Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy.

BACKGROUND: Worldwide, over 10 million individuals suffer from drug-resistant epilepsy. New therapeutic strategies are needed to address this debilitating disease. Inhibition of sodium-glucose linked transporters (SGLTs), which are variably expressed in the brain, has been demonstrated to reduce seizure activity in murine models of epilepsy. Here we investigated the effects of dapagliflozin, a highly competitive SGLT2 inhibitor currently used as a drug for diabetes mellitus, on seizure activity in rats with pentylenetetrazol (PTZ) induced seizures. METHODS: Laboratory rats (n = 48) were evenly randomized into two experiments, each with four study arms: (1) a vehicle-treated (placebo) arm infused with saline; (2) a control arm infused with PTZ; (3) a treatment arm with PTZ and dapagliflozin at 75 mg/kg, and (4) another treatment arm with PTZ and dapagliflozin at 150 mg/kg. Study subjects were assessed for seizures either via EEG as measured by spike wave percentage (SWP), or clinically via Racine's scales scores (RSS) and time to first myoclonic jerk (TFMJ). RESULTS: Rats treated with dapagliflozin had lower mean SWP on EEG (20.4% versus 75.3% for untreated rats). Behaviorally, treatment with dapagliflozin improved means RSS (2.33 versus 5.5) and mean TFMJ (68.3 versus 196.7 s). All of these findings were statistically significant with p-values of < 0.0001. There was a trend towards even better seizure control with the higher dose of dapagliflozin at 150 mg/kg, however this was not consistently statistically significant. CONCLUSIONS: Dapagliflozin decreased seizure activity in rats with PTZ-induced seizures. This may be explained by the anti-seizure effects of decreased glucose availability and a reduction in sodium transport across neuronal membranes which can confer a stabilizing effect against excitability and unwanted depolarization. The potential clinical role of dapagliflozin and other SGLT2 inhibitors as anti-seizure medications should be further explored.

JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is the leading open-access database of matrix profiles describing the DNA-binding patterns of transcription factors (TFs) and other proteins interacting with DNA in a sequence-specific manner. Its fourth major release is the largest expansion of the core database to date: the database now holds 457 non-redundant, curated profiles. The new entries include the first batch of profiles derived from ChIP-seq and ChIP-chip whole-genome binding experiments, and 177 yeast TF binding profiles. The introduction of a yeast division brings the convenience of JASPAR to an active research community. As binding models are refined by newer data, the JASPAR database now uses versioning of matrices: in this release, 12% of the older models were updated to improved versions. Classification of TF families has been improved by adopting a new DNA-binding domain nomenclature. A curated catalog of mammalian TFs is provided, extending the use of the JASPAR profiles to additional TFs belonging to the same structural family. The changes in the database set the system ready for more rapid acquisition of new high-throughput data sources. Additionally, three new special collections provide matrix profile data produced by recent alternative high-throughput approaches.

A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada.

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19-99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

A Population-based Study of Treatment Patterns and Survival of Patients With De Novo Stage IV Non-Small Cell Lung Cancer.

BACKGROUND: Treatment strategies for metastatic non-small cell lung cancer (NSCLC) are evolving rapidly and can be highly variable. Real-world evidence of treatment patterns and outcomes can provide an understanding of our current practice and offer insights on ways to incorporate emerging therapies into our treatment paradigm. In this population-based study, we investigated treatments and outcomes of stage IV NSCLC patients from a large Canadian province. METHODS: Patients diagnosed with de novo stage IV NSCLC from April 1, 2010 to March 31, 2015 were identified. Data for baseline characteristics, treatments, and outcomes were obtained from provincial data sources, including the cancer registry and electronic medical records. We classified systemic treatments as chemotherapy, targeted therapy (anti-epidermal growth factor receptor, and anti-anaplastic lymphoma kinase) and immunotherapy (checkpoint inhibitors) and characterized clinical outcomes by treatment type. RESULTS: A total of 6438 patients were identified with NSCLC, of whom 3606 (56%) had de novo stage IV disease. The median age of diagnosis was 69 (range: 20 to 100) years and 52.4% were men. First-line palliative treatments included: chemotherapy in 19.5% (n=703), targeted agents in 5.7% (n=204), immunotherapy in 1% (n=1), radiotherapy in 6.8% (n=246), and best supportive care in 74.8% (n=2,698). Median overall survival (mOS) from diagnosis for the whole cohort was 3.8 months. Within subgroups, mOS was 18.0 months for targeted therapies, 9.4 months for chemotherapy, and 2.5 months for best supportive care. Only 1.0% of patients (n=34) received immunotherapy at any line. CONCLUSIONS: Survival benefit was dependent on type of treatment received, with significantly better mOS observed with the use of small-molecule targeted therapy against epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements, as compared with best supportive care.

Population-based Treatment Patterns and Outcomes for Stage III Non-Small Cell Lung Cancer Patients: A Real-world Evidence Study.

BACKGROUND: Most patients with stage III non-small cell lung cancer (NSCLC) develop metastases and succumb to their cancer. Approaches to the treatment of stage III disease can be highly variable. Understanding current treatment patterns can inform the optimal integration of emerging therapies. In this study, we describe contemporary treatment patterns and outcomes for a population-based cohort of stage III NSCLC patients from a large Canadian province. METHODS: On the basis of the provincial cancer registry, all adult patients diagnosed with stage III NSCLC from April 1, 2010 to March 31, 2015 were identified. Analyses of these patients' existing electronic medical records and administrative claims data were conducted to describe patient characteristics, treatment patterns, and survival outcomes. RESULTS: In total, we screened 6438 patients diagnosed with NSCLC, of whom 1151 (17.9%) had stage III disease. Among them, 61.2% were stage IIIA, 36.4% were stage IIIB, and 2.4% were unspecified. Median age at diagnosis was 70 (22 to 94) years and 50.2% were men. In this cohort, a significant proportion of patients received only palliative radiotherapy (35.6%), palliative chemotherapy (8.8%), or best supportive care (24.8%) as initial treatment. Conversely, relatively few underwent concurrent chemoradiotherapy (11.7%) or trimodality therapy (1.7%). Surgery±adjuvant treatments were performed in 14.8% of stage III patients. Median overall survival was 13.2 months (95% confidence interval [CI], 12.2-14.0) among stage III patients. Patients who received initial curative treatment had statistically significant better survival compared with those who received noncurative treatment (P<0.001); median overall survival 29.8 months (95% CI, 22.3-34.6) and 8.9 months (95% CI, 7.6-11.6), respectively. CONCLUSIONS: In a population-based setting that includes community, regional, and tertiary cancer centers, use of concurrent chemoradiotherapy and trimodality therapy in stage III NSCLC was low despite evidence supporting the potential benefits of these strategies.

Outcomes of patients with relapsed or refractory acute myeloid leukemia: a population-based real-world study.

With standard therapies for patients with acute myeloid leukemia (AML), many patients either do not achieve complete response (CR) or relapse after CR. There are a scarcity of real-world data on outcomes of unselected patients with relapsed/refractory acute myeloid leukemia (RR-AML). We retrospectively evaluated treatment patterns and survival outcomes of unselected patients aged ≥18 years diagnosed with RR-AML identified from the Alberta Cancer Registry, Alberta, Canada, between January 2013 and December 2016. We included 199 patients who met predefined criteria for RR-AML. Following RR-AML diagnosis, 23% of patients received intensive therapy (IT), 33% non-intensive therapy (NIT), and 44% best supportive care (BSC). The unadjusted median overall survival (OS) of the study cohort was 5.3 months from the time of RR-AML diagnosis, with a 5-year OS rate of 12.6% (95% confidence interval 7.5-21.1). According to treatment intensity after RR-AML, the median OS outcomes were 13.6, 9.4, and 2.0 months for IT, NIT, and BSC groups, respectively (P<0.001). Patients who received treatment (IT or NIT) had better survival than those who received only BSC. This study emphasizes the need for newer therapy options for patients with RR-AML.

Development of a Model for Predicting Early Discontinuation of Adjuvant Chemotherapy in Stage III Colon Cancer.

PURPOSE: To develop a tool that can be used to predict early discontinuation of adjuvant chemotherapy among patients with stage III colon cancer. PATIENTS AND METHODS: Through record linkage of Alberta administrative and tumor registry databases, we identified a cohort of individuals age ≥ 18 years who were diagnosed with stage III colon cancer and who received adjuvant chemotherapy in Alberta between 2004 and 2015. Early discontinuation was defined as receipt of < 5 months of a planned 6-month course of chemotherapy. By a systematic review of the literature and a survey of medical oncologists, the following candidate variables were identified: age (years), number of comorbidities (0, 1, ≥ 2), cancer stage (IIIC v IIIA-B), type of chemotherapy (fluorouracil, leucovorin, and oxaliplatin; capecitabine and oxaliplatin; or monotherapy), time from surgery to chemotherapy initiation (weeks), type of treatment facility (academic or community), and distance from home to treatment center (kilometers). Models developed using penalized logistic regression and the random forest algorithm were compared. Model performance was assessed using the C-statistic, Brier score, and a calibration plot. Internal validation was performed using the bootstrap method. RESULTS: From an initial 3,115 patients identified, 1,378 were deemed eligible for inclusion. Of these patients, 474 patients (34.4%) failed to complete at least 5 months of chemotherapy. Although well calibrated, the penalized logistic regression model had poor discrimination (optimism-adjusted C-statistic, 0.63; 95% CI, 0.60 to 0.67). In contrast, the random forest model achieved adequate discrimination (optimism-adjusted C-statistic, 0.80; 95% CI, 0.79 to 0.82). Although the degree of calibration of the random forest was acceptable, it was slightly worse than that of the penalized logistic regression model. CONCLUSION: Internal validation of our random forest model suggests that it may have clinical utility. Additional research regarding its external validation and clinical impact is needed.

Levodropropizine suppresses seizure activity in rats with pentylenetetrazol-induced epilepsy.

BACKGROUND: Millions of individuals worldwide suffer from epilepsy, and up to 25% of patients have seizures that are resistant to currently available antiepileptic drugs. Hence, there continues to be a need for more seizure medications that are effective yet tolerable. Levodropropizine (LVDP) is an established antitussive drug that, based on preclinical data, may also have antiepileptic activity. METHODS: We treated rats with either intraperitoneal (IP) LVDP at two different doses or placebo in randomized fashion and then exposed them to IP pentylenetetrazol (PTZ), a potent seizure-inducing compound. We measured the rats' subsequent seizure activity with electroencephalography (EEG), Racine's convulsion scale (RCS) and time to first myoclonic jerk (TFMJ) to determine whether LVDP has antiepileptic properties in our murine model for epilepsy. RESULTS: When compared to placebo, LVDP at both doses significantly suppressed seizure activity. Mean EEG spike wave percentage score decreased from 76.8% (placebo) to 13.1% (lower dose) and 7.6% (higher dose, bothp < 0.0001). RCS decreased from a mean of 5.8 (placebo) to 1.83 (lower dose) and 1.16 (higher dose, both p < 0.05). TFMJ had increased from a mean of 65.1 s (placebo), to 247.3 s (lower dose) and 295.5 s (higher dose, both p < 0.0001). CONCLUSIONS: Levodropropizine, a common antitussive drug, suppresses seizure activity in rats with PTZ-induced status epilepticus. Given the ongoing need to find effective therapies for refractory epilepsy, the possibility of using levodropropizine as an antiepilepticshould be further explored.

Predictive and Prognostic Properties of Human Equilibrative Nucleoside Transporter 1 Expression in Gemcitabine-Treated Pancreatobiliary Cancer: A Meta-Analysis.

PURPOSE: Gemcitabine, the primary drug for the treatment of pancreatobiliary cancer (PBC), requires human equilibrative nucleoside transporter 1 (hENT1) to enter cells. High tumoral hENT1 expression has been linked with improved survival among patients with PBC treated with gemcitabine; however, this finding has been inconsistent, and studies used different expression assays. METHODS: Databases were reviewed for studies that examined hENT1 and clinical outcome in PBC. Of 307 publications, 34 studies were found that used immunohistochemistry (IHC) with one of eight anti-hENT1 antibody assays. Five studies were excluded for redundancy, and 29 studies underwent detailed review. RESULTS: On average, 51% of tumor samples had high hENT1 expression (range, 7% to 92%). Among studies that examined hENT1 expression and overall survival (OS), 58% (15 of 26 studies) showed an association between high tumoral hENT1 and improved OS for gemcitabine-treated patients. Among 10D7G2 antibody studies, 88% (seven of eight studies) demonstrated this association. Studies with other antibodies-in particular, SP120 (two of nine studies)-were less consistent. The ability to detect an association between improved OS and high hENT1 was antibody dependent (χ2 P = .0237). An association between high tumoral hENT1 expression and improved disease-free/progression-free survival (DFS/PFS) was demonstrated in 71% of studies (15 of 21 studies). Pooled hazard ratio (HR) analyses of all antibody studies demonstrated a link between high hENT1 tumor expression and improved OS (HR, 0.674; 95% CI, 0.509 to 0.893; P = .006) and DFS/PFS (HR, 0.740; 95% CI, 0.517 to 0.1.059; P = .10). This signal was stronger among studies that used the 10D7G2 antibody in comparison to those in which another antibody was used, with HRs of 0.488 (95% CI, 0.396 to 0.602; P < .001) and 0.410 (95% CI, 0.280 to 0.599; P < .001), respectively. CONCLUSION: High tumoral hENT1 expression on IHC with 10D7G2 is a strong and reproducible prognostic marker for improved outcome among gemcitabine-treated patients with PBC.

A case report of nifedipine-induced hepatitis with jaundice.

BACKGROUND: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal's angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve. CASE PRESENTATION: Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases. CONCLUSION: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4-8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.

The Gene Set Builder: collation, curation, and distribution of sets of genes.

BACKGROUND: In bioinformatics and genomics, there are many applications designed to investigate the common properties for a set of genes. Often, these multi-gene analysis tools attempt to reveal sequential, functional, and expressional ties. However, while tremendous effort has been invested in developing tools that can analyze a set of genes, minimal effort has been invested in developing tools that can help researchers compile, store, and annotate gene sets in the first place. As a result, the process of making or accessing a set often involves tedious and time consuming steps such as finding identifiers for each individual gene. These steps are often repeated extensively to shift from one identifier type to another; or to recreate a published set. In this paper, we present a simple online tool which - with the help of the gene catalogs Ensembl and GeneLynx - can help researchers build and annotate sets of genes quickly and easily. DESCRIPTION: The Gene Set Builder is a database-driven, web-based tool designed to help researchers compile, store, export, and share sets of genes. This application supports the 17 eukaryotic genomes found in version 32 of the Ensembl database, which includes species from yeast to human. User-created information such as sets and customized annotations are stored to facilitate easy access. Gene sets stored in the system can be "exported" in a variety of output formats - as lists of identifiers, in tables, or as sequences. In addition, gene sets can be "shared" with specific users to facilitate collaborations or fully released to provide access to published results. The application also features a Perl API (Application Programming Interface) for direct connectivity to custom analysis tools. A downloadable Quick Reference guide and an online tutorial are available to help new users learn its functionalities. CONCLUSION: The Gene Set Builder is an Ensembl-facilitated online tool designed to help researchers compile and manage sets of genes in a user-friendly environment. The application can be accessed via http://www.cisreg.ca/gsb/.

The transcription factor encyclopedia.

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

Gene characterization index: assessing the depth of gene annotation.

BACKGROUND: We introduce the Gene Characterization Index, a bioinformatics method for scoring the extent to which a protein-encoding gene is functionally described. Inherently a reflection of human perception, the Gene Characterization Index is applied for assessing the characterization status of individual genes, thus serving the advancement of both genome annotation and applied genomics research by rapid and unbiased identification of groups of uncharacterized genes for diverse applications such as directed functional studies and delineation of novel drug targets. METHODOLOGY/PRINCIPAL FINDINGS: The scoring procedure is based on a global survey of researchers, who assigned characterization scores from 1 (poor) to 10 (extensive) for a sample of genes based on major online resources. By evaluating the survey as training data, we developed a bioinformatics procedure to assign gene characterization scores to all genes in the human genome. We analyzed snapshots of functional genome annotation over a period of 6 years to assess temporal changes reflected by the increase of the average Gene Characterization Index. Applying the Gene Characterization Index to genes within pharmaceutically relevant classes, we confirmed known drug targets as high-scoring genes and revealed potentially interesting novel targets with low characterization indexes. Removing known drug targets and genes linked to sequence-related patent filings from the entirety of indexed genes, we identified sets of low-scoring genes particularly suited for further experimental investigation. CONCLUSIONS/SIGNIFICANCE: The Gene Characterization Index is intended to serve as a tool to the scientific community and granting agencies for focusing resources and efforts on unexplored areas of the genome. The Gene Characterization Index is available from http://cisreg.ca/gci/.