DNA-Dependent Protein Kinase Inhibitor Peposertib Potentiates the Cytotoxicity of Topoisomerase II Inhibitors in Synovial Sarcoma Models.

Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients.

Synthetic lethality prediction in DNA damage repair, chromatin remodeling and the cell cycle using multi-omics data from cell lines and patients.

Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT.

Deep learning-based tumor microenvironment segmentation is predictive of tumor mutations and patient survival in non-small-cell lung cancer.

Background: Despite the fact that tumor microenvironment (TME) and gene mutations are the main determinants of progression of the deadliest cancer in the world - lung cancer, their interrelations are not well understood. Digital pathology data provides a unique insight into the spatial composition of the TME. Various spatial metrics and machine learning approaches were proposed for prediction of either patient survival or gene mutations from this data.

Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.

Hepatitis B virus (HBV) integration into the host cell genome occurs early on in infection and reportedly induces pro-oncogenic changes in hepatocytes that drive HCC initiation. However, it remains unclear when these changes occur during hepatocarcinogenesis. Extensive expansion of hepatocyte clones with a selective advantage was shown to occur prior to cancer formation during the HBeAg-seroconversion phase of chronic HBV infection.

Cellular Genomic Sites of Hepatitis B Virus DNA Integration.

Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These reported pathways include: induction of chromosomal instability; generation of insertional mutagenesis in key cancer-associated genes; transcription of downstream cancer-associated cellular genes; and/or formation of a persistent source of viral protein expression (particularly HBV surface and X proteins).

Hepatitis B Virus DNA Integration Occurs Early in the Viral Life Cycle in an Infection Model via Sodium Taurocholate Cotransporting Polypeptide-Dependent Uptake of Enveloped Virus Particles.

Chronic infection by hepatitis B virus (HBV) is the major contributor to liver disease worldwide. Though HBV replicates via a nuclear episomal DNA (covalently closed circular DNA [cccDNA]), integration of HBV DNA into the host cell genome is regularly observed in the liver in infected patients. While reported as a prooncogenic alteration, the mechanism(s) and timing of HBV DNA integration are not well understood, chiefly due to the lack of infection models that have detectable integration events.

HBV DNA Integration: Molecular Mechanisms and Clinical Implications.

Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown.

Accumulation of Deleterious Passenger Mutations Is Associated with the Progression of Hepatocellular Carcinoma.

In hepatocellular carcinoma (HCC), somatic genome-wide DNA mutations are numerous, universal and heterogeneous. Some of these somatic mutations are drivers of the malignant process but the vast majority are passenger mutations. These passenger mutations can be deleterious to individual protein function but are tolerated by the cell or are offset by a survival advantage conferred by driver mutations.

Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?

Chronic liver disease causes significant morbidity and mortality through progressive fibrosis, cirrhosis, and liver cancer. The classical theory of fibrogenesis has hepatic stellate cells (HSCs) as the principal and only significant source of abnormal extracellular matrix (ECM). Further, HSCs have the major role in abnormal ECM turnover.

Conceptual models for the initiation of hepatitis B virus-associated hepatocellular carcinoma.

Although chronic hepatitis B virus (HBV) infection is a known risk factor for the development of hepatocellular carcinoma (HCC), the steps involved in the progression from normal liver to HCC are poorly understood. In this review, we apply five conceptual models, previously proposed by Vineis et al. to explain carcinogenesis in general, to explore the possible steps involved in the initiation and evolution of HBV-associated HCC.

Novel aspects of the liver microenvironment in hepatocellular carcinoma pathogenesis and development.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia.