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Dr. Pieter Borger
Swiss Hepato-Pancreatico-Biliary and Transplantation Center, Department of Surgery & Transplantation, University Hospital Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland

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0 Protein Analysis
0 Signaling Pathways
0 Adaptive Evolution
0 RNA analysis
0 Transposable Elements Genetics

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Original research article
Published: 19 November 2019 in Frontiers in Oncology
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Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown. Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4–5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity. Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes. Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection—it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.

ACS Style

Pieter Borger; Marcel André Schneider; Lukas Frick; Magda Langiewicz; Maksim Sorokin; Anton Buzdin; Ekaterina Kachaylo; Rolf Graf; Bostjan Humar; Pierre-Alain Clavien. Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration. Frontiers in Oncology 2019, 9, 1206 .

AMA Style

Pieter Borger, Marcel André Schneider, Lukas Frick, Magda Langiewicz, Maksim Sorokin, Anton Buzdin, Ekaterina Kachaylo, Rolf Graf, Bostjan Humar, Pierre-Alain Clavien. Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration. Frontiers in Oncology. 2019; 9 ():1206.

Chicago/Turabian Style

Pieter Borger; Marcel André Schneider; Lukas Frick; Magda Langiewicz; Maksim Sorokin; Anton Buzdin; Ekaterina Kachaylo; Rolf Graf; Bostjan Humar; Pierre-Alain Clavien. 2019. "Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration." Frontiers in Oncology 9, no. : 1206.

Opinion
Published: 12 December 2017 in Biology
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In functional genomics studies, research is dedicated to unveiling the function of genes using gene-knockouts, model organisms in which a gene is artificially inactivated. The idea is that, by knocking out the gene, the provoked phenotype would inform us about the function of the gene. Still, the function of many genes cannot be elucidated, because disruption of conserved sequences, including protein-coding genes, often does not directly affect the phenotype. Since the phenomenon was first observed in the early nineties of the last century, these so-called ‘no-phenotype knockouts’ have met with great skepticism and resistance by died-in-the-wool selectionists. Still, functional genomics of the late 20th and early 21st centuries has taught us two important lessons. First, two or more unrelated genes can often substitute for each other; and second, some genes are only present in the genome in a silent state. In the laboratory, the disruption of such genes does not negatively influence reproductive success, and does not show measurable fitness effects of the species. The genes are redundant. Genetic redundancy, one of the big surprises of modern biology, can thus be defined as the condition in which the inactivation of a gene is selectively neutral. The no-phenotype knockout is not just a freak of the laboratory. Genetic variants known as homozygous loss-of-function (HLOF) variants are of considerable scientific and clinical interest, as they represent experiments of nature qualifying as “natural knockouts”. Such natural knockouts challenge the conventional NeoDarwinian appraisal that genetic information is the result of natural selection acting on random genetic variation.

ACS Style

Peter Borger. Natural Knockouts: Natural Selection Knocked Out. Biology 2017, 6, 43 .

AMA Style

Peter Borger. Natural Knockouts: Natural Selection Knocked Out. Biology. 2017; 6 (4):43.

Chicago/Turabian Style

Peter Borger. 2017. "Natural Knockouts: Natural Selection Knocked Out." Biology 6, no. 4: 43.