The importance of preclinical models for cholangiocarcinoma drug discovery.

Introduction: Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.

Areas Covered: The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens.

Cerebrovascular risk in rheumatoid arthritis patients: insights from carotid artery atherosclerosis in the Paracelsus 10,000 study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by systemic inflammation. While RA primarily affects the joints, its systemic effects may lead to an increased cerebro- and cardiovascular risk. Atherosclerosis of the carotid arteries is a significant risk factor for cerebrovascular events and serves as a surrogate marker for cardiovascular risk.

The Cdk inhibitor dinaciclib as a promising anti-tumorigenic agent in biliary tract cancer.

Biliary tract cancer (BTC) is a rare malignancy with rising incidence. The therapeutic options are limited and the overall survival remains poor. Cyclin-dependent kinases, drivers of cell cycle and transcription have numerous biological functions and are known to be dysregulated in numerous tumor entities.

HtrA-Dependent E-Cadherin Shedding Impairs the Epithelial Barrier Function in Primary Gastric Epithelial Cells and Gastric Organoids.

Impaired E-cadherin (Cdh1) functions are closely associated with cellular dedifferentiation, infiltrative tumor growth and metastasis, particularly in gastric cancer. The class-I carcinogen () colonizes gastric epithelial cells and induces Cdh1 shedding, which is primarily mediated by the secreted bacterial protease high temperature requirement A (HtrA). In this study, we used human primary epithelial cell lines derived from gastroids and mucosoids from different healthy donors to investigate HtrA-mediated Cdh1 cleavage and the subsequent impact on bacterial pathogenesis in a non-neoplastic context.

NLRP3 promotes allergic responses to birch pollen extract in a model of intranasal sensitization.

Introduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest.

The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study.

Post-hepatectomy liver failure (PHLF) remains the major contributor to death after liver resection. Oxidative stress is associated with postoperative complications, but its impact on liver function is unclear. This first in-human, prospective, single-center, observational pilot study evaluated perioperative oxidative stress and PHLF according to the ISGLS (International Study Group for Liver Surgery).

New insights into possible HDAC inhibitor resistance in DLBCL - Comment on 'defining cellular responses to HDAC-selective inhibitors reveals that efficient targeting of HDAC3 is required to elicit cytotoxicity and overcome naïve resistance to pan-HDACi in diffuse large B cell lymphoma' by Havas et al.

• This editorial provides a brief overview of the role of HDACs in diffuse large B-cell lymphoma (DLBCL). • Possible mechanisms of HDAC inhibitor resistance in DLBCL are discussed in detail. • It highlights the need for developing HDAC isoform-specific inhibitors.

Enhancing anti-CD274 (PD-L1) targeting through combinatorial immunotherapy with bispecific antibodies and fusion proteins: from preclinical to phase II clinical trials.

Introduction: Immune checkpoint inhibitors have achieved great success in the treatment of many different types of cancer. Programmed cell death protein ligand 1 (PD-L1, CD274) is a major immunosuppressive immune checkpoint and a target for several already approved monoclonal antibodies. Despite this, novel strategies are under development, as the overall response remains low.

Gene expression inhibitors for the treatment of liver fibrosis: drugs under preclinical and early clinical investigation.

Introduction: Liver fibrosis represents an unmet medical condition with growing incidence and only limited therapeutic options. Interfering with dysregulated gene expression was considered a specific treatment approach, and we are here reviewing the current options to modulate transcription and translation with small molecule inhibitors of involved enzymes, transcription factors or by using non-coding RNA molecules (RNA interference) or DNA antisense oligonucleotides. Despite promising results in preclinical models, only limited data are available from studies in humans.

An artificial intelligence-based approach for identifying rare disease patients using retrospective electronic health records applied for Pompe disease.

Objective: We retrospectively screened 350,116 electronic health records (EHRs) to identify suspected patients for Pompe disease. Using these suspected patients, we then describe their phenotypical characteristics and estimate the prevalence in the respective population covered by the EHRs.

Methods: We applied Symptoma's Artificial Intelligence-based approach for identifying rare disease patients to retrospective anonymized EHRs provided by the "University Hospital Salzburg" clinic group.

Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer.

Biliary tract cancer (BTC) is a gastrointestinal malignancy associated with a poor survival rate. Current therapies encompass palliative and chemotherapeutic treatment as well as radiation therapy, which results in a median survival of only one year due to standard therapeutic ineffectiveness or resistance. Tazemetostat is an FDA-approved inhibitor of enhancer of Zeste homolog 2 (EZH2), a methyltransferase involved in BTC tumorigenesis via trimethylation of histone 3 at lysine 27 (H3K27me3), an epigenetic mark associated with silencing of tumor suppressor genes.

HDACs as an emerging target in endocrine tumors: a comprehensive review.

Introduction: The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved.

Areas Covered: Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors.

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide.

The 3-triangle method preserves the posterior tibial slope during high tibial valgus osteotomy: first preliminary data using a mathematical model.

Purpose: Despite much improved preoperative planning techniques accurate intraoperative assessment of the high tibial valgus osteotomy (HTO) remains challenging and often results in coronal over- and under-corrections as well as unintended changes of the posterior tibial slope. Noyes et al. reported a novel method for accurate intraoperative coronal and sagittal alignment correction based on a three-dimensional mathematical model.

Chemoresistance and resistance to targeted therapies in biliary tract cancer: what have we learned?

Introduction: Biliary tract cancer (BTC), including intra- and extrahepatic cholangiocarcinoma and gallbladder cancer, is a rare and highly difficult to manage human malignancy. Besides late diagnosis and associated unresectability, frequently observed unresponsiveness toward and recurrence following chemotherapy or targeted therapy essentially contribute to the dismal prognosis of BTC patients.

Areas Covered: The review provides an update on individual mechanisms involved resistance of BTC toward conventional chemotherapy as well as targeted therapies.

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future.

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic "door" to improve outcome and response rate for patients with HCC.

Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail.

Impact of the COVID-19 pandemic lockdown on the utilization of acute surgical care in the State of Salzburg, Austria: retrospective, multicenter analysis.

Background: Some medical disciplines have reported a strong decrease of emergencies during the coronavirus disease 2019 (COVID-19) pandemic; however, the effect of the lockdown on general surgery emergencies remains unclear.

Methods: This study is a retrospective, multicenter analysis of general surgery emergency operations performed during the period from 1 March to 15th 2020 lockdown and in the same time period of 2019 in three medical centers providing emergency surgical care to the area Salzburg-North, Austria.

Results: In total 165 emergency surgeries were performed in the study period of 2020 compared to 287 in 2019.

Antifungal susceptibility of yeast bloodstream isolates collected during a 10-year period in Austria.

Background: Candida-associated infections put a significant burden on western healthcare systems. Development of (multi-)resistant fungi can become untreatable and threaten especially vulnerable target groups, such as the immunocompromised.

Objectives: We assessed antifungal susceptibility and explored possible influence factors of clinical Candida isolates collected from Austrian hospitals between 2007 and 2016.

Mobile Phone-Supported Physiotherapy for Frozen Shoulder: Feasibility Assessment Based on a Usability Study.

Background: Patients with frozen shoulder show limited shoulder mobility often accompanied by pain. Common treatment methods include physiotherapy, pain medication, administration of corticosteroids, and surgical capsulotomy. Frozen shoulder often lasts from months to years and mostly affects persons in the age group of 40 to 70 years.