence ...from previous studies has steadily accumulated regarding the roles of TTF‐1 in transcriptional regulation of protein‐coding genes, little is known about its regulatory relationship with microRNAs. Here, we utilized an integrative approach designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF‐1‐inducible cell lines in vitro, which identified microRNA (miR)‐532‐5p as a novel transcriptional target of TTF‐1. We found that miR‐532‐5p is directly regulated by TTF‐1 through its binding to a genomic region located 8 kb upstream of miR‐532‐5p, which appears to impose transcriptional regulation independent of that of CLCN5, a protein‐coding gene harboring miR‐532‐5p in its intron 3. Furthermore, our results identified KRAS and MKL2 as novel direct targets of miR‐532‐5p. Introduction of miR‐532‐5p mimics markedly induced apoptosis in KRAS‐mutant as well as KRAS wild‐type lung adenocarcinoma cell lines. Interestingly, miR‐532‐5p showed effects on MEK‐ERK pathway signaling, specifically in cell lines sensitive to siKRAS treatment, whereas those miR‐532‐5p‐mediated effects were clearly rendered as phenocopies by repressing expression or inhibiting the function of MKL2 regardless of KRAS mutation status. In summary, our findings show that miR‐532‐5p is a novel transcriptional target of TTF‐1 that plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma.
By applying an integrative approach combining in vitro with in vivo data, we identified miR‐532‐5p as a novel transcriptional target of TTF‐1/NKX2‐1, which regulates miR‐532‐5p independent of its host gene CLCN5. Furthermore, we showed that miR‐532‐5p directly represses oncogenic KRAS and MKL2 and causes apoptosis in lung adenocarcinoma cells.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ...ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
To clarify the relationship between nerve conduction study (NCS) and prognosis in patients with amyotrophic lateral sclerosis (ALS).
Methods
We included 190 patients with sporadic ALS. We ...used onset age, sex, onset site (bulbar vs. spinal), revised El Escorial criteria category (definite vs. others), and the King’s clinical systems, and the Milano–Torino (MiToS) functional staging systems, and decline rates of revised ALS functional rating scale (ALSFRS-R) as known prognostic factors. An NCS was performed on the median, ulnar, tibial, and sural nerves. The endpoint was death or the introduction of tracheostomy positive-pressure ventilation. Multivariate analysis for each NCS variable, known prognostic factors was performed using Cox stepwise proportional hazards analysis. Univariate analysis was performed for NCS variables that showed a significant association with prognosis in multivariate analysis. Survival was analyzed with a Kaplan–Meier curve and log-rank test.
Results
The Cox model identified the compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of the median nerve as prognostic factors. In the log-rank test, patients with higher median nerve CMAP amplitude had a significantly better prognosis than those with lower amplitude, regardless of age. And prognosis was better in the group with lower median nerve SNAP amplitude only in patients younger than the 25th percentile (~ 57 years).
Conclusions
CMAP and SNAP amplitudes of the median nerve are considered to be independent prognostic factors of sporadic ALS.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Adding segment 4 (S4) portal vein embolization (PVE) to right PVE before right hepatic trisectionectomy is controversial. We retrospectively examined the effect of S4 PVE on segments 2 and ...3 (S2 + 3) hypertrophy.
Methods
We reviewed patients with biliary carcinoma who underwent right PVE with (R3PVE) or without (R2PVE) S4 PVE using gelatin sponge particles and coils (2010‐2019). Propensity score matching balanced the cohort for baseline characteristics, including total liver volume and S2 + 3 volume before PVE. We compared the groups regarding the S2 + 3 volume changes after PVE.
Results
Of 178 enrolled patients, 38 underwent R3PVE for right hepatic trisectionectomy and 140 underwent R2PVE for right hepatectomy. Twenty‐eight patients from each group were respectively matched. The median absolute volume increase in (146 cm3 vs 70 cm3), hypertrophy rate of (52.4% vs 32.3%), and kinetic growth rate of (3.1%/wk vs 2.0%/wk) S2 + 3 were significantly higher in the R3PVE group than in the R2PVE group. In the pre‐matched cohort, the rate of posthepatectomy liver failure and postoperative hospital stay did not significantly differ between the patients who underwent right hepatic trisectionectomy and right hepatectomy.
Conclusion
R3PVE increased the S2 + 3 volume more effectively than R2PVE in patients with biliary carcinoma.
Highlight
Comparing patients who underwent right trisegment portal vein embolization and right portal vein embolization, Ito and colleagues demonstrated that segment 4 portal vein embolization added to right portal vein embolization before right hepatic trisectionectomy significantly improved segment 2 and 3 hypertrophy. Propensity score matching balanced the cohort for baseline characteristics.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
