Glioblastoma is the most aggressive and invasive brain tumor and has a poor prognosis; elucidating the underlying molecular mechanisms is essential to select molecular targeted therapies. Here, we investigated the effect of microRNAs on the marked invasiveness of glioblastoma. U373 glioblastoma cells were infected with 140 different microRNAs from an OncomiR library, and the effects of the invasion-related microRNAs and targeted molecules were investigated after repeated Matrigel invasion assays. Screening of the OncomiR library identified miR-23a as a key regulator of glioblastoma invasion. In six glioblastoma cell lines, a positive correlation was detected between the expression levels of miR-23a and invasiveness. A luciferase reporter assay demonstrated that homeobox D10 (HOXD10) was a miR-23a-target molecule, which was verified by high scores from both the PicTar and miRanda algorithms. Forced expression of miR-23a induced expression of invasion-related molecules, including uPAR, RhoA, and RhoC, and altered expression of glial-mesenchymal transition markers such as Snail, Slug, MMP2, MMP9, MMP14, and E-cadherin; however, these changes in expression levels were reversed by HOXD10 overexpression. Thus, miR-23a significantly promoted invasion of glioblastoma cells with polarized formation of focal adhesions, while exogenous HOXD10 overexpression reversed these phenomena. Here, we identify miR-23a-regulated HOXD10 as a pivotal regulator of invasion in glioblastoma, providing a novel mechanism for the aggressive invasiveness of this tumor and providing insight into potential therapeutic targets.

To the authors' knowledge, limited data are available regarding the association between Electrocardiogram (ECG) signs of right ventricular hypertrophy (RVH) and pulmonary hypertension (PH) in patients with dilated cardiomyopathy (DCM). We aimed to assess the accuracy of the recommended ECG criteria of RVH for predicting PH in patients with DCM.

To evaluate the efficacy of main portal vein stents combined with iodine-125 (125I) to treat main portal vein tumor thrombus.

To detect diffuse myocardial fibrosis in different severity levels of left ventricular diastolic dysfunction (DD) in spontaneous type 2 diabetes mellitus (T2DM) rhesus monkeys.

Background: The gene Hedgehog interacting protein (HHIP) is a pivotal morphogen for multiple developmental processes. However, the expression and clinical correlation of HHIP in gastric cancer (GC) has not been fully investigated. Here, we aimed to explore the expression of HHIP in gastric cancer (GC) and evaluate its clinicopathological and functional correlations. Methods: The expression of HHIP mRNA was first determined in the Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) GC database and then validated by RT-qPCR (n = 41) and immunohistochemistry (IHC, n = 95) in a cohort of in-house GC patients and in 29 cases of gastric intraepithelial neoplasia (GIN). The clinicopathological and functional relationship of HHIP with GC were also analyzed. Results: We found that HHIP mRNA were significantly downregulated in GC in the TCGA and HPA databases, as well as in our in-house cohort (P < 0.05). HHIP mRNA is mainly located in the cell nucleus, while HHIP protein is mainly located in the cell cytoplasm. Moreover, the HHIP protein level in the GIN tissues was significantly higher than that in the GC tissues (P < 0.001) and significantly lower than that in adjacent normal controls (P < 0.001). In addition, low HHIP expression was correlated with lymphatic metastasis (P = 0.041), pTNM stage (P = 0.007) and nervous system invasion (P = 0.001). Furthermore, we observed strong positive correlations between HHIP protein expression and overall survival (P < 0.001) and disease-free survival (P = 0.027) in GC patients. HHIP protein expression was an independent prognostic factor for overall survival (P < 0.001). Functional experimental results showed that overexpression of HHIP attenuated the migration and invasion ability of GC cells (P < 0.01). Conclusion: HHIP may be a promising tumor metastatic-suppressor and prognostic biomarker for gastric cancer.

RNA sequencing (RNA-seq) has become the widely preferred choice for surveying the genome-wide transcriptome complexity in many organisms. However, the broad adaptation of this methodology into the clinic still needs further evaluation of potential effect of sample preparation factors on its analytical reliability using patient samples. In this study, we examined the impact of three major sample preparation factors (i.e., cDNA library storage time, the quantity of input RNA, and cryopreservation of cell samples) on sequence biases, gene expression profiles, and enriched biological functions using RNAs isolated from primary B cell and CD4+ cell blood samples of healthy subjects. Our comprehensive comparison results suggested that different cDNA library storage time, quantity of input RNA, and cryopreservation of cell samples did not significantly alter gene transcriptional expression profiles generated by RNA-seq experiments. These findings shed new lights on the potential applications of RNA-seq technique to patient samples in a regular clinical setting.

Accumulating evidence progressively indicated that microRNAs (miRNAs) play a significant role in the pathogenesis of diseases through many experimental studies; therefore, developing powerful computational models to identify potential human miRNA⁻disease associations is vital for an understanding of the disease etiology and pathogenesis. In this paper, a weighted interactive network was firstly constructed by combining known miRNA⁻disease associations, as well as the integrated similarity between diseases and the integrated similarity between miRNAs. Then, a new computational method implementing the newly weighted interactive network was developed for discovering potential miRNA⁻disease associations (WINMDA) by integrating the T most similar neighbors and the shortest path algorithm. Simulation results show that WINMDA can achieve reliable area under the receiver operating characteristics (ROC) curve (AUC) results of 0.9183 ± 0.0007 in 5-fold cross-validation, 0.9200 ± 0.0004 in 10-fold cross-validation, 0.9243 in global leave-one-out cross-validation (LOOCV), and 0.8856 in local LOOCV. Furthermore, case studies of colon neoplasms, gastric neoplasms, and prostate neoplasms based on the Human microRNA Disease Database (HMDD) database were implemented, for which 94% (colon neoplasms), 96% (gastric neoplasms), and 96% (prostate neoplasms) of the top 50 predicting miRNAs were confirmed by recent experimental reports, which also demonstrates that WINMDA can effectively uncover potential miRNA⁻disease associations.

Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for female infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.

Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. Notably, phosphorylation of Ero1α is induced under hypoxia, reductive stress, and secretion-demanding conditions such as mammalian lactation. Collectively, our findings open a door to uncover how oxidative protein folding is regulated by phosphorylation in the secretory pathway.

Myocardial infarction (MI) is the leading cause of congestive heart failure and mortality. Hypoxia is an important trigger in the cardiac remodeling of the myocardium in the development and progression of cardiac diseases.

Patients with diabetes in China have low health literacy, which likely leads to poor clinical outcomes. This study aimed to assess the effectiveness of health literacy and exercise interventions on clinical measurements in Chinese adults with type 2 diabetes mellitus (T2DM).

MicroRNA-1303 (miR-1303) is involved in the tumorigenesis and progression of several cancers, and yet the role of miR-1303 in prostate cancer (PCa) and its underlying mechanism are unknown. To explore this issue, the present study aimed to use PCa tissues, cell lines and a PCa-engrafted mouse model to determine the expression and roles of miR-1303 in PCa. Furthermore, a series of experiments were conducted to explore the underlying mechanisms of action of miR-1303 in PCa cells. miR-1303 was demonstrated to be highly expressed in PCa tissues and cell lines. The level of miR-1303 expression was closely associated with higher Gleason scores and a more developed tumor stage in patients with PCa, and patients with higher levels of miR-1303 displayed a reduced overall survival rate. miR-1303 overexpression promoted the proliferation, migration and invasion of PCa cells. In vivo experiments showed that miR-1303 inhibition suppressed the growth of PCa tumors in mice. Additionally, dickkopf Wnt signaling pathway inhibitor 3 (DKK3) was identified as a target of miR-1303. Knockdown of miR-1303 suppressed the proliferation, migration and invasion of PCa cells, increased DKK3 expression, and inhibited the activity of the Wnt/β-catenin pathway. In conclusion, miR-1303 may promote proliferation, migration and invasion of PCa cells through activating the Wnt/β-catenin pathway by regulating DKK3 expression. These results indicated that miR-1303 may be considered as a potential biomarker for PCa treatment.

Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis. Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression. Therefore, this study aimed to investigate whether metformin, which has ameliorated atherosclerosis in animal models and clinical trials, modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism.

With the availability of large geospatial datasets, the study of collective human mobility spatiotemporal patterns provides a new way to explore urban spatial environments from the perspective of residents. In this paper, we constructed a classification model for mobility patterns that is suitable for taxi OD (Origin-Destination) point data, and it is comprised of three parts. First, a new aggregate unit, which uses a road intersection as the constraint condition, is designed for the analysis of the taxi OD point data. Second, the time series similarity measurement is improved by adding a normalization procedure and time windows to address the particular characteristics of the taxi time series data. Finally, the DBSCAN algorithm is used to classify the time series into different mobility patterns based on a proximity index that is calculated using the improved similarity measurement. In addition, we used the random forest algorithm to establish a correlation model between the mobility patterns and the regional functional characteristics. Based on the taxi OD point data from Nanjing, we delimited seven mobility patterns and illustrated that the regional functions have obvious driving effects on these mobility patterns. These findings are applicable to urban planning, traffic management and planning, and land use analyses in the future.

Endoscopic biliary drainage (EBD) and percutaneous biliary drainage (PTBD) are the two main strategies of preoperative biliary drainage (PBD) for resectable malignant biliary obstruction (MBO) worldwide, but which is better remains unclear. Seeding metastasis (SM) has been reported repeatedly in the recent decade, although it is rarely taken into consideration in the choice of PBD. Hence, a systematic review was badly warranted to evaluate the incidence of SM between PTBD and EBD in the preoperative treatment of MBO.

Background: High serum levels of alpha-fetoprotein (AFP) are observed in some gastrointestinal cancers. However, primary AFP-producing colorectal cancer (CRC) is extremely rare and causes confusion among clinicians. In this study, we analyzed the clinicopathological features and clinical outcomes of AFP-producing CRC and provide a brief view of this rare carcinoma. Patients and methods: Twenty patients with AFP-producing CRC were enrolled at the Fudan University Shanghai Cancer Center from 2012 to 2015. Clinical information, including serum AFP and CEA levels, and outcomes were collected. Tumors were divided into three histologic types: the common adenocarcinoma (COM) type, mucinous adenocarcinoma type and hepatoid type (HPT). Immunohistochemical (IHC) staining of GPC3, Hepa-1, SALL4 and Arg-1 was performed. Additionally, mutations of the KRAS, NRAS and BRAF genes were examined. Finally, another 40 stage-matched patients with traditional CRC were enrolled as controls for survival analysis. Results: AFP-producing CRC was more likely to occur in males (60%) and arose mainly from the ascending (40%) and sigmoid (35%) colon. In addition, the majority of patients with AFP-producing CRC had poor differentiation (50%), advanced local invasion (80%) and lymph node (LN) metastasis (60%). Synchronous distant metastasis was commonly observed (35%). Interestingly, serum AFP levels were closely associated with LN metastasis. Histopathologically, the COM type was the most common pattern. In IHC staining, the HPT pattern was the most distinct due to high positivity rates of GPC3, Hepa-1 and Arg-1. One patient had mismatch repair deficiency, and another had a KRAS mutation. Patients with AFP-producing CRC had worse progression-free and overall survival than patients with traditional CRC. Conclusion: AFP-producing CRC has unique clinical and histopathological characteristics, showing an aggressive biological behavior and worse prognosis than traditional CRC.

Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tumors during disease progression is needed. Because artificially immortalized cell lines do not rightly represent the disease progression, studying genetics of tumors in spontaneous models is warranted. In the current study, we generated a spectrum of spontaneous human (UM-PDC1; UM-PDC2) and murine (HI-PanL, HI-PancI, HI-PanM) models representing localized, invasive, and metastatic PDAC from a patient and transgenic mice (K-rasG12D/Pdxcre/Ink4a/p16-/). These spontaneous models grow vigorously under hypoxia and exhibit activated K-ras signaling, progressive loss of PTEN, and tumorigenicity in vivo. Whereas UM-PDC1 form localized tumors, the UM-PDC2 metastasize to lungs in mice. In an order of progression, these models exhibit genomic instability marked by gross chromosomal rearrangements, centrosome-number variations, Aurora-kinase/H2AX colocalization, loss of primary cilia, and α-tubulin acetylation. The RNA sequencing of hypoxic models followed by qRT-PCR validation and gene-set enrichment identified Intestine-Specific Homeobox factor (ISX)-driven molecular pathway as an indicator PDAC aggressivness. TCGA-PAAD clinical data analysis showed high ISX expression correlation to poor survival of PDAC patients, particularly women. The functional studies showed ISX as a regulator of i) invasiveness and migratory potential and ii) VEGF, MMP2, and NFκB activation in PDAC cells. We suggest that ISX is a potential druggable target and newly developed spontaneous cell models are valuable tools for studying mechanism and testing therapies for PDAC.

Oil produced by castor (Ricinus communis) has broad industrial applications. However, knowledge on the genetic diversity, especially genetic alterations that occurred during domestication and subsequent traits selection, of this oil crop is limited. Here, our population genomics analyses show that the Chinese castors have developed a geographic pattern, classified into the southern-, the middle-, and the northern-China groups. We detect a number of candidate genomic loci that are associated with the selection signals during the geographical differentiation and domestication. Using genome-wide association analysis, we identify candidate genes associated with nine agronomically important traits. One of the candidate genes encoding a glycosyltransferase related to cellulose and lignin biosynthesis is associated with both capsule dehiscence and endocarp thickness. We hypothesize that the abundance of cellulose or lignin in endocarp is an important factor for capsule dehiscence. Our results provide foundation for castor breeding and genetic study.

Since the number of known lncRNA-disease associations verified by biological experiments is quite limited, it has been a challenging task to uncover human disease-related lncRNAs in recent years. Moreover, considering the fact that biological experiments are very expensive and time-consuming, it is important to develop efficient computational models to discover potential lncRNA-disease associations.

Anemia is a serious nutritional deficiency among infants and toddlers in rural China. However, it is unclear how the anemia status changes among China's rural children as they age. This study investigates the prevalence of anemia as children grow from infancy to preschool-age, as well as the dynamic anemia status of children over time. We conducted longitudinal surveys of 1170 children in the Qinba Mountain Area of China in 2013, 2015 and 2017. The results show that 51% of children were anemic in infancy (6-12 months), 24% in toddlerhood (22-30 months) and 19% at preschool-age (49-65 months). An even larger share of children (67%) suffered from anemia at some point over the course of study. The data also show that although only 4% of children were persistently anemic from infancy to preschool-age, 8% of children saw their anemia status deteriorate. We further found that children may be at greater risk for developing anemia, or for having persistent anemia, during the period between toddlerhood and preschool-age. Combined with the finding that children with improving anemia status showed higher cognition than persistently anemic children, there is an urgent need for effective nutritional interventions to combat anemia as children grow, especially between toddlerhood and preschool age.