Adjuvant Chemotherapy in Patients with Locally Advanced Upper Tract Urothelial Carcinoma with or without Kidney Transplantation.

Background: The incidence of upper tract urothelial carcinoma (UTUC) is uniquely high in kidney transplant (KT) recipients in Taiwan. The evidence of adjuvant chemotherapy (AC) in UTUC is contradictory. We have sought to determine whether AC is associated with potential benefits related to locally advanced UTUC after KT. Methods: We retrospectively analyzed 134 patients with locally advanced UTUC (at least stage T2) and patients who were administrated AC after unilateral or bilateral nephroureterectomy with bladder cuff excision. Of these 134 patients, 57 patients fulfilled our inclusion criteria. We used 23 KT and 34 non-KT locally advanced UTUC patients for comparison. Results: The mean follow-up time was 52.35 ± 34.56 and 64.71 ± 42.29 months for the KT and non-KT groups, respectively. The five-year disease-free survival (DFS) and overall survival (OS) rates were 45.7% vs. 70.2% and 62.8% vs. 77.6%, for the KT and non-KT groups. The Kaplan-Meier curve and the log rank test revealed significant differences in the DFS and OS rates between the two groups, p = 0.015 and 0.036. The influence of chemotherapy on graft kidney function was mild. Only three in the KT group and two in the non-KT group developed > grade 2 nephrotoxicity. Conclusions: Our study suggested that KT patients with locally advanced UTUC who had been administered AC after surgery presented worse OS and DFS than non-KT patients. KT patients tolerated the AC course well, and their nephrotoxicity levels were mild and acceptable.

Feasibility estimation of injected hydrodissection before definitive radiotherapy of pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma is often not diagnosed until an advanced stage, and so most patients are not eligible for resection. For patients who are inoperable, definitive radiotherapy is crucial for local disease control. However, the pancreas is located close to other vulnerable gastrointestinal organs, making it challenging to deliver an adequate radiation dose. The surgical insertion of spacers or injection of fluids such as hydrogel before radiotherapy has been proposed, however, no study has discussed which patients are suitable for the procedure. METHODS: In this study, we reviewed 50 consecutive patients who received definitive radiotherapy at our institute to determine how many could have benefitted from hydrodissection to separate the pancreatic tumor from the adjacent gastrointestinal tract. By hypothetically injecting a substance using either computed tomography (CT)-guided or endoscopic methods, we aimed to increase the distance between the pancreatic tumor and surrounding hollow organs, as this would reduce the radiation dose delivered to the organs at risk. RESULTS: An interventional radiologist considered that hydrodissection was feasible in 23 (46%) patients with a CT-guided injection, while a gastroenterologist considered that hydrodissection was feasible in 31 (62%) patients with an endoscopic injection. Overall, we found 14 (28%) discrepancies among the 50 patients reviewed. Except for 1 patient who had no available trajectory with a CT-guided approach but in whom hydrodissection was considered feasible with an endoscopic injection, the other 13 patients had different interpretations of whether direct invasion was present in the CT images. CONCLUSION: Our results suggested that about half of the patients could have benefited from hydrodissection before radiotherapy. This finding could allow for a higher radiation dose and potentially better disease control.

Effect of iodized oil embolization on temperature change during cryoablation for renal cell carcinoma.

INTRODUCTION: We aimed to evaluate the effect of transcatheter arterial embolization (TAE) with iodized oil (Lipiodol) on temperature change during cryoablation (CA) for renal cell carcinoma (RCC). MATERIAL AND METHODS: We retrospectively reviewed patients receiving CA for RCC from February 2020 to July 2021, including those who received Lipiodol TAE prior to CA (TAE group) and those who underwent only CA with comparable clinical and tumor characteristics (non-TAE group). Clinical data and tumor characteristics of both groups were recorded. The temperature readings of each cryoprobe at every 15 s and 'time to -100 °C' were compared between the groups. RESULTS: A total of 17 patients with 18 RCCs were recruited (seven in the TAE group and 11 in the non-TAE group). The 'time to -100 °C' was significantly longer in the TAE group than in the non-TAE group (64.5 ± 24.3 s vs. 48.8 ± 9.7 s, p = 0.018). Positive correlation between 'time to -100 °C' and tumor maximal diameter, RENAL nephrometry and PADUA score were observed in the non-TAE group, while no corresponding correlation was found in the TAE group. CONCLUSIONS: Pre-embolization with iodized oil influences the temporal temperature changes during cryoablation by disrupting the positive correlation between the time to reach the target temperature and tumor characteristics.

Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Complex Cell-Cell Communication Networks in the Mouse Cornea.

Purpose: To generate a single-cell RNA-sequencing (scRNA-seq) map and construct cell-cell communication networks of mouse corneas. Methods: C57BL/6 mouse corneas were dissociated to single cells and subjected to scRNA-seq. Cell populations were clustered and annotated for bioinformatic analysis using the R package "Seurat." Differential expression patterns were validated and spatially mapped with whole-mount immunofluorescence staining. Global intercellular signaling networks were constructed using CellChat. Results: Unbiased clustering of scRNA-seq transcriptomes of 14,732 cells from 40 corneas revealed 17 cell clusters of six major cell types: nine epithelial cell, three keratocyte, two corneal endothelial cell, and one each of immune cell, vascular endothelial cell, and fibroblast clusters. The nine epithelial cell subtypes included quiescent limbal stem cells, transit-amplifying cells, and differentiated cells from corneas and two minor conjunctival epithelial clusters. CellChat analysis provided an atlas of the complex intercellular signaling communications among all cell types. Conclusions: We constructed a complete single-cell transcriptomic map and the complex signaling cross-talk among all cell types of the cornea, which can be used as a foundation atlas for further research on the cornea. This study also deepens the understanding of the cellular heterogeneity and heterotypic cell-cell interaction within corneas.

Ectopic ATP synthase stimulates the secretion of extracellular vesicles in cancer cells.

ABSTARCT: Ectopic ATP synthase on the plasma membrane (eATP synthase) has been found in various cancer types and is a potential target for cancer therapy. However, whether it provides a functional role in tumor progression remains unclear. Here, quantitative proteomics reveals that cancer cells under starvation stress express higher eATP synthase and enhance the production of extracellular vesicles (EVs), which are vital regulators within the tumor microenvironment. Further results show that eATP synthase generates extracellular ATP to stimulate EV secretion by enhancing P2X7 receptor-triggered Ca2+ influx. Surprisingly, eATP synthase is also located on the surface of tumor-secreted EVs. The EVs-surface eATP synthase increases the uptake of tumor-secreted EVs in Jurkat T-cells via association with Fyn, a plasma membrane protein found in immune cells. The eATP synthase-coated EVs uptake subsequently represses the proliferation and cytokine secretion of Jurkat T-cells. This study clarifies the role of eATP synthase on EV secretion and its influence on immune cells.

[The Role and Function of Music Therapy in Child-Friendly Healthcare].

Child-friendly healthcare relates to the development and application by professionals of integrated methods specifically for children in any healthcare activity context. Music therapy is one of these methods. Three roles (noise masker, emotional adjustment, and cognitive learning) and two functions (activity participation and non-verbal expression and decision making) of child-friendly-healthcare-related music therapy are presented in this article. Also, suggestions and insights regarding how to optimize the effectiveness of music therapy in the context of pediatric healthcare are provided.

Lockdown period during SARS COVID-19 endemic outbreak in Taiwan did not cause an increase of the complications nor mortality of patients received endoscopic retrograde cholangiopancreatography: A single-center retrospective study.

BACKGROUND: Coronavirus disease 2019, known as a widespread, aerosol spreading disease, has affected >549 000 000 people since 2019. During the lockdown period, dramatic reduction of elective endoscopic procedures, including endoscopic retrograde cholangiopancreatography, had been reported worldwide, leading to delayed diagnosis and treatment. Nevertheless, whether patients' hospital stays and complication rate of endoscopic retrograde cholangiopancreatography (ERCP) during the lockdown period were influenced by the pandemic still remains controversial. METHODS: Patients who diagnosed with obstructive jaundice and acute cholangitis in the lockdown period, May 16 to July 26, 2021, were compared to the same prepandemic period in 2019. RESULTS: A total of 204 patients in 2019 and 168 patients in 2021 were diagnosed with acute biliary cholangitis or obstructive jaundice, and 82 of the patients in 2019 and 77 patients in 2021 underwent ERCP ( p = 0.274). Patients whose quick Sequential Organ Failure Assessment (qSOFA) score was ≥ 2 occurred more during the lockdown period than during the normal period (24/77, 31.1% vs 12/82, 14.6%; p = 0.013). The initial laboratory data, including, total bilirubin (4.12 in 2021 vs 3.08 mg/dL in 2019; p = 0.014), gamma-glutamyl transferase (378 in 2021 vs 261 U/L in 2019; p = 0.009), and alkaline phosphatase (254 in 2021 vs 174 U/L in 2019; p = 0.002) were higher during the lockdown period compared to 2019. Hospital stay was statistically significant longer in the lockdown period (11 days [7.00-22.00] in 2021 vs 8 days in 2019 [6.00-12.00]; p value = 0.02). Multivariate analysis showed that qSOFA ≥ 2 (hazard ratio [HR] = 3.837, 95% confidence interval [CI] = 1.471-10.003; p = 0.006), and malignant etiology (HR = 2.932, 95% CI = 1.271-6.765; p = 0.012) were the statistically significant factors for a prolonged hospital stay, which was defined as hospital stay >21 days. ERCP-related complications and mortality rate were not statistically different between the two periods. CONCLUSION: Patients from May 16 to July 26, 2021, the lockdown period, had longer hospital stays and higher biliary tract enzyme levels, which indicated more severe disease. Nevertheless, ERCP could be safely and successfully performed even during the medical level 3 alert lockdown period without causing an increase in procedure-related complications and mortality.

First-Pass Arrival Interval of Ultrasound Contrast Medium in the Hepatic Artery and Portal Vein as a Marker for Assessment of Liver Transplant Recipients.

BACKGROUND: This study measures the first-pass arrival times in the hepatic artery and portal vein of the transplanted liver using contrast-enhanced ultrasound (CEUS) and assess its correlation with graft performance in the early posttransplant period. METHODS: This study evaluated 35 liver transplant recipients who underwent CEUS examination within 1 month of transplant surgery. CEUS under contrast-specific harmonic imaging mode were recorded for 60 seconds immediately after intravenous administration of microbubble ultrasound contrast medium (Sonazoid, GE Healthcare, Oslo, Norway). The recorded video clips were reviewed by 2 readers to determine the first-pass arrival times in the hepatic artery and portal vein, and the difference between the 2 was defined as the arterial-portal arrival interval (APAI). Laboratory data on the same date of CEUS examination were collected as indicators to correlate with APAI. RESULTS: The intra- and inter-rater reliability for APAI measurement were excellent, with intraclass correlation coefficients > .95. The mean APAI was 4.5 ± 1.8 seconds (range, 2.0-10.5 seconds). The APAI was positively correlated with the serum total bilirubin level (r = 0.357, P = .035) and negatively correlated with the platelet count (r = -0.354, P = .037). At the 5 second cutoff point, a total serum bilirubin of >8 mg/dL was reported in 5 of 11 patients (45.4%) with APAI of >5 seconds and in only 3 of 24 patients (12.5%) with APAI of <5 seconds (P < .05). CONCLUSIONS: The APAI is a quantitative marker that links the hemodynamics and the clinical status of the liver graft.

Increased risk for sleep disorders in burn patients: A 14-year nationwide, population-based cohort study.

BACKGROUND: Burn is a major trauma that causes physical and psychosocial impairments, leading to sleep disorders. However, the data about risks for sleep disorders in patients over 3 years following burn injury are limited. AIM: To investigate the long-term risks for sleep disorders in patients after burn injury and identify the high-risk population. METHODS: A 14-year population-based cohort study was performed using data from the 2000-2013 Taiwan National Health Insurance Research Database (NHIRD) which was a valid representative sample of the total population. All diagnoses of medical records in NHIRD were made by physicians and coded according to the ICD-9-CM. Cases diagnosed with burns (ICD-9 CM: N-code 940-949 and E-code 890-899) were included. The control group (non-burn injury group) was comprised quadruple the number of cases matched by index date, sex and age. RESULTS: In 2000-2013, among the 10,289 burn patients included and followed-up after the index year, burn injury significantly increased the risks for sleep disorders (Hazard Ratio; HR = 1.36, p = 0.044), including insomnia (HR = 1.41, p = 0.036), sleep disturbance (HR = 2.39, p = 0.005) and sleep apnoea (HR = 1.38, p = 0.029). Compared with the control group, those who were women (HR = 1.73, p = 0.021), adolescents (HR = 5.45, p < 0.001), aged 19-24 years (HR = 1.36, p = 0.034), aged 25-44 years (HR = 1.67, p = 0.007), had low income (HR = 2.14, p = 0.001), and without a history of mental disorders (HR = 1.41, p = 0.024) had significantly higher risks for developing sleep disorders when suffered burn injury. CONCLUSION: Burn had long-term negative effects on sleep during both the first year of burn injury and the subsequent follow-up 14 years. It is important for physicians to long-term assess the sleep quality of burn patients regardless of the number of years after burn injury.

Trends of Testicular Cancer Mortality-to-Incidence Ratios in Relation to Health Expenditure: An Ecological Study of 54 Countries.

Favorable testicular cancer mortality-to-incidence ratios (MIRs) are associated with health care disparities, including health care expenditures, but the trends of testicular MIR and health care disparity remain unclear. We evaluated changes in MIR as the difference between 2012 and 2018, termed delta MIR (δMIR). Health care expenditures and the human development index (HDI) were obtained from the World Health Organization and the Human Development Report Office of the United Nations Development Programme. The association between the variables was analyzed by Spearman's rank correlation coefficient. A total of 54 countries were included in the criteria of data quality reports and missing data. By continent, the most favorable MIR was in Oceania (0.03) while it was 0.36 in Africa. In these areas, the incidence rates were positively correlated to health care expenditure, but the mortality rates showed a reversed correlation. The MIR ranged from 0.01 to 0.34 and the δMIR ranged from -0.05 to 0.34. The favorable MIRs are correlated to high health care expenditure and HDI (all p < 0.001). Interestingly, favorable δMIRs tend to be seen in countries with relatively low health care expenditure and HDI (all p < 0.001). In conclusion, favorable testicular cancer MIRs are associated with high HDI and health care expenditure, but the improvement in MIR between 2012 and 2018 (δMIR) is negatively correlated with HDI and health care expenditure.

miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database.

MicroRNAs (miRNAs) are small non-coding RNAs (typically consisting of 18-25 nucleotides) that negatively control expression of target genes at the post-transcriptional level. Owing to the biological significance of miRNAs, miRTarBase was developed to provide comprehensive information on experimentally validated miRNA-target interactions (MTIs). To date, the database has accumulated >13,404 validated MTIs from 11,021 articles from manual curations. In this update, a text-mining system was incorporated to enhance the recognition of MTI-related articles by adopting a scoring system. In addition, a variety of biological databases were integrated to provide information on the regulatory network of miRNAs and its expression in blood. Not only targets of miRNAs but also regulators of miRNAs are provided to users for investigating the up- and downstream regulations of miRNAs. Moreover, the number of MTIs with high-throughput experimental evidence increased remarkably (validated by CLIP-seq technology). In conclusion, these improvements promote the miRTarBase as one of the most comprehensively annotated and experimentally validated miRNA-target interaction databases. The updated version of miRTarBase is now available at http://miRTarBase.cuhk.edu.cn/.

The RNA degradation pathway is involved in PPARα-modulated anti-oral tumorigenesis.

BACKGROUND: The activation of peroxisome proliferator-activated receptor alpha (PPARα) has been shown to reprogram tumor metabolism and exhibits great potential for treating anti-oral tumorigenesis. METHODS: In this study, we used a pathway-based strategy to explore possible functional pathways involved in the anticancer activity of PPARα in oral cancer cells through next-generation sequencing (NGS) and bioinformatic approaches. RESULTS: We found that 3919 genes were upregulated and 1060 genes were downregulated through PPARα activation. These genes were mainly involved in the proteasomal, mRNA surveillance, spliceosomal, RNA transport, and RNA degradation pathways, as indicated by GO and KEGG enrichment analysis. Importantly, a total of 13 upregulated genes in the RNA degradation pathway were identified including 3 core exosome factor genes (RRP43, RRP42, and CSL4), 2 TRAMP complex genes (TRF4 and Mtr4), 2 exosome cofactor genes (RRP6 and MPP6), 2 CCR4-NOT complex genes (CNOT2 and CNOT3), 2 Ski complex genes (SKI2 and Ski3), 1 decapping complex gene (EDC4), and 1 gene involved in 5' exoribonuclease activity (XRN1). CONCLUSION: Our findings suggest that the activation of PPARα to upregulate the RNA degradation pathway might provide a new strategy for oral cancer treatment.

Statistical principle-based approach for recognizing and normalizing microRNAs described in scientific literature.

The detection of MicroRNA (miRNA) mentions in scientific literature facilitates researchers with the ability to find relevant and appropriate literature based on queries formulated using miRNA information. Considering most published biological studies elaborated on signal transduction pathways or genetic regulatory information in the form of figure captions, the extraction of miRNA from both the main content and figure captions of a manuscript is useful in aggregate analysis and comparative analysis of the studies published. In this study, we present a statistical principle-based miRNA recognition and normalization method to identify miRNAs and link them to the identifiers in the Rfam database. As one of the core components in the text mining pipeline of the database miRTarBase, the proposed method combined the advantages of previous works relying on pattern, dictionary and supervised learning and provided an integrated solution for the problem of miRNA identification. Furthermore, the knowledge learned from the training data was organized in a human-interpretable manner to understand the reason why the system considers a span of text as a miRNA mention, and the represented knowledge can be further complemented by domain experts. We studied the ambiguity level of miRNA nomenclature to connect the miRNA mentions to the Rfam database and evaluated the performance of our approach on two datasets: the BioCreative VI Bio-ID corpus and the miRNA interaction corpus by extending the later corpus with additional Rfam normalization information. Our study highlights and also proposes a better understanding of the challenges associated with miRNA identification and normalization in scientific literature and the research gap that needs to be further explored in prospective studies.

The effectiveness of music therapy for individuals with Rett syndrome and their families.

BACKGROUND: Patients with Rett syndrome (RTT) present characteristic regression in communication and hand skills, which eventually leads to intellectual and physical disability. Moreover, caregivers of patients with RTT face stressors related to patients' medical and developmental concerns. Given the indications from case reports, this pilot study investigated the effectiveness of music therapy on RTT patients, as well as on parental stress for families of children with RTT. METHODS: Families in the study group were enrolled in a twice-weekly 120-minute music therapy program for 24 weeks (n = 11), whereas families in the control group did not receive music therapy (n = 12). Participants were administered the Vineland Adaptive Behavior Scales, Rett Syndrome Clinical Severity Scale, Rett Syndrome Motor Behavioral Assessment, and Parenting Stress Index for caregivers of RTT children before and after the music therapy program. RESULTS: Music therapy improved receptive language, verbal and non-verbal communication skills, and social interaction for RTT patients. In addition, purposeful hand function, breathing patterns, and eye contact were significantly improved. Of note, music therapy also decreased the frequency of epileptic seizures. Lastly, caregivers in the study group exhibited significantly lower stress following the program. CONCLUSION: The 24-week music therapy program was effective in improving social interaction, communication skills, eye contact, hand function, and reducing seizure frequency among RTT patients. Additionally, music therapy was effective in relieving parenting stress, which may help healthcare providers initiate early intervention strategies that can prevent parenting stress and reduce the risk of depression.

Peroxisome proliferator-activated receptor alpha accelerates neuronal differentiation and this might involve the mitogen-activated protein kinase pathway.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to modulate cell proliferation, migration, and differentiation in astrocytes. In this study, we used a retinoic acid (RA)-induced differentiation model of NTERA-2/clone D1 (NT2) cells to explore the functional significance of PPARα in neuronal differentiation. We found that activating PPARα by Wy14643 accelerated neuronal differentiation via regulating the expression of neuronal markers. RT-PCR assays showed a significant increase in NeuroD expression and a decrease in nestin expression in cells treated concomitantly with RA and Wy14643 for 2 days compared to the levels in cells treated with RA alone. Expression of MAP2 protein, a mature neuronal marker, was markedly upregulated at day 10 of Wy14643 treatment, which was maintained after 21 days of neuronal formation. Corresponding to the changes in MAP2 expression, the expression of Cdk5 was upregulated with Wy14643 exposure from day 10 to day 21. Moreover, cells treated with Wy14643 displayed higher expression levels of phospho-ERK and phospho-p38 in the differentiation process than cell treated with RA alone. These results indicated that activation of PPARα accelerated neuronal differentiation through upregulating the expression of NeuroD, MAP2, and Cdk5 and downregulating the expression of nestin. MAPK signals, ERK and p38, might contribute to the accelerated differentiation process. These findings suggest that PPARα plays a role in regulating neuronal differentiation and may be beneficial for functional recovery from neurological disorders.

miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions.

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/.

speG Is Required for Intracellular Replication of Salmonella in Various Human Cells and Affects Its Polyamine Metabolism and Global Transcriptomes.

The speG gene has been reported to regulate polyamine metabolism in Escherichia coli and Shigella, but its role in Salmonella remains unknown. Our preliminary studies have revealed that speG widely affects the transcriptomes of infected in vitro M and Caco-2 cells and that it is required for the intracellular replication of Salmonella enterica serovar Typhimurium (S. Typhimurium) in HeLa cells. In this study, we demonstrated that speG plays a time-dependent and cell type-independent role in the intracellular replication of S. Typhimurium. Moreover, high-performance liquid chromatography (HPLC) of four major polyamines demonstrated putrescine, spermine, and cadaverine as the leading polyamines in S. Typhimurium. The deletion of speG significantly increased the levels of the three polyamines in intracellular S. Typhimurium, suggesting the inhibitory effect of speG on the biosynthesis of these polyamines. The deletion of speG was associated with elevated levels of these polyamines in the attenuated intracellular replication of S. Typhimurium in host cells. This result was subsequently validated by the dose-dependent suppression of intracellular proliferation after the addition of the polyamines. Furthermore, our RNA transcriptome analysis of S. Typhimurium SL1344 and its speG mutant outside and inside Caco-2 cells revealed that speG regulates the genes associated with flagellar biosynthesis, fimbrial expression, and functions of types III and I secretion systems. speG also affects the expression of genes that have been rarely reported to correlate with polyamine metabolism in Salmonella, including those associated with the periplasmic nitrate reductase system, glucarate metabolism, the phosphotransferase system, cytochromes, and the succinate reductase complex in S. Typhimurium in the mid-log growth phase, as well as those in the ilv-leu and histidine biosynthesis operons of intracellular S. Typhimurium after invasion in Caco-2 cells. In the present study, we characterized the phenotypes and transcriptome effects of speG in S. Typhimurium and reviewed the relevant literature to facilitate a more comprehensive understanding of the potential role of speG in the polyamine metabolism and virulence regulation of Salmonella.

Proteomic analysis of oral cancer reveals new potential therapeutic targets involved in the Warburg effect.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to disrupt tumour metabolism and to promote anticancer activity through interfering with the Warburg effect. This study is to investigate whether Warburg effect-related proteins also could be identified in oral tumour lesions and to explore the functional significance of PPARα in metabolic shift. Five pairs of tongue tumour tissues and adjacent reference tissues obtained from 4-NQO/arecoline induced mouse model were analyzed by 2-d-gel-electrophoresis and LC-MS. Further, the hexokinase II level, pyruvate dehydrogenase (PDH) activity, and metabolites of glycolysis and TCA cycle were all examined in order to validate the effect of PPARα on metabolic shift. Changes in protein expression levels revealed that seven proteins, which were involved in glycolysis, the tricarboxylic acid cycle, and the respiratory chain, were down-regulated in tumour tissues. We found that activation of PPARα through fenofibrate could inhibit oral cancer cell growth and switch the way of energy production from the Warburg effect to oxidative phosphorylation. Fenofibrate induced a reduction of hexokinase II protein levels, increases in PDH activity and metabolites of the TCA cycle, and an impairment of ATP production. These findings suggested that activation of the PPARα to reprogram the metabolic pathway might impair the Warburg effect and trigger cancer cell death. The study provides a novel view of changes in protein expression profiles involved in the Warburg effect during oral tumourigenesis. Activation of the PPARα to impair the Warburg effect might offer a new strategy for oral cancer treatment.

Biomarker identification of hepatocellular carcinoma using a methodical literature mining strategy.

Hepatocellular carcinoma (HCC), one of the most common causes of cancer-related deaths, carries a 5-year survival rate of 18%, underscoring the need for robust biomarkers. In spite of the increased availability of HCC related literatures, many of the promising biomarkers reported have not been validated for clinical use. To narrow down the wide range of possible biomarkers for further clinical validation, bioinformaticians need to sort them out using information provided in published works. Biomedical text mining is an automated way to obtain information of interest within the massive collection of biomedical knowledge, thus enabling extraction of data for biomarkers associated with certain diseases. This method can significantly reduce both the time and effort spent on studying important maladies such as liver diseases. Herein, we report a text mining-aided curation pipeline to identify potential biomarkers for liver cancer. The curation pipeline integrates PubMed E-Utilities to collect abstracts from PubMed and recognize several types of named entities by machine learning-based and pattern-based methods. Genes/proteins from evidential sentences were classified as candidate biomarkers using a convolutional neural network. Lastly, extracted biomarkers were ranked depending on several criteria, such as the frequency of keywords and articles and the journal impact factor, and then integrated into a meaningful list for bioinformaticians. Based on the developed pipeline, we constructed MarkerHub, which contains 2128 candidate biomarkers extracted from PubMed publications from 2008 to 2017. Database URL: http://markerhub.iis.sinica.edu.tw.

Improving the dictionary lookup approach for disease normalization using enhanced dictionary and query expansion.

The rapidly increasing biomedical literature calls for the need of an automatic approach in the recognition and normalization of disease mentions in order to increase the precision and effectivity of disease based information retrieval. A variety of methods have been proposed to deal with the problem of disease named entity recognition and normalization. Among all the proposed methods, conditional random fields (CRFs) and dictionary lookup method are widely used for named entity recognition and normalization respectively. We herein developed a CRF-based model to allow automated recognition of disease mentions, and studied the effect of various techniques in improving the normalization results based on the dictionary lookup approach. The dataset from the BioCreative V CDR track was used to report the performance of the developed normalization methods and compare with other existing dictionary lookup based normalization methods. The best configuration achieved an F-measure of 0.77 for the disease normalization, which outperformed the best dictionary lookup based baseline method studied in this work by an F-measure of 0.13.Database URL: https://github.com/TCRNBioinformatics/DiseaseExtract.