Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted

/pdf/cholangiocarcinoma-2020-the-next-horizon-in-mechanisms-and-4ua2gtq2hw.pdf

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids - which are stem cell-derived 3D culture systems - it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.

/pdf/human-organoids-model-systems-for-human-biology-and-medicine-3jnss0v9ch.pdf

Human organoids: model systems for human biology and medicine.

The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. In this Review, we evaluate tumour organoid protocols and how they can be utilized as an alternative model for cancer research.

Organoids in cancer research

Predicting the effects of drugs before human clinical trials is at the heart of drug screening and discovery processes. The cost of drug discovery is steadily increasing owing to the limited predictability of 2D cell culture and animal models. The convergence of microfabrication and tissue engineering gave rise to organ-on-a-chip technologies, which offer an alternative to conventional preclinical models for drug screening. Organ-on-a-chip devices can replicate key aspects of human physiology crucial for the understanding of drug effects, improving preclinical safety and efficacy testing. In this Review, we discuss how organ-on-a-chip technologies can recreate functions of organs, focusing on tissue barrier properties, parenchymal tissue function and multi-organ interactions, which are three key aspects of human physiology. Specific organ-on-a-chip systems are examined in terms of cell sources, functional hallmarks and available disease models. Finally, we highlight the challenges that need to be overcome for the clinical translation of organ-on-a-chip devices regarding materials, cellular fidelity, multiplexing, sensing, scalability and validation. Organ-on-a-chip devices can recreate key aspects of human physiology in vitro, offering an alternative to animal models for preclinical drug testing. This Review examines how tissue barrier properties, parenchymal tissue function and multi-organ interactions can be recreated in organ-on-a-chip systems and applied for drug screening.

Advances in organ-on-a-chip engineering

A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.

/pdf/human-primary-liver-cancer-derived-organoid-cultures-for-cbieemhnh7.pdf

Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

Mitochondria are cellular organelles that produce energy in the form of ATP. For this reason, they are called “power stations” or “energy factories”. Mitochondria have their own DNA. Part of mitochondrial DNA in the process of phylogenesis moved into nuclear DNA.

/pdf/mitochondrial-disorders-and-their-correction-in-neurological-1qura19p.pdf

Mitochondrial disorders and their correction in neurological pathology

Mitochondria are cellular organelles that produce energy in the form of ATP. For this reason, they are called "power stations" or "energy factories". Mitochondria have their DNA. Part of mitochondrial DNA in the process of phylogenesis moved into nuclear DNA. There are 4 types of metabolism in mitochondria: a) Transfer of electrons in the respiratory chain with the formation of ATP and oxygen, b) Fat metabolism with the participation of carnitine, c) Amino acid metabolism, d) Carbohydrate metabolism. There are 2 groups of mitochondrial pathology: Primary mitochondrial pathology is hereditary syndromes caused by mutations in genes responsible for mitochondrial proteins (Kearns-Sayre syndrome, Pearson syndrome, MELAS syndrome, MERRF syndrome, and others). Secondary mitochondrial pathology includes dysfunction of mitochondria as an important link in pathogenesis. Primary mitochondrial diseases are caused by mutations in mitochondrial DNA or nuclear DNA that affect the respiratory chain or mtDNA homeostasis. Secondary mitochondrial disorders have been identified in common sporadic neurological diseases, including Alzheimer's disease, Parkinson's disease, and other pathologies. ASEAN Journal of Psychiatry, Vol. 23(1) January, 2022; 1-9.

Mitochondrial disorders and their correction in neurological diseases

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Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

Mitochondrial disorders and their correction in neurological pathology

Mitochondrial disorders and their correction in neurological diseases