Children with strabismus and amblyopia presented abnormal spontaneous brain activities measured through fractional amplitude of low-frequency fluctuation (fALFF).

Purpose: Based on fMRI technology, we explored whether children with strabismus and amblyopia (SA) showed significant change in fractional amplitude of low-frequency fluctuation (fALFF) values in specific brain regions compared with healthy controls and whether this change could point to the clinical manifestations and pathogenesis of children with strabismus to a certain extent. Methods: We enrolled 23 children with SA and the same number matched healthy controls in the ophthalmology department of the First Affiliated Hospital of Nanchang University, and the whole brain was scanned by rs-fMRI. The fALFF value of each brain area was derived to examine whether there is a statistical difference between the two groups. Meanwhile, the ROC curve was made in a view to evaluate whether this difference proves useful as a diagnostic index. Finally, we analyzed whether changes in the fALFF value of some specific brain regions are related to clinical manifestations. Results: Compared with HCs, children with SA presented decreased fALFF values in the left temporal pole: the superior temporal gyrus, right middle temporal gyrus, right superior frontal gyrus, and right supplementary motor area. Meanwhile, they also showed higher fALFF values in specific brain areas, which included the left precentral gyrus, left inferior parietal, and left precuneus. Conclusion: Children with SA showed abnormal fALFF values in different brain regions. Most of these regions were allocated to the visual formation pathway, the eye movement-related pathway, or other visual-related pathways, suggesting the pathological mechanism of the patient.

Voxel-Mirrored Homotopic Connectivity Is Altered in Meibomian Gland Dysfunction Patients That Are Morbidly Obese.

PURPOSE: To investigate the altered functional connectivity (FC) of the cerebral hemispheres in patients with morbid obesity (MO) with meibomian gland dysfunction (MGD) by voxel-mirrored homotopic connectivity (VMHC). METHODS: Patients and matched healthy controls (HCs) were recruited, and all subjects underwent functional resonance magnetic imaging (fMRI), and VMHC results were processed statistically to assess the differences in FC in different brain regions between the two groups. We further used ROC curves to evaluate the diagnostic value of these differences. We also used Pearson's correlation analysis to explore the relationship between changes in VMHC values in specific brain regions, visual acuity, and Mini-Mental State Examination (MMSE) score. CONCLUSIONS: Patients with morbid obesity and MGD had abnormal FC in the cerebral hemispheres in several specific brain areas, which were mainly concentrated in pathways related to vision and perception and may correlate to some extent with the clinical presentations of the patients.

Cognitive Reserve and Mild Cognitive Impairment: Predictors and Rates of Reversion to Intact Cognition vs Progression to Dementia.

BACKGROUND AND OBJECTIVES: Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling. METHODS: We estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age, APOE, and potential cognitive reserve indicators: education, academic performance (high school grades), and written language skills (idea density, grammatical complexity). RESULTS: Of the 619 participants, 472 were assessed with MCI during the study period. Of these 472, 143 (30.3%) experienced at least one reverse transition to NC, and 120 of the 143 (83.9%) never developed dementia (mean follow-up = 8.6 years). In models adjusted for age group and APOE, higher levels of education more than doubled the RR ratio of reversion vs progression. Novel cognitive reserve indicators were significantly associated with a higher adjusted RR of reversion vs progression (higher vs lower levels for English grades: RR ratio = 1.83; idea density: RR ratio = 3.93; and grammatical complexity: RR ratio = 5.78). DISCUSSION: Knowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.

Functional connectivity density alterations in children with strabismus and amblyopia based on resting-state functional magnetic resonance imaging (fMRI).

PURPOSE: To explore functional connectivity density (FCD) values of brain areas in children with strabismus and amblyopia (SA) based on blood oxygen level-dependent (BOLD) signals. METHODS: This study recruited 26 children (14 male, 12 females) with SA and 26 healthy children (14 male, 12 female) as healthy controls (HCs). Both groups matched in age, gender, educational level and socioeconomic background. While resting, all participants underwent fMRI scanning and global FCD (gFCD) and local FCD (lFCD) values were calculated. Receiver operating characteristic (ROC) curves were created to investigate whether there was a significant difference between children with SA and healthy controls. RESULTS: When compared with healthy controls, children with SA had significantly lower gFCD values in the right cerebellum, left putamen, and right superior frontal gyrus; however, the same metrics showed opposite changes in the right angular gyrus, left middle cingulate gyrus, left angular gyrus, right superior parietal gyrus, and right middle frontal gyrus. In children with SA, lFCD values were found to be remarkably decreased in regions of the middle right temporal pole, right cerebellum, left putamen, left hippocampus, right hippocampus, left thalamus, left cerebellum; values were increased in the right superior parietal gyrus as compared with healthy controls. CONCLUSION: We noted abnormal neural connectivity in some brain areas of children with SA; detailing such connectivity aberrations is useful in exploring the pathophysiology of SA and providing useful information for future clinical management.

Integrative analyses identified ion channel genes GJB2 and SCNN1B as prognostic biomarkers and therapeutic targets for lung adenocarcinoma.

OBJECTIVES: Abnormal expressions of ion channel genes are associated with the occurrence and progression of tumors. At present, their roles in the carcinogenesis of lung adenocarcinoma (LUAD) are not clear. MATERIALS AND METHODS: Differentially expressed (DE) genes in the tumorigenesis were identified from 328 ion channel genes in 102 LUAD and paired adjacent normal samples. Similar analyses were performed between 177 metastatic and 286 non-metastatic LUAD samples to identify DE ion channel genes in the progression of LUAD. Independent prognostic factors selected from DE ion channel genes were used to construct a prognostic model. Correlation analysis and drugs-drug targets interaction network were used to screen the potential drugs for LUAD patients stratified by GJB2 or SCNN1B. RESULTS: Six ion channel genes (GJB2, CACNA1D, KCNQ1, SCNN1B, SCNN1G and TRPV6) were continuous differentially expressed in the tumorigenesis and progression of LUAD. The survival analysis in four datasets with 522 LUAD samples showed that GJB2 and SCNN1B were independent prognostic biomarkers. Patients with overexpression of GJB2 or underexpression of SCNN1B had shorter overall survival. Moreover, multi-omics analysis showed that hypomethylation of GJB2 and hypermethylation of SCNN1B in the promoter region may contribute to their aberrant expressions. KEGG enrichment analysis showed that the overexpressed genes in the group with high GJB2 or low SCNN1B were enriched in cancer-related pathways, while the underexpressed genes were enriched in metabolism-related pathways. The prognostic model with GJB2 and SCNN1B can stratify all LUAD patients into two groups with significantly different survival. Correlation analysis and drugs-drug targets interaction network suggested that GJB2 and SCNN1B expression might have indicative therapeutic values for LUAD patients. Finally, pan-cancer analysis in other eight cancer types showed that GJB2 and SCNN1B might be also potential prognostic factors for KIRC. CONCLUSIONS: GJB2 and SCNN1B were identified as prognostic biomarkers and therapeutic targets for LUAD.

Augmented likelihood for incorporating auxiliary information into left-truncated data.

Time-to-event data are often subject to left-truncation. Lack of consideration of the sampling condition will introduce bias and loss in efficiency of the estimation. While auxiliary information from the same or similar cohorts may be available, challenges arise due to the practical issue of accessibility of individual-level data and taking account of various sampling conditions for different cohorts. In this paper, we introduce a likelihood-based method to incorporate information from auxiliary data to eliminate the left-truncation problem and improve efficiency. A one-step Monte-Carlo Expectation-Maximization algorithm is developed to calculate an augmented likelihood through creating pseudo-data sets which extend the form and conditions of the observed sample. The method is illustrated by both a real dataset and simulation studies.

Integrative Pan-Cancer Analysis Reveals Decreased Melatonergic Gene Expression in Carcinogenesis and RORA as a Prognostic Marker for Hepatocellular Carcinoma.

BACKGROUND: Melatonin has been shown to play a protective role in the development and progression of cancer. However, the relationship between alterations in the melatonergic microenvironment and cancer development has remained unclear. METHODS: We performed a comprehensive investigation on 12 melatonergic genes and their relevance to cancer occurrence, progression and survival by integrating multi-omics data from microarray analysis and RNA sequencing across 11 cancer types. Specifically, the 12 melatonergic genes that we investigated, which reflect the melatonergic microenvironment, included three membrane receptor genes, three nuclear receptor genes, two intracellular receptor genes, one synthetic gene, and three metabolic genes. RESULTS: Widely coherent underexpression of nuclear receptor genes, intracellular receptor genes, and metabolic genes was observed in cancerous samples from multiple cancer types compared to that in normal samples. Furthermore, genomic and/or epigenetic alterations partially contributed to these abnormal expression patterns in cancerous samples. Moreover, the majority of melatonergic genes had significant prognostic effects in predicting overall survival. Nevertheless, few corresponding alterations in expression were observed during cancer progression, and alterations in expression patterns varied greatly across cancer types. However, the association of melatonergic genes with one specific cancer type, hepatocellular carcinoma, identified RORA as a tumor suppressor and a prognostic marker for patients with hepatocellular carcinoma. CONCLUSIONS: Overall, our study revealed decreased melatonergic gene expression in various cancers, which may help to better elucidate the relationship between melatonin and cancer development. Taken together, our findings highlight the potential prognostic significance of melatonergic genes in various cancers.

Identification of Genes Universally Differentially Expressed in Gastric Cancer.

Owing to the remarkable heterogeneity of gastric cancer (GC), population-level differentially expressed genes (DEGs) identified using case-control comparison cannot indicate the dysregulated frequency of each DEG in GC. In this work, first, the individual-level DEGs were identified for 1,090 GC tissues without paired normal tissues using the RankComp method. Second, we directly compared the gene expression in a cancer tissue to that in paired normal tissue to identify individual-level DEGs among 448 paired cancer-normal gastric tissues. We found 25 DEGs to be dysregulated in more than 90% of 1,090 GC tissues and also in more than 90% of 448 GC tissues with paired normal tissues. The 25 genes were defined as universal DEGs for GC. Then, we measured 24 paired cancer-normal gastric tissues by RNA-seq to validate them further. Among the universal DEGs, 4 upregulated genes (BGN, E2F3, PLAU, and SPP1) and 1 downregulated gene (UBL3) were found to be cancer genes already documented in the COSMIC or F-Census databases. By analyzing protein-protein interaction networks, we found 12 universally upregulated genes, and we found that their 284 direct neighbor genes were significantly enriched with cancer genes and key biological pathways related to cancer, such as the MAPK signaling pathway, cell cycle, and focal adhesion. The 13 universally downregulated genes and 16 direct neighbor genes were also significantly enriched with cancer genes and pathways related to gastric acid secretion. These universal DEGs may be of special importance to GC diagnosis and treatment targets, and they may make it easier to study the molecular mechanisms underlying GC.

Voxel-based morphometry reveals altered gray matter volume related to cognitive dysfunctioning in neovascular glaucoma patients.

We used correlation analysis to examine whether changes in grey matter volume in patients correlated with clinical presentation. gray matter volume was markedly reduced in neovascular glaucoma patients than healthy controls in the following brain regions: left cingulum anterior/medial frontal gyrus; left middle frontal gyrus, orbital part; left inferior frontal gyrus, orbital part; superior temporal gyrus/right frontal inferior orbital part. VBM directly suggests that neovascular glaucoma patients have changed in the volume of multiple brain regions. These changes exist in brain areas related to the visual pathway, as well as other brain areas which are not related to vision. The alteration of specific brain areas are closely related to clinical symptoms such as increased intraocular pressure and optic nerve atrophy in neovascular glaucoma patients. In conclusion, neovascular glaucoma may cause paralgesia, anxiety, and depression in patients.

A qualitative classification signature for post-surgery 5-fluorouracil-based adjuvant chemoradiotherapy in gastric cancer.

BACKGROUND AND PURPOSE: Currently, 5-fluorouracil (5-FU)-based adjuvant chemoradiotherapy (ACRT) is a preferred regimen for post-surgery gastric cancer (GC). However, the survival outcome of 5-FU-based ACRT varies greatly among different GC patients. Thus, it is necessary to classify which patients may benefit from 5-FU-based ACRT. MATERIALS AND METHODS: We collected 577 GC and 84 adjacent normal samples for training and 675 GC samples for validation. Based on the within-sample relative expression orderings (REOs) of gene expression levels, reversal gene pairs were selected, and the pairs correlating with overall survival (OS) of GC patients receiving 5-FU-based ACRT were identified as candidates. Finally, an optimized set of candidate gene pairs was selected as a classification signature in training data and validated in validation data. RESULTS: A signature consisting of 34 gene pairs was identified in training data and validated in three independent datasets. The classified low-risk group had better OS than the classified high-risk group. We also analyzed the recurrent free survival or disease free survival (RFS/DFS) of the validation datasets, and the similar results were shown. Furthermore, although the signature was identified based on the OS of GC patients receiving ACRT, it was not a prognostic signature for patients treated with surgery alone, but may be a potential signature for 5-FU-based chemotherapy alone. CONCLUSIONS: The signature can accurately classify GC patients who may benefit from 5-FU-based ACRT, which could aid clinicians in tailoring more effective GC treatments.

Correction to: MGUS Predicts Worse Prognosis in Patients with CoronaryArtery Disease.

The captions to Figures 1-4 in this article as originally published were mismatched with the figures themselves.

A qualitative transcriptional signature for predicting the biochemical recurrence risk of prostate cancer patients after radical prostatectomy.

BACKGROUND: The qualitative transcriptional characteristics, the within-sample relative expression orderings (REOs) of genes, are highly robust against batch effects and sample quality variations. Hence, we develop a qualitative transcriptional signature based on REOs to predict the biochemical recurrence risk of prostate cancer (PCa) patients after radical prostatectomy. METHODS: Gene pairs with REOs significantly correlated with the biochemical recurrence-free survival (BFS) were identified from 131 PCa samples in the training data set. From these gene pairs, we selected a qualitative transcriptional signature based on the within-sample REOs of gene pairs which could predict the recurrence risk of PCa patients after radical prostatectomy. RESULTS: A signature consisting of 74 gene pairs, named 74-GPS, was developed for predicting the recurrence risk of PCa patients after radical prostatectomy based on the majority voting rule that a sample was assigned as high risk when at least 37 gene pairs of the 74-GPS voted for high risk; otherwise, low risk. The signature was validated in six independent datasets produced by different platforms. In each of the validation datasets, the Kaplan-Meier survival analysis showed that the average BFS of the low-risk group was significantly better than that of the high-risk group. Analyses of multiomics data of PCa samples from TCGA suggested that both the epigenomic and genomic alternations could cause the reproducible transcriptional differences between the two different prognostic groups. CONCLUSIONS: The proposed qualitative transcriptional signature can robustly stratify PCa patients after radical prostatectomy into two groups with different recurrence risk and distinct multiomics characteristics. Hence, 74-GPS may serve as a helpful tool for guiding the management of PCa patients with radical prostatectomy at the individual level.

MGUS Predicts Worse Prognosis in Patients with Coronary Artery Disease.

We performed a retrospective cohort study to analyze all 87 CAD patients with MGUS and 178 CAD patients without MGUS admitted in Zhongshan Hospital Fudan University from 2015 to 2017. Patients were followed up via regular patient visits or telephone, and the median follow-up period was 2.9 years. The end point of follow-up was the occurrence of major adverse cardiac events (MACE). CAD patients with MGUS had a higher risk of MACE than those without MGUS (log-rank P = 0.0015). After adjustment for other markers in the stepwise Cox regression model, MGUS was still related to the increasing risk of MACE incident (P = 0.002, HR = 2.308). Then, we constructed the nomogram based on the Cox regression model, and the concordance index (C-index) was 0.667. Hence, MGUS might be added into the risk model of CAD.

Identification of molecular alterations in leukocytes from gene expression profiles of peripheral whole blood of Alzheimer's disease.

Blood-based test has been considered as a promising way to diagnose and study Alzheimer's disease (AD). However, the changed proportions of the leukocytes under disease states could confound the aberrant expression signals observed in mixed-cell blood samples. We have previously proposed a method, Ref-REO, to detect the leukocyte specific expression alterations from mixed-cell blood samples. In this study, by applying Ref-REO, we detect 42 and 45 differentially expressed genes (DEGs) between AD and normal peripheral whole blood (PWB) samples in two datasets, respectively. These DEGs are mainly associated with AD-associated functions such as Wnt signaling pathways and mitochondrion dysfunctions. They are also reproducible in AD brain tissue, and tend to interact with the reported AD-associated biomarkers and overlap with targets of AD-associated PWB miRNAs. Moreover, they are closely associated with aging and have severer expression alterations in the younger adults with AD. Finally, diagnostic signatures are constructed from these leukocyte specific alterations, whose area under the curve (AUC) for predicting AD is higher than 0.73 in the two AD PWB datasets. In conclusion, gene expression alterations in leukocytes could be extracted from AD PWB samples, which are closely associated with AD progression, and used as a diagnostic signature of AD.