CAR T cell-based immunotherapy and radiation therapy: potential, promises and risks.

CAR T cell-based therapies have revolutionized the treatment of hematological malignancies such as leukemia and lymphoma within the last years. In contrast to the success in hematological cancers, the treatment of solid tumors with CAR T cells is still a major challenge in the field and attempts to overcome these hurdles have not been successful yet. Radiation therapy is used for management of various malignancies for decades and its therapeutic role ranges from local therapy to a priming agent in cancer immunotherapy. Combinations of radiation with immune checkpoint inhibitors have already proven successful in clinical trials. Therefore, a combination of radiation therapy may have the potential to overcome the current limitations of CAR T cell therapy in solid tumor entities. So far, only limited research was conducted in the area of CAR T cells and radiation. In this review we will discuss the potential and risks of such a combination in the treatment of cancer patients.

Moving Research-Based Learning in Life Sciences Upstream, and Beyond Borders: An International Group Research Project for High School Youth.

International cooperation beyond borders, institutions, and intergenerationally is an important aspect of science and research-based learning. Timing of learning also matters. Early exposure to group research-based learning can potentially have lasting positive impacts on youth and their careers in life sciences. Here, we report our work on the International Group Project (IGP), which builds on the International Biology Olympiad (IBO) organized in Yerevan, Armenia, in 2022. The IBO is an annual international competition for high school students held since 1990 around the world. We envisioned the IGP as a novel opportunity for life sciences research-based education among youth. We formed diverse IGP research teams 2 months before the IBO, and comprised high school students from 32 countries, communicating in a digital environment via videoconferencing. Each team formulated a research question in an IGP theme from five domains of life sciences: "Biomedicine," "Molecular and cell biology," "Bioinformatics and Artificial Intelligence," "Bionics and Biomimicry," "Across Species." Subsequently, team members collectively solved their research question by applying life sciences methodologies under supervision from a facilitator scientist. Each team created a poster based on their research and presented in-person to the public at a satellite activity at the IBO. A special subcommittee of the IBO International Jury graded posters and allocated prizes based on scientific ingenuity and presentation quality. This experience from the IGP lends evidence to the feasibility of research-based learning in life sciences for high school youth beyond borders. Moving research-based learning upstream and internationally is well poised to advance 21st century life sciences from both interdisciplinary and intergenerational standpoints. The historic impact of the COVID-19 pandemic suggests that youth engagement in research-based learning and innovation in life sciences is timely.

Tumour mutations in long noncoding RNAs enhance cell fitness.

Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic "driver" mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness.

DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions.

The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire.