miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures.

Primary non-function (PNF) of an allograft defines an irreversible graft failure and although rare, constitutes a life-threatening condition that requires high-urgency re-transplantation. Equally, drug induced acute liver failures (ALF) are seldom but the rapid loss of hepatic function may require orthotropic liver transplantation (OLT). Recently, we reported the development of a rodent PNF-disease model of fatty allografts and showed that a dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of PNF.

miR-106b-5p protects against drug-induced liver injury by targeting vimentin to stimulate liver regeneration.

Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling.

Genomics of human NAFLD: Lack of data reproducibility and high interpatient variability in drug target expression as major causes of drug failures.

Background And Aims: NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail.

Sex differences in the tumor promoting effects of tobacco smoke in a cRaf transgenic lung cancer disease model.

Tobacco smoke (TS) is the leading cause for lung cancer (LC), and female smokers are at a greater risk for LC. Yet, the underlying causes are unknown. We performed whole genome scans in TS exposed wild type and histologically characterized tumor lesions of cRaf transgenic mice.

A genomic perspective of the aging human and mouse lung with a focus on immune response and cellular senescence.

Background: The aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated 89 mouse and 414 individual human lung genomic data sets with a focus on genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant, and we interrogated single cell RNAseq data to fingerprint cell type specific changes.

Dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of primary nonfunction of fatty liver allografts.

Orthotopic liver transplantation (OLT) is a lifesaving procedure. However, grafts may fail due to primary nonfunction (PNF). In the past, we demonstrated PNFs to be mainly associated with fatty allografts, and given its unpredictable nature, the development of a disease model is urgently needed.

Sex disparities in non-small cell lung cancer: mechanistic insights from a cRaf transgenic disease model.

Background: Women are at greater risk of developing non-small cell lung cancer (NSCLC), yet the underlying causes remain unclear.

Methods: We performed whole genome scans in lung tumours of cRaf transgenic mice and identified miRNA, transcription factor and hormone receptor dependent gene regulations. We confirmed hormone receptors by immunohistochemistry and constructed regulatory gene networks by considering experimentally validated miRNA-gene and transcription factor-miRNA/gene targets.

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.

Background: Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment.

Artificial intelligence and real-world data for drug and food safety - A regulatory science perspective.

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net).

Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury-A Repeated Dose Study in Minipigs for 28 Days.

Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment.

Petasites for Migraine Prevention: New Data on Mode of Action, Pharmacology and Safety. A Narrative Review.

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons.

Reliable miRNA biomarker quantification in clinical practice - are we there yet?

Blood-borne miRNAs serve as disease diagnostic biomarkers and await clinical validation. Here, we evaluated Cel-miR-39-3p and miRNA16-5p as calibrator for the quantification of 15 miRNAs linked to hepatic impairment. We added defined copy numbers of Cel-miR-39-3p to plasma of healthy controls (N = 5) and patient samples undergoing liver resection (N = 51).

A systematic comparison of hepatobiliary adverse drug reactions in FDA and EMA drug labeling reveals discrepancies.

Drug labeling informs physicians and patients on the safe and effective use of medication. However, recent studies suggested discrepancies in labeling of the same drug between different regulatory agencies. Here, we evaluated the hepatic safety information in labeling for 549 medications approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Advances in Liver Cancer Stem Cell Isolation and their Characterization.

Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e.

miRNAs in lung cancer. A systematic review identifies predictive and prognostic miRNA candidates for precision medicine in lung cancer.

Lung cancer (LC) is the leading cause of cancer-related death worldwide and miRNAs play a key role in LC development. To better diagnose LC and to predict drug treatment responses we evaluated 228 articles encompassing 16,697 patients and 12,582 healthy controls. Based on the criteria of ≥3 independent studies and a sensitivity and specificity of >0.

Cancer genomics predicts disease relapse and therapeutic response to neoadjuvant chemotherapy of hormone sensitive breast cancers.

Several studies provide insight into the landscape of breast cancer genomics with the genomic characterization of tumors offering exceptional opportunities in defining therapies tailored to the patient's specific need. However, translating genomic data into personalized treatment regimens has been hampered partly due to uncertainties in deviating from guideline based clinical protocols. Here we report a genomic approach to predict favorable outcome to treatment responses thus enabling personalized medicine in the selection of specific treatment regimens.

An adverse outcome pathway for immune-mediated and allergic hepatitis: a case study with the NSAID diclofenac.

Many drugs have the potential to cause drug-induced liver injury (DILI); however, underlying mechanisms are diverse. The concept of adverse outcome pathways (AOPs) has become instrumental for risk assessment of drug class effects. We report AOPs specific for immune-mediated and drug hypersensitivity/allergic hepatitis by considering genomic, histo- and clinical pathology data of mice and dogs treated with diclofenac.

The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis.

Recent evidence suggests herbal-induced liver injury (HILI) to account for 20% of cases among the U.S. Drug-Induced-Liver-Injury-Network.

Hepatobiliary Events in Migraine Therapy with Herbs-The Case of Petadolex, A Petasites Hybridus Extract.

Petadolex, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4-730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3-153; AST 2-104-fold ULN).

Correction: Oncogenomics of c-Myc transgenic mice reveal novel regulators of extracellular signaling, angiogenesis and invasion with clinical significance for human lung adenocarcinoma.

[This corrects the article DOI: 10.18632/oncotarget.21981.

Genomics of lipid-laden human hepatocyte cultures enables drug target screening for the treatment of non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a major health burden in need for new medication. To identify potential drug targets a genomic study was performed in lipid-laden primary human hepatocyte (PHH) and human hepatoma cell cultures.

Methods: PHH, HuH7 and HepG2 hepatoma cell cultures were treated with lipids and/or TNFα.

The Development of a Database for Herbal and Dietary Supplement Induced Liver Toxicity.

The growing use of herbal dietary supplements (HDS) in the United States provides compelling evidence for risk of herbal-induced liver injury (HILI). Information on HDS products was retrieved from MedlinePlus of the U.S.

Serum proteome mapping of EGF transgenic mice reveal mechanistic biomarkers of lung cancer precursor lesions with clinical significance for human adenocarcinomas.

Atypical adenomatous hyperplasia (AAH) of the lung is a pre-invasive lesion (PL) with high risk of progression to lung cancer (LC). However, the pathways involved are uncertain. We searched for novel mechanistic biomarkers of AAH in an EGF transgenic disease model of lung cancer.