RLFDDA: a meta-path based graph representation learning model for drug-disease association prediction.

BACKGROUND: Drug repositioning is a very important task that provides critical information for exploring the potential efficacy of drugs. Yet developing computational models that can effectively predict drug-disease associations (DDAs) is still a challenging task. Previous studies suggest that the accuracy of DDA prediction can be improved by integrating different types of biological features. But how to conduct an effective integration remains a challenging problem for accurately discovering new indications for approved drugs. METHODS: In this paper, we propose a novel meta-path based graph representation learning model, namely RLFDDA, to predict potential DDAs on heterogeneous biological networks. RLFDDA first calculates drug-drug similarities and disease-disease similarities as the intrinsic biological features of drugs and diseases. A heterogeneous network is then constructed by integrating DDAs, disease-protein associations and drug-protein associations. With such a network, RLFDDA adopts a meta-path random walk model to learn the latent representations of drugs and diseases, which are concatenated to construct joint representations of drug-disease associations. As the last step, we employ the random forest classifier to predict potential DDAs with their joint representations. RESULTS: To demonstrate the effectiveness of RLFDDA, we have conducted a series of experiments on two benchmark datasets by following a ten-fold cross-validation scheme. The results show that RLFDDA yields the best performance in terms of AUC and F1-score when compared with several state-of-the-art DDAs prediction models. We have also conducted a case study on two common diseases, i.e., paclitaxel and lung tumors, and found that 7 out of top-10 diseases and 8 out of top-10 drugs have already been validated for paclitaxel and lung tumors respectively with literature evidence. Hence, the promising performance of RLFDDA may provide a new perspective for novel DDAs discovery over heterogeneous networks.

Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway.

UNLABELLED: Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity, depending on tumor cell biology and background. However, the role of HIF member HIF-2α remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2α expression was measured in HCC and paired peritumoral tissues by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were up-regulated or down-regulated by use of expression or short hairpin RNA recombinant plasmid, respectively. Cells were analyzed by immunoblotting, chromatin immunoprecipitation coupled with microarray, coimmunoprecipitation, and immunohistochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (P=0.006). High HIF-2α expression in HCC cells induced higher levels of apoptosis and expression of proapoptotic proteins and inhibited cell and tumor growth. Furthermore, HIF-2α inhibited expression of the novel target gene, transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and -independent pathways. Reintroduction of TFDP3 expression reversed HIF-2α-induced apoptosis. CONCLUSIONS: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor-suppressor role for HIF-2α and has uncovered a mechanism that links HIF-2α to a fundamental biological regulator, E2F1.

Motif-Aware miRNA-Disease Association Prediction via Hierarchical Attention Network.

As post-transcriptional regulators of gene expression, micro-ribonucleic acids (miRNAs) are regarded as potential biomarkers for a variety of diseases. Hence, the prediction of miRNA-disease associations (MDAs) is of great significance for an in-depth understanding of disease pathogenesis and progression. Existing prediction models are mainly concentrated on incorporating different sources of biological information to perform the MDA prediction task while failing to consider the fully potential utility of MDA network information at the motif-level. To overcome this problem, we propose a novel motif-aware MDA prediction model, namely MotifMDA, by fusing a variety of high- and low-order structural information. In particular, we first design several motifs of interest considering their ability to characterize how miRNAs are associated with diseases through different network structural patterns. Then, MotifMDA adopts a two-layer hierarchical attention to identify novel MDAs. Specifically, the first attention layer learns high-order motif preferences based on their occurrences in the given MDA network, while the second one learns the final embeddings of miRNAs and diseases through coupling high- and low-order preferences. Experimental results on two benchmark datasets have demonstrated the superior performance of MotifMDA over several state-of-the-art prediction models. This strongly indicates that accurate MDA prediction can be achieved by relying solely on MDA network information. Furthermore, our case studies indicate that the incorporation of motif-level structure information allows MotifMDA to discover novel MDAs from different perspectives.

Effect of admission time on mortality in an intensive care unit in Mainland China: a propensity score matching analysis.

INTRODUCTION: The relationship between admission time and intensive care unit (ICU) mortality is inconclusive and influenced by various factors. This study aims to estimate the effect of admission time on ICU outcomes in a tertiary teaching hospital in China by propensity score matching (PSM) and stratified analysis. METHODS: A total of 2,891 consecutive patients were enrolled in this study from 1 January 2009 to 29 December 2011. Multivariate logistic regression and survival analysis were performed in this retrospective study. PSM and stratified analysis were applied for confounding factors, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) score and admission types. RESULTS: Compared with office hour subgroup (n = 2,716), nighttime (NT, n = 175) subgroup had higher APACHE II scores (14 vs. 8, P < 0.001), prolonged length of stay in the ICU (42 vs. 24 h, P = 0.011), and higher percentages of medical (8.6% vs. 3.3%, P < 0.001) and emergency (59.4% vs. 12.2%, P < 0.001) patients. Moreover, NT admissions were related to higher ICU mortality [odds ratio (OR), 1.725 (95% CI 1.118-2.744), P = 0.01] and elevated mortality risk at 28 days [14.3% vs. 3.2%; OR, 1.920 (95% CI 1.171-3.150), P = 0.01]. PSM showed that admission time remained related to ICU outcome (P = 0.045) and mortality risk at 28 days [OR, 2.187 (95% CI 1.119-4.271), P = 0.022]. However, no mortality difference was found between weekend and workday admissions (P = 0.849), even if weekend admissions were more related to higher APACHE II scores compared with workday admissions. CONCLUSIONS: NT admission was associated with poor ICU outcomes. This finding may be related to shortage of onsite intensivists and qualified residents during NT. The current staffing model and training system should be improved in the future.

Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients.

Pneumocystis jirovecii pneumonia (PJP) is a severe and life-threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP-SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP-SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off-label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low-dose TMP-SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP-SMZ-related adverse effects.

Enhancing patient-centred care in Taiwan's dental education system: Exploring the feasibility of doctor-patient communication education and training.

Background/purpose: Improved communication can optimize treatment outcomes and patient satisfaction. Findings emphasize the need for tailored communication strategies based on patient characteristics. Implementing communication courses can enhance patient-centered care and reduce conflicts. Therefore, this study examined the feasibility of integrating doctor-patient communication education in Taiwan's dental education system. Materials and methods: Using interviews and questionnaires, we conducted descriptive statistics and generalized linear mixed-effects model analysis on the importance of doctor-patient communication from the dentist and patient perspectives. Results: More than 600 patient surveys and four interviewed dentists with 20+ years of experience stressed doctor-patient communication in dentistry. Patients' age and income were positively related to the emphasis on physician-patient communication but negatively associated with dental assistants' communication. Dentists valued communication education but differed in its execution and importance. Conclusion: It is recommended to initiate dentist-patient communication education during university studies and continue its practice to adapt to the changing societal dynamics. Individuals with higher socioeconomic status and older age show a greater appreciation for dentist-patient communication, potentially driven by self-promotion, thereby highlighting the diverse nature of doctor-patient relationships. Based on our findings, we suggest to implement the doctor-patient communication courses in Taiwan.

Comparison of past and current dental school curricula for dental students of National Taiwan University.

Background/purpose: The complete curriculum schedule of the School of Dentistry, National Taiwan University (NTU) appeared in 1960. This study aimed to understand the development of dental education in Taiwan by comparing the past and current dental school curricula of NTU. Materials and methods: This study collected the 1960, 1990 and 2020 dental school curriculum schedules for dental students of NTU from the related websites and used the documentary and secondary data analyses to further compare the obtained data. Results: The number of credits for all the curricula offered by NTU to undergraduate dental students decreased from 264 in 1960 to 243 in 1990 and further to 242 in 2020 with a total decrease of 22 credits by 8.3%. The number (proportion) of credits of medicine courses decreased from 102 (38.6%) in 1960 to 52 (21.4%) in 1990, and then increased to 60 (24.8%) in 2020, with a total decrease of 42 credits by 41.2%, while those of dentistry courses increased from 70 (26.5%) in 1960 to 122 (50.2%) in 1990 and further to 132 (54.5%) in 2020, with a total increase of 62 credits by 88.6%. Among them, clinical practice of dentistry had the greatest growth with a total increase of 42 credits by 233.3%. Conclusion: The increase of dentistry courses and the decrease of medicine courses are the general trends for modern dental education. The dental school of NTU has the ability to provide more refined dentistry courses to catch the world trend of dental education.

Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection.

PURPOSE: Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research. The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients. EXPERIMENTAL DESIGN: CK10 expression in stepwise metastatic HCC cell lines and tumor tissues from 50 HCC patients was investigated using immunofluorescence assay, quantitative real-time reverse transcription-PCR, and Western blot analyses. Tumor tissue microarrays of 300 HCC patients who underwent curative resection between 1997 and 2000 were used to detect the expressions of CK10 and CK19. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. RESULTS: CK10 was overexpressed in the high metastatic HCC cell line and in tumor tissues of recurrent patients. Both univariate and multivariate analyses revealed that CK10 was a significant predictor for overall survival (OS) and disease-free survival, and that CK19 was a significant predictor for OS. CK10 expression was correlated with poor prognosis regardless of alpha-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and disease-free survival rates in CK10+ and/or CK19+ patients were 30.0% and 37.6%, respectively, which were significantly lower than that of CK10-/CK19- patients (56.1% and 60.0%, respectively; P < 0.001). CONCLUSION: CK10 is associated with HCC invasiveness. CK10 alone, or in combination with CK19, can be a novel predictor for poor prognosis of HCC patients after curative resection.

The predictive value of plasma cytokines on gastroesophageal anastomotic leakage at an early stage in patients undergoing esophagectomy.

BACKGROUND: It's difficult to diagnose gastroesophageal anastomotic leakage (GAL) at early postoperative stage. This study was conducted to evaluate the early predictive value of plasma cytokines levels on GAL in patients undergoing esophagectomy. METHODS: Consecutive esophageal cancer patients who underwent esophagectomy and admitted to Surgical Intensive Care Unit (SICU) just after surgery were retrospectively analyzed. The baseline and postoperative 1 day plasma cytokine levels were collected and analyzed to evaluate the predictive value for clinically important anastomotic leakage. Area under receiver operating characteristic curve (AUROC) analysis was also performed. RESULTS: A total of 183 patients were included. Sixteen patients (8.74%) experienced GAL (GAL group) and the others did not (non-GAL group). The concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2R, IL-6, IL-8 and IL-10 in plasma on the first postoperative day significantly increased in the GAL group than in the non-GAL group (P<0.05). IL-6, IL-8 and IL-10 were fair predictors of GAL (AUROC >0.7) and the other two cytokines were poorly predictive (AUROC <0.7). The mean length of ICU and hospital stay were significantly longer in the GAL group than in the non-GAL group (P<0.05). CONCLUSIONS: Plasma concentrations of IL-6, IL-8 and IL-10 on the first postoperative day can predict clinically important GAL in patients undergoing esophagectomy.

A comparison of longitudinal and transverse approaches to ultrasound-guided axillary vein cannulation by experienced operators.

BACKGROUND: The axillary vein is an easily accessible vessel that can be used for ultrasound-guided central vascular access and offers an alternative to the internal jugular and subclavian veins. The objective of this study was to identify which transducer orientation, longitudinal or transverse, is better for imaging the axillary vein with ultrasound. METHODS: We analyzed 236 patients who had undergone central venous cannulation of axillary vein in this retrospective study. Patients were divided into two groups, the longitudinal approach group (n=120) and transverse approach group (n=116). Recorded the one-attempt success rate, operation time, arterial puncture rate and pneumothorax rate. We perform chest radiography to confirm pneumothorax on all patients. We compared the one-attempt success rate, operation time, arterial puncture rate and pneumothorax rate between the two groups. RESULTS: The two groups were comparable with clinical characters of patients. The overall success rates of the longitudinal group and the transverse group were both 100%. The rate of one-attempt success in the longitudinal approach group is higher than the transverse approach group (91.7% vs. 82.8%, P=0.040). The transverse approach group had shorter operation time than the longitudinal group (184.7±8.1 vs. 287.5±19.6 seconds, P=0.000). The two groups had lower postoperative complications. Arterial puncture occurred in 1 of 120 longitudinal and 2 of 116 transverse attempts and this difference was no significant (P=0.541). No pneumothorax occurred in the two groups. CONCLUSIONS: The longitudinal approach during ultrasound-guided axillary vein cannulation is associated with greater one-attempt success rate compared with the transverse approach by experienced operators. The transverse approach has shorter operation time. The two groups have lower postoperative complications and are comparable with pneumothorax and arterial puncture.

UBAP2 negatively regulates the invasion of hepatocellular carcinoma cell by ubiquitinating and degradating Annexin A2.

The ubiquitin-dependent proteasomal degradation of proteins controls signaling and cellular survival. In this study, we found that ubiquitin associated protein 2 (UBAP2) was significantly downregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, higher expression of UBAP2 in cancer tissues was correlated with good prognosis in HCC patients. Knockdown of UBAP2 significantly enhanced the invasion and proliferation of HCC cells in vitro and promoted tumor growth in vivo, while enforced expression of UBAP2 impaired the aggressive ability and tumor growth of HCC cells. Mechanistically, UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination, and then inhibited HCC progression. Collectively, UBAP2 appears as a novel marker for predicting prognosis and a therapeutic target for HCC.

Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway.

The protein tyrosine phosphatase PTP4A1 is a key molecule that activates tyrosine phosphorylation, which is important for cancer progression and metastasis. However, the clinical implications and biological function of PTP4A1 in intrahepatic cholangiocarcinoma (ICC) remains unknown. Here, we showed that PTP4A1 was frequently overexpressed in ICC versus adjacent non-tumor tissues. This overexpression significantly correlated with aggressive tumor characteristics like the presence of lymph node metastasis and advanced tumor stages. Survival analysis further indicated that high PTP4A1 expression was significantly and independently associated with worse survival and increased recurrence in ICC patients. Moreover, through forced overexpression and knock-down of PTPT4A1, we demonstrated that PTP4A1 could significantly promote ICC cells proliferation, colony formation, migration, and invasion in vitro, and markedly enhance tumor progression in vivo. Mechanistically, PTP4A1 was involved in PI3K/AKT signaling and its downstream molecules, such as phosphorylation level of GSK3ß and up-regulation of CyclinD1, in ICC cells to promote proliferation. Importantly, PTP4A1 induced ICC cells invasion was through activating PI3K/AKT signaling controlled epithelial-mesenchymal transition (EMT) process by up-regulating Zeb1 and Snail. Thus, PTP4A1 may serve as a potential oncogene that was a valuable prognostic biomarker and therapeutic target for ICC.

Predictive value of N-terminal pro-brain natriuretic peptide in combination with the sequential organ failure assessment score in sepsis.

BACKGROUND: The prognostic power of n-terminal pro-brain natriuretic peptide (NT-proBNP) in sepsis is disputable and unstable among different models. We attempt to evaluate the prognostic potential of NT-proBNP in combination with the sequential organ failure assessment (SOFA) score in sepsis. METHODS: In this retrospective study, 100 consecutive sepsis patients were enrolled. Clinical data such as admission SOFA, the Acute Physiologic and Chronic Health Evaluation score, shock prevalence, use of lung protective ventilation, vasopressors, and glucocorticoids were recorded. Additionally, serum creatinine (Scr1 and Scr3) and NT-proBNP (NT-proBNP1 and NT-proBNP3) were assayed and evaluated at admission and on day 3 respectively. RESULTS: DNT-proBNP (NT-proBNP3 minus NT-proBNP1) (P < 0.001, Hazard ratio (HR) = 1.245, 95% confidence interval (CI), 1.137 - 1.362) and admission SOFA (P < 0.001, HR = 1.197, 95%CI, 1.106 - 1.295) were independently related to in-hospital mortality. Their combination was a more robust predictor for in-hospital mortality than either of them individually. Patients with high DNT-proBNP and SOFA had the poorest prognosis. CONCLUSIONS: In our study, both DNT-proBNP and SOFA were independent predictors of septic patients' prognosis. Moreover, the combination of DNT-proBNP and admission SOFA provided a novel strategy that contained information regarding both the response to treatment and sepsis severity.

Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials.

PURPOSE: To identify the side population (SP) cells from four hepatocellular carcinoma (HCC) cell lines with stepwise metastatic potentials. METHODS: SP cells were sorted from HCCLM3, MHCC97-H, MHCC97-L and Hep3B by flow cytometry, and then analyzed by differentiation study, clonogenic assay, chemoresistance study and tumorigenicity assay in vivo. The expression of ABCG(2) in SP cells was detected by immunocytochemistry, western blotting and real-time quantitative PCR, respectively. RESULTS: There was significant difference in SP proportion among HCCLM3, MHCC97-H, MHCC97-L and Hep3B (28.7 +/- 1.6%, 14.5 +/- 0.6%, 4.2 +/- 0.4%, 0.9 +/- 0.1%, respectively, P < 0.01). All the SP cells showed similar characteristics of self-renewal, high clonogenicity, remarkable chemo-resistance and high expression of ABCG(2). As low as 2,000 SP cells could initiate tumors in non-obese diabetic/severe combined immunodeficiency mice successfully. CONCLUSIONS: SP cells purified from HCC cell lines harbors cancer stem cell-like properties, and may be related to the metastatic potentials and therapeutic-resistance of HCC.