Development and evaluation of an artificial intelligence-based workflow for the prioritization of patient portal messages.

Objectives: Accelerating demand for patient messaging has impacted the practice of many providers. Messages are not recommended for urgent medical issues, but some do require rapid attention. This presents an opportunity for artificial intelligence (AI) methods to prioritize review of messages.

Impact of oral vancomycin treatment duration on rate of recurrence in patients requiring concurrent systemic antibiotics.

Background: There is a paucity of data guiding treatment duration of oral vancomycin for infection (CDI) in patients requiring concomitant systemic antibiotics.

Objectives: To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence.

Methods: In this retrospective cohort study, we evaluated adult hospitalized patients with an initial episode of CDI who were treated with vancomycin and who received overlapping systemic antibiotics for >72 hours.

Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma.

Background: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome.

Methods: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA).

Treatment of Piperacillin-Tazobactam-Nonsusceptible/Ceftriaxone-Susceptible Infections With Carbapenem Versus Carbapenem-Sparing Antimicrobials.

Background: and with a piperacillin-tazobactam-nonsusceptible/ceftriaxone-susceptible (TZP-NS/CRO-S) phenotype have been increasingly identified, with limited available literature evaluating treatment strategies.

Methods: This was a retrospective study of noncritically ill adults hospitalized between 2013 and 2021 and treated at least 48 hours for TZP-NS/CRO-S or infections. The primary composite endpoint included escalation to intensive care unit, infection- or treatment-related readmission, mortality, and infection recurrence.

Utilizing clinical, pathological and radiological information to guide postoperative radiotherapy in prostate cancer.

Introduction: A detectable and rising PSA following radical prostatectomy is indicative of recurrent prostate cancer. Salvage radiotherapy (SRT) with/without androgen deprivation therapy represents the main treatment option for these patients and has been historically associated with a biochemical control rate of ~70%. To determine the optimal timing, diagnostic workup, radiotherapy dosefractionation, treatment volume, and use of systemic therapy, several informative studies have been conducted in the last decade.

VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2.

Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes.

CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies.

Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART.

Quality and Quantity: Evaluating Tumor Biology Alongside Novel Imaging on Diagnosis of Metastatic Hormone-sensitive Prostate Cancer.

Tumor biology may play an important role as an effective predictive biomarker that is complementary to functional imaging for metastatic hormone-sensitive prostate cancer.

YAP1 and PRDM14 converge to promote cell survival and tumorigenesis.

The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration, and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival, and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA.

RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern.

p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer.

Background: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia.

Transcription factor networks of oligodendrogliomas treated with adjuvant radiotherapy or observation inform prognosis.

Background: Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways.

Methods: mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA "Brain Lower Grade Glioma" provisional dataset.

Genomic Amplification and Functional Dependency of the Gamma Actin Gene in Uterine Cancer.

Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages.

A combined biological and clinical rationale for evaluating metastasis directed therapy in the management of oligometastatic prostate cancer.

The initial management of potentially oligometastatic hormone sensitive prostate cancer has been complicated by rapid advances in the field. Clinically, subgroup analyses of two randomized control trials have suggested that a specific synchronous oligometastatic prostate cancer state may be predictive for benefit from radiation to the primary. Further exploration of metastasis-directed therapy has been supported for various prostate cancer populations among three phase II clinical trials.

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer.

Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts.

An Investigation of the Anti-Parkinsonism Potential of Co-enzyme Q and Co-enzyme Q /Levodopa-carbidopa Combination in Mice.

Despite decades of research, neurodegenerative disorders like Parkinson's disease remain a leading cause of disability worldwide, due to the insufficient reduction of disease burden by available medications. Recently, the benefits of dietary supplements like co-enzyme Q in neurodegenerative diseases have been reported. ; Aim: The protective effects of supplemental co-enzyme Q (CQ) and possible additive benefits of CQ /Levodopa-Carbidopa (LD) in Chlorpromazine (CPZ)-induced Parkinsonism-like changes in mice were investigated.

A Survey Of Americans With High-Deductible Health Plans Identifies Opportunities To Enhance Consumer Behaviors.

Most high-deductible health plan (HDHP) enrollees do not engage in consumer behaviors such as price shopping. Why not? We surveyed 1,637 Americans in HDHPs-which can be linked to health savings accounts (HSAs) but usually are not-about factors that may predict, facilitate, or impede HDHP enrollees' engagement in consumer behaviors. We found that having an HSA was associated with saving for future care, high financial literacy was associated with comparing prices and quality, and high confidence in talking with providers about costs and trying to negotiate prices was associated with engaging in these behaviors.

Attitudes About Consumer Strategies Among Americans in High-deductible Health Plans.

Background: More than 70 million Americans are enrolled in a high-deductible health plan (HDHP), with high upfront cost-sharing to encourage strategies such as price shopping to mitigate out-of-pocket spending. Recent research suggests HDHP enrollees are reluctant to engage in these consumer strategies, but there is little information on why.

Objectives: To describe associations between HDHP enrollees' attitudes about and intent to engage in consumer strategies.

Targeting DNA repair for precision radiotherapy: Balancing the therapeutic ratio.

Genomic instability is underpinned by defects in the DNA damage response and DNA repair pathways. Subsequent clonal selection and adaption can lead to a mutator phenotype and tumor aggression. Importantly, tumor cell sensitivity to chemotherapy and radiotherapy can depend highly on the cellular capacity to repair DNA damage within and between tumor types.

Chromosomal instability as a prognostic marker in cervical cancer.

Background: Cervical cancer is the third most common cancer in women globally, and despite treatment, distant metastasis and nodal recurrence will still develop in approximately 30% of patients. The ability to predict which patients are likely to experience distant relapse would allow clinicians to better tailor treatment. Previous studies have investigated the role of chromosomal instability (CIN) in cancer, which can promote tumour initiation and growth; a hallmark of human malignancies.

CoreFlow: a computational platform for integration, analysis and modeling of complex biological data.

Unlabelled: A major challenge in mass spectrometry and other large-scale applications is how to handle, integrate, and model the data that is produced. Given the speed at which technology advances and the need to keep pace with biological experiments, we designed a computational platform, CoreFlow, which provides programmers with a framework to manage data in real-time. It allows users to upload data into a relational database (MySQL), and to create custom scripts in high-level languages such as R, Python, or Perl for processing, correcting and modeling this data.

Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder.

Background: Aberrant intracellular calcium (Ca2+) signaling in patients with bipolar-I disorder (BD-I) suggests disturbed endoplasmic reticulum (ER) function in BD. We examined whether the ER stress response is altered in BD-I patients and the relationship to basal intracellular Ca2+ levels ([Ca2+]B), in B lymphoblasts (BLCLs) from BD-I patients.

Methods: Endoplasmic reticulum stress-induced X-box binding protein 1 (XBP1), C/EBP homologous protein (CHOP), and GRP78 expression in BLCLs from BD-I subjects stratified on elevated or normal [Ca2+]B and control subjects were determined by real-time quantitative reverse transcription polymerase chain reaction.

Formation and removal of alkylthiolate self-assembled monolayers on gold in aqueous solutions.

We report the development of novel reagents and approaches for generating recyclable biosensors. The use of aqueous media for the formation of protein binding alkylthiolate monolayers on Au surfaces results in accelerated alkylthiolate monolayer formation and improvement in monolayer integrity as visualized by fluorescence microscopy and CV techniques. We have also developed an electrocleaning protocol that is compatible with microfluidics devices, and this technique serves as an on-chip method for cleaning Au substrates both before and after monolayer formation.