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Efficacy of cancer immunotherapies relies on correct recognition of tumor antigens by lymphocytes, eliciting thus functional responses capable of eliminating tumor cells. Therefore, important efforts have been carried out in antigen identification, with the aim of understanding mechanisms of response to immunotherapy and to design safer and more efficient strategies. In addition to classical tumor-associated antigens identified during the last decades, implementation of next-generation sequencing methodologies is enabling the identification of neoantigens (neoAgs) arising from mutations, leading to the development of new neoAg-directed therapies. Moreover, there are numerous non-classical tumor antigens originated from other sources and identified by new methodologies. Here, we review the relevance of neoAgs in different immunotherapies and the results obtained by applying neoAg-based strategies. In addition, the different types of non-classical tumor antigens and the best approaches for their identification are described. This will help to increase the spectrum of targetable molecules useful in cancer immunotherapies.

The development of cancer immunology heavily relies on the interaction between long non-coding RNAs (lncRNAs) and molecular chaperones. By participating in gene regulation, lncRNAs interact with molecular chaperones, which play a critical role in protein folding and stress responses, to influence oncogenic pathways. This interaction has an impact on both the immune cells within the tumor microenvironment and the tumor cells themselves. Understanding these mechanisms provides valuable insights into innovative approaches for diagnosis and treatment. Targeting the lncRNA-chaperone axis has the potential to strengthen anti-tumor immunity and enhance cancer treatment outcomes. Further research is necessary to uncover specific associations, identify biomarkers, and develop personalized therapies aimed at disrupting this axis, which could potentially revolutionize cancer diagnosis and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Programmed death protein 1 (PD-1) inhibitors have potent anti-tumor activities. However, they often result in immune-related adverse events (irAEs) of varying severity. Therefore, the factors affecting the incidence of irAEs warrant urgent investigation. This study aimed to identify specific and sensitive predictors of irAEs in a Chinese population. We conducted a genome-wide association study (GWAS) comprising 80 patients with malignant tumors to evaluate single-nucleotide polymorphism (SNP) loci associated with the incidence of irAEs. The SNP rs2157775 on the LOC339166 gene had the lowest P value but did not reach the significance threshold after Bonferroni correction. Therefore, potentially associated SNPs were further investigated through the mechanism-related PD-1 pathway using the ImmPort and PathCards Human Gene Databases. A binary logistic regression model revealed that CD3E (rs3782040) A/A was associated with a lower incidence of irAEs in patients with malignant tumors who received PD-1 inhibitors. In contrast, PTPN11 (rs143894582) C/CA was associated with a higher incidence of irAEs. These findings provide a basis for the verification and identification of new loci to provide insight into the etiology of irAEs., (Copyright © 2024. Published by Elsevier B.V.)

Oxford Nanopore Technologies sequencing, also referred to as Nanopore sequencing, stands at the forefront of a revolution in clinical genetics, offering the potential for rapid, long read, and real-time DNA and RNA sequencing. This technology is currently making sequencing more accessible and affordable. In this comprehensive review, we explore its potential regarding precision cancer diagnostics and treatment. We encompass a critical analysis of clinical cases where Nanopore sequencing was successfully applied to identify point mutations, splice variants, gene fusions, epigenetic modifications, non-coding RNAs, and other pivotal biomarkers that defined subsequent treatment strategies. Additionally, we address the challenges of clinical applications of Nanopore sequencing and discuss the current efforts to overcome them., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cancer neoantigens are tumor-specific non-synonymous mutant peptides that activate the immune system to produce an anti-tumor response. Personalized cancer vaccines based on neoantigens are currently one of the most promising therapeutic approaches for cancer treatment. By utilizing the unique mutations within each patient's tumor, these vaccines aim to elicit a strong and specific immune response against cancer cells. However, the identification of neoantigens remains challenging due to the low accuracy of current prediction tools and the high false-positive rate of candidate neoantigens. Since the concept of "proteogenomics" emerged in 2004, it has evolved rapidly with the increased sequencing depth of next-generation sequencing technologies and the maturation of mass spectrometry-based proteomics technologies to become a more comprehensive approach to neoantigen identification, allowing the discovery of high-confidence candidate neoantigens. In this review, we summarize the reason why cancer neoantigens have become attractive targets for immunotherapy, the mechanism of cancer vaccines and the advances in cancer immunotherapy. Considerations relevant to the application emerging of proteogenomics technologies for neoantigen identification and challenges in this field are described., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

ZBTB7A, alternatively referred to Pokemon, FBI-1, LRF, and OCZF, is classified as a member of POK/ZBTB protein family of transcriptional repressors. ZBTB7A binds to targeted DNA via C-terminal zinc fingers and recruits co-compression complexes through N-terminal BTB ⁄ POZ domain to impede transcription. ZBTB7A regulates a range of fundamental biological processes such as cell proliferation, differentiation and apoptosis, B- and T-lymphocyte fate determination and thymic insulin expression and self-tolerance. Accumulating evidence has demonstrated an important role of ZBTB7A in the initiation and advancement of tumors, thus making ZBTB7A emerge as an appealing target. This review examines the functions and regulatory mechanisms of ZBTB7A in a range of common solid tumors, including hepatocellular carcinoma, breast cancer, prostate cancer and lung cancer, as well as hematological malignancies. Notably, the review concludes with a summary of the recent applications of targeting ZBTB7A in clinical treatments through gene silencing, immunotherapy and chemotherapeutic approaches to halt or slow tumor progression. We focus on the functional role and regulatory mechanisms of ZBTB7A in cancer with the goal of providing new insights for the development of more effective cancer therapeutic strategies., Competing Interests: Declaration of competing interest No potential conflicts of interest were disclosed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

PACIFIC-PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype-guided dosing on severe fluoropyrimidine (FP) and irinotecan-related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild-Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild-Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23-89/34-74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle-1 (96%), average 5-7 days from sample collection. PGx-dosing for DPYD variant allele carriers reduced high-grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01-0.97, p = 0.024). High-grade toxicities among Wild-Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64-1.54, p = 0.490). PGx-dosing reduced FP-related hospitalizations (-22%) and deaths (-3.7%) compared to controls. There were no high-grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Core regulatory circuitry refers to the network of lineage-specific transcription factors regulating expression of both their own coding genes, and that of other transcription factors. Such autoregulatory feedback loops coordinate the transcriptome and epigenome during development and cell fate decisions. This circuitry is hijacked during oncogenesis resulting in cancer cell fate being maintained by lineage-specific transcription factors. Major advances in functional genomics and chemical biology are paving the way for a new generation of cancer therapeutics aimed at disrupting this circuitry through both direct and indirect means. Here we review these critical advances in mechanistic understanding of transcription factor addiction in cancer and how the advent of proteolysis targeting chimeras and CRISPR screen assays are leading the way for a new paradigm in targeted cancer treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The extracellular matrix (ECM) serves as a physical scaffold for tissues that is composed of structural proteins such as laminins, collagens, proteoglycans and fibronectin, forming a three dimensional network, and a wide variety of other matrix proteins with ECM-remodeling and signaling functions. The activity of ECM-associated signaling proteins is tightly regulated. Thus, the ECM serves as a reservoir for water and growth regulatory signals. The ECM architecture is dynamically modulated by multiple serine proteases that process both structural and signaling proteins to regulate physiological processes such as organogenesis and tissue homeostasis but they also contribute to pathological events, especially cancer progression. Here, we review the current literature regarding the role of ECM remodeling by serine proteases (KLKs, uPA, furin, HtrAs, granzymes, matriptase, hepsin) in tumorigenesis., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Progress in understanding nervous system-cancer interconnections has emphasized the functional role of semaphorins (SEMAs) and their receptors, neuropilins (NRPs) and plexins (PLXNs), in cancer progression. SEMAs are a conserved and extensive family of broadly expressed soluble and membrane-associated proteins that were first described as regulators of axon guidance and neural and vascular development. However, recent advances have shown that they can have a dual role in cancer progression, acting either as tumor promoters or suppressors. SEMAs effects result from their interaction with specific co-receptors/receptors NRPs/PLXNs, that have also been described to play a role in cancer progression. They can influence both cancer cells and tumor microenvironment components modulating various aspects of tumorigenesis such as oncogenesis, tumor growth, invasion and metastatic spread or treatment resistance. In this review we focus on the role of these axon guidance signals and their receptors and co-receptors in various aspects of cancer. Furthermore, we also highlight their potential application as novel approaches for cancer treatment in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and degrades premature aberrant transcripts and importantly, it also takes part in gene expression regulation by regulating the endogenous transcripts. NMD distinguishes aberrant and non-aberrant transcript by looking after the NMD signatures such as long 3' UTR. NMD modulates cellular surveillance and eliminates the plausible synthesis of truncated proteins as because if the aberrant mRNA escapes the surveillance pathway it can lead to potential negative phenotype resulting in genetic diseases. NMD involves multiple proteins and any alteration or mutation within these proteins results in various pathophysiological consequences. NMD plays a complex role in cancer, it can either aggravate or downregulates the tumour. Some tumours agitate NMD to deteriorate mRNAs encoding tumour suppressor proteins, stress response proteins and neoantigens. In other case, tumours suppress the NMD to encourage the expression of oncoproteins for tumour growth and survival. In this review, we have shed light on the core and associated proteins of NMD, further summarized the mechanism of the NMD pathway and also described the implications of mutations in NMD factors resulting in severe pathological conditions including neurodevelopmental disorder, effects on male sterility and cancer. Understanding the complexities of NMD regulation and its interaction with other cellular processes can lead to the development of new interventions for various diseases. This review summarizes the current understanding of NMD and its role in controlling various cellular processes in both development and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom., Methods: A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results., Results: After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491)., Conclusions: The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients., Competing Interests: Competing interests: ADB receives laboratory support and consultancy fees from Illumina Inc and Oxford Nanopore. Ethical approval and consent to participate: The current work is a retrospective analysis of participants enroled in the 100,000 genome project in the West Midlands. All data analysed was routinely collected as part of the 100,000 genome project. The 100,000 genome project was approved by the HRA Committee East of England Cambridge South (REC Ref 14/EE/1112). All participants provided written informed consent. All work was conducted in accordance with relevant guidelines and regulations, including Good Clinical Practice and the Declaration of Helsinki’s ethical principles for medical research., (© 2024. The Author(s).)

Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy., Competing Interests: Competing interests: RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd. AH receives research support from Novartis, BMS, Incyte and Pfizer., (© 2024. The Author(s).)

Tumours are composed of tumour cells and the surrounding tumour microenvironment (TME), and the molecular characterisation of the various elements of the TME and their interactions is essential for elucidating the mechanisms of tumour progression and developing better therapeutic strategies. Multiplex imaging is a technique that can quantify the expression of multiple protein markers on the same tissue section while maintaining spatial positioning, and this method has been rapidly developed in cancer research in recent years. Many multiplex imaging technologies and spatial analysis methods are emerging, and the elucidation of their principles and features is essential. In this review, we provide an overview of the latest multiplex imaging techniques by type of imaging and staining method and an introduction to image analysis methods, primarily focusing on spatial cellular properties, providing deeper insight into tumour organisation and spatial molecular biology in the TME., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: After written informed consent was obtained, pathological specimens were obtained from gastric cancer patients who underwent gastrectomy at Kumamoto University Hospital. This study was approved by the Medical Ethics Committee of Kumamoto University (approval number: 1277). Consent for publication: All of the authors reviewed the paper and agreed on its publication., (© 2024. The Author(s).)

Early detection and intervention of cancer or precancerous lesions hold great promise to improve patient survival. However, the processes of cancer initiation and the normal-precancer-cancer progression within a non-cancerous tissue context remain poorly understood. This is, in part, due to the scarcity of early-stage clinical samples or suitable models to study early cancer. In this Review, we introduce clinical samples and model systems, such as autochthonous mice and organoid-derived or stem cell-derived models that allow longitudinal analysis of early cancer development. We also present the emerging techniques and computational tools that enhance our understanding of cancer initiation and early progression, including direct imaging, lineage tracing, single-cell and spatial multi-omics, and artificial intelligence models. Together, these models and techniques facilitate a more comprehensive understanding of the poorly characterized early malignant transformation cascade, holding great potential to unveil key drivers and early biomarkers for cancer development. Finally, we discuss how these new insights can potentially be translated into mechanism-based strategies for early cancer detection and prevention., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Genomic instability is crucial in tumorigenesis, with Tumour Mutation Burden (TMB) being a biomarker to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor and displays heterogeneity. Non-B DNA, susceptible to mutations, play a significant role in cancer development, indicating their potential merit when combined with mutation for enhanced markers in cancer., Methods: We assessed mutations and non-B DNA interplay as biomarkers. Our methodology quantifies tumour mutations and their co-localization with non-B DNA, using survival and drug sensitivity assessments for clinical relevance., Results: We introduce two novel markers, 'nbTMB' (non-B-informed tumour mutation burden) and 'mlTNB' (mutation-localised tumour non-B burden). In case studies: (1) nbTMB informs on survival heterogeneity among TMB-high patients undergoing immunotherapy whereas TMB is unable to further differentiate; (2) nbTMB informs on altered cisplatin sensitivity among ovarian cancer cell lines whereas TMB is unable to differentiate; and (3) mlTNB informs on survival heterogeneity among early-stage pancreatic cancer progressors in whom other markers of genomic instability fail to differentiate., Conclusions: These novel markers offer a nuanced approach to enhance our understanding of treatment responses and outcomes in cancer, underscoring the need for a comprehensive exploration of the interplay between non-B and B-DNA features., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The LMNA gene, which is responsible for encoding lamin A/C proteins, is recognized as a primary constituent of the nuclear lamina. This protein serves crucial roles in various cellular physiological activities, including the maintenance of cellular structural stability, regulation of gene expression, mechanosensing and cellular motility. A significant association has been established between the LMNA gene and several major human diseases. Mutations, dysregulated expression of the LMNA gene, and improper processing of its encoded protein can result in a spectrum of pathological conditions. These diseases, collectively termed laminopathies, are directly attributed to LMNA gene dysfunction. The present review examines the recent advancements in research concerning the LMNA gene and its association with human diseases, while exploring its pathological roles. Particular emphasis is placed on the current status of LMNA gene research in the context of tumors. This includes an analysis of the abundance of LMNA alterations in cancer and its interplay with various signaling pathways. The aim of the present review was to provide novel perspectives for studying the development of LMNA‑related diseases and additional theoretical insights for basic and clinical translational research in this field.

Salt‑induced kinase 1 (SIK1) is a serine/threonine protein kinase that is a member of the AMP‑activated protein kinase family. SIK is catalytically activated through its phosphorylation by the upstream kinase LKB1. SIK1 has been reported to be associated with numerous types of cancer. The present review summarizes the structure, regulatory factors and inhibitors of SIK1, and also describes how SIK1 is a signal regulatory factor that fulfills connecting roles in various signal regulatory pathways. Furthermore, the anti‑inflammatory effects of SIK1 during the early stage of tumor occurrence and its different regulatory effects following tumor occurrence, are summarized, and through collating the tumor signal regulatory mechanisms in which SIK1 participates, it has been demonstrated that SIK1 acts as a necessary node in cancer signal transduction. In conclusion, SIK1 is discussed independent of the SIKs family, its research results and recent progress in oncology are summarized in detail with a focus on SIK1, and its potential as a therapeutic target is highlighted, underscoring the need for SIK1‑targeted regulatory strategies in future cancer therapy.

Collagen type X α1 chain ( COL10A1 ), a gene encoding the α‑1 chain of type X collagen, serves a key role in conferring tensile strength and structural integrity to tissues. Upregulation of COL10A1 expression has been observed in different malignancies, including lung, gastric and pancreatic cancer, and is associated with poor prognosis. The present review provides an updated synthesis of the evolving biological understanding of COL10A1, with a particular focus on its mechanisms of action and regulatory functions within the context of tumorigenesis. For example, it has been established that increased COL10A1 expression promotes cancer progression by activating multiple signaling pathways, including the TGF‑β1/Smad, MEK/ERK and focal adhesion kinase signaling pathways, thereby inducing proliferation, invasion and migration. Additionally, COL10A1 has been demonstrated to induce epithelial‑mesenchymal transition and reshapes the extracellular matrix within tumor tissues. Furthermore, on the basis of methyltransferase‑like 3‑mediated N6‑methyladenosine methylation, COL10A1 intricately regulates the epitranscriptomic machinery, thereby augmenting its oncogenic role. However, although COL10A1 serves a pivotal role in gene transcription and the orchestration of tumor growth, the question of whether COL10A1 would serve as a viable therapeutic target remains a subject of scientific hypothesis requiring rigorous examination. Variables such as distinct tumor microenvironments and treatment associations necessitate further experimental validation. Therefore, a comprehensive assessment and understanding of the functional and mechanistic roles of COL10A1 in cancer may pave the way for the development of innovative cancer treatment strategies.

SPARC/osteonectin, CWCV and Kazal‑like domain proteoglycan (SPOCK) is a family of highly conserved multidomain proteins. In total, three such family members, SPOCK1 , SPOCK2 and SPOCK3 , constitute the majority of extracellular matrix glycoproteins. The SPOCK gene family has been demonstrated to serve key roles in tumor regulation by affecting MMPs, which accelerates the progression of cancer epithelial‑mesenchymal transition. In addition, they can regulate the cell cycle via overexpression, inhibit tumor cell proliferation by inactivating PI3K/AKT signaling and have been associated with numerous microRNAs that influence the expression of downstream genes. Therefore, the SPOCK gene family are potential cancer‑regulating genes. The present review summarizes the molecular structure, tissue distribution and biological function of the SPOCK family of proteins, in addition to its association with cancer. Furthermore, the present review documents the progress made in investigations into the role of SPOCK, whilst also discussing prospects for the future of SPOCK‑targeted therapy, to provide novel ideas for clinical application and treatment.

Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens., Competing Interests: Competing interests: J.V. is a member of the Advisory Boards of Remix Therapeutics, Stoke Therapeutics and IntronX. K.M.W. is an adviser to and holds equity in Ribometrix, ForagR Medicines and A-Form Solutions. O.A. is a member of the Advisory Boards of Caeruleus Genomics., (© 2024. Springer Nature Limited.)

Only a limited number of tumour biomarkers are currently available in veterinary medicine, particularly in cats. Cell-free DNA (cfDNA) is an extracellular DNA fragment released upon cell death and is considered a minimally invasive biomarker for the diagnosis and monitoring of various human malignancies. This study aimed to clarify the utility of circulating cfDNA as a liquid biopsy for various feline tumours. Plasma samples were collected from 44 cats with various tumours, 24 cats with other diseases and 10 healthy controls. A follow-up study was conducted in three tumour-bearing patients. All cfDNA concentrations were quantified via real-time polymerase chain reaction (PCR), which provided short and long fragments of a newly identified feline LINE-1 gene. We found that cfDNA levels were significantly higher in cats with various tumours than in those with other diseases or healthy controls. The cfDNA concentration was not correlated with serum amyloid A (SAA) levels. Cats with tumours exhibited elevated cfDNA levels that predicted tumour-bearing with a sensitivity and specificity of 50.5% and 91.2%, respectively (AUC 0.736; p < 0.001). In lymphoma cases, cats with high cfDNA levels had significantly shorter survival times than those with low cfDNA levels (median: 33 days vs. 178 days; p = 0.003). In addition, the cfDNA levels of the three patients correlated with clinical status during follow-up. Collectively, these findings indicate the potential of cfDNA as a useful biomarker for the diagnosis, therapeutic monitoring and prognostic assessment of tumours in cats., (© 2024 John Wiley & Sons Ltd.)

The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the US Food and Drug Administration for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer remains a leading cause of death worldwide and although prognosis and survivorship after therapy have improved significantly, current cancer treatments have long-term health consequences. For decades telomerase-mediated telomere maintenance has been an attractive anti-cancer therapeutic target due to its abundance and role in telomere maintenance, pathogenesis, and growth in neoplasms. Telomere maintenance-specific cancer therapies, however, are marred by off-target side effects that must be addressed before they reach clinical practice. Regular exercise training is associated with telomerase-mediated telomere maintenance in normal cells, which is associated with healthy aging. A single bout of endurance exercise training dynamically, but temporarily, increases TERT mRNA and telomerase activity, as well as several molecules that control genomic stability and telomere length (i.e., shelterin and TERRA). Considering the epidemiological findings and accumulating research highlighting that exercise significantly reduces the risk of many types of cancers and the anti-carcinogenic effects of exercise on tumor growth in vitro , investigating the governing molecular mechanisms of telomerase control in context with exercise and cancer may provide important new insights to explain these findings. Specifically, the molecular mechanisms controlling telomerase in both healthy cells and tumors after exercise could reveal novel therapeutic targets for tumor-specific telomere maintenance and offer important evidence that may refine current physical activity and exercise guidelines for all stages of cancer care.

Clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) are recently recognized diagnostic entities that serve as independent risk factors for cardiovascular disease and myeloid malignancy. CH is an incidental finding, and evaluation of the incidence of CH/CCUS-associated mutations in solid tumor next-generation sequencing samples was undertaken to better understand the prevalence of mutations in this population. A retrospective review of clinical sequencing data for solid tumor malignancies diagnosed between February 2022 and April 2023 on next-generation sequencing data was performed. Cases were reviewed for variants in genes associated with CH/CCUS. Variant allele frequencies and other factors of the sequencing data were assessed for determining risk of CH/CCUS. A total of 2479 cases were evaluated during the study period. Of these, 29 cases demonstrated potential CH/CCUS-associated mutations, with a total of 33 variants identified. These were identified in a variety of tumor types, with gliomas being the most common. Significant cardiac histories were found in over half of cases identified, and few cases had abnormal blood counts. Detailed criteria for flagging variants as suspicious for CH and recommendations for these criteria as future guidelines for reporting are described. These variants are incidental findings that require more extensive follow-up or change in therapy management using a single institutional cohort., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins (IGF2BP1-3), is expressed in a broad range of fetal tissues, placenta and more than sixteen cancer types but only in a limited number of normal adult tissues. IGF2BP1is required for the transport from nucleus to cytoplasm of certain mRNAs that play essential roles in embryogenesis, carcinogenesis, and multidrug resistance (MDR), by affecting their stability, translation, or localization. The purpose of this review is to gather and present information on MDR mechanisms in cancer and the significance of IGF2BP1 in this context. Within this review, we will provide an overview of IGF2BP1, including its tissue distribution, expression, molecular targets in the context of tumorigenesis and its inhibitors. Our main focus will be on elucidating the interplay between IGF2BP1 and MDR, particularly with regard to chemoresistance mediated by ABC transporters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Genome DNA methylation profiling is a promising yet costly method for cancer classification, involving substantial data. We developed an ensemble learning model to identify cancer types using methylation profiles from a limited number of CpG sites., Methods: Analyzing methylation data from 890 samples across 10 cancer types from the TCGA database, we utilized ANOVA and Gain Ratio to select the most significant CpG sites, then employed Gradient Boosting to reduce these to just 100 sites., Results: This approach maintained high accuracy across multiple machine learning models, with classification accuracy rates between 87.7% and 93.5% for methods including Extreme Gradient Boosting, CatBoost, and Random Forest. This method effectively minimizes the number of features needed without losing performance, helping to classify primary organs and uncover subgroups within specific cancers like breast and lung., Conclusions: Using a gradient boosting feature selector shows potential for streamlining methylation-based cancer classification., Competing Interests: Declarations. Conflict of interest: MAV received research funds from AstraZeneca. HH received lecture fees or honoraria from AstraZeneca, Bristol Myers Squibb, Amgen, Chugai Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, and Pfizer Japan, and research funds from PAREXEL International, Japan Clinical Research Operations, Daiichi Sankyo, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Sysmex, Ono Pharmaceutical, Takeda Pharmaceutical, PPD-SNBL, Nippon Boehringer Ingelheim, SYNEOS HEALTH CLINICAL, IQVIA Services JAPAN, Covance Japan, GlaxoSmithKline, Sanofi and EPS, and scholarship from Chugai Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Eisai. KN received lecture fee from Chugai Pharmaceutical, and research funds from Nippon Boehringer Ingelheim, Clinical Research Support Center Kyushu, West Japan Oncology Group, Nichirei Biosciences, Osakaminami Hospital, Eli Lilly Japan, Hitachi, and Otsuka Pharmaceutical. Kazuto Nishio is an editorial board member of Cancer Science. The other authors have no conflict of interest. Ethical approval: The research protocol was approved by the Ethical Review Board of Kindai University Faculty of Medicine (R05-006)., (© 2024. The Author(s).)

Background and Objective: Accurate prognosis prediction for cancer patients plays a significant role in the formulation of treatment strategies, considerably impacting personalized medicine. Recent advancements in this field indicate that integrating information from various modalities, such as genetic and clinical data, and developing multi-modal deep learning models can enhance prediction accuracy. However, most existing multi-modal deep learning methods either overlook patient similarities that benefit prognosis prediction or fail to effectively capture diverse information due to measuring patient similarities from a single perspective. To address these issues, a novel framework called multi-modal multi-view graph convolutional networks (MMGCN) is proposed for cancer prognosis prediction., Methods: Initially, we utilize the similarity network fusion (SNF) algorithm to merge patient similarity networks (PSNs), individually constructed using gene expression, copy number alteration, and clinical data, into a fused PSN for integrating multi-modal information. To capture diverse perspectives of patient similarities, we treat the fused PSN as a multi-view graph by considering each single-edge-type subgraph as a view graph, and propose multi-view graph convolutional networks (GCNs) with a view-level attention mechanism. Moreover, an edge homophily prediction module is designed to alleviate the adverse effects of heterophilic edges on the representation power of GCNs. Finally, comprehensive representations of patient nodes are obtained to predict cancer prognosis., Results: Experimental results demonstrate that MMGCN outperforms state-of-the-art baselines on four public datasets, including METABRIC, TCGA-BRCA, TCGA-LGG, and TCGA-LUSC, with the area under the receiver operating characteristic curve achieving 0.827 ± 0.005, 0.805 ± 0.014, 0.925 ± 0.007, and 0.746 ± 0.013, respectively., Conclusions: Our study reveals the effectiveness of the proposed MMGCN, which deeply explores patient similarities related to different modalities from a broad perspective, in enhancing the performance of multi-modal cancer prognosis prediction. The source code is publicly available at https://github.com/ping-y/MMGCN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artificial Intelligence (AI) has made significant strides due to advancements in processing algorithms and data availability. Recent years have shown a resurgence in AI, driven by breakthroughs in deep machine learning. AI has attracted particular interest in the medical sector, especially in the field of personalized medicine, which for example uses large-scale genomic and molecular data to predict individual patient treatment responses. The applications of AI in disease diagnosis, monitoring, and treatment are expanding rapidly, leading to a growing number of registered trials. Therefore, this study aimed to identify and evaluate clinical trials registered between January 1st 2016, and September 30th 2023 that connect AI and cancer. Our findings show that the number of clinical trials linking AI with cancer research has grown significantly compared to other diseases, with colorectal and breast tumour types showing the highest number of registered trials. The most frequent intervention was disease diagnosis and monitoring. Regarding countries, China and the United States hold the highest numbers of registered trials. In conclusion, oncology is a field with a great interest in AI, where the developed countries are leading the studies in this field. Unfortunately, developing countries are still crawling in this aspect and government policies should be made to improve that area., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests or personal relationships that could have influenced the work carried out in this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

MCM10 plays a vital role in genome duplication and is crucial for DNA replication initiation, elongation, and termination. It coordinates several proteins to assemble at the fork, form a functional replisome, trigger origin unwinding, and stabilize the replication bubble. MCM10 overexpression is associated with increased aggressiveness in breast, cervical, and several other cancers. Disruption of MCM10 leads to altered replication timing associated with initiation site gains and losses accompanied by genome instability. Knockdown of MCM10 affects the proliferation and migration of cancer cells, manifested by DNA damage and replication fork arrest, and has recently been shown to be associated with clinical conditions like CNKD and RCM. Loss of MCM10 function is associated with impaired telomerase activity, leading to the accumulation of abnormal replication forks and compromised telomere length. MCM10 interacts with histones, aids in nucleosome assembly, binds BRCA2 to maintain genome integrity during DNA damage, prevents lesion skipping, and inhibits PRIMPOL-mediated repriming. It also interacts with the fork reversal enzyme SMARCAL1 and inhibits fork regression. Additionally, MCM10 undergoes several post-translational modifications and contributes to transcriptional silencing by interacting with the SIR proteins. This review explores the mechanism associated with MCM10's multifaceted role in DNA replication initiation, chromatin organization, transcriptional silencing, replication stress, fork stability, telomere length maintenance, and DNA damage response. Finally, we discuss the role of MCM10 in the early detection of cancer, its prognostic significance, and its potential use in therapeutics for cancer treatment., Competing Interests: Declarations Ethical approval Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Accurate identification of cancer subtypes is crucial for disease prognosis evaluation and personalized patient management. Recent advances in computational methods have demonstrated that multi-omics data provides valuable insights into tumor molecular subtyping. However, the high dimensionality and small sample size of the data may result in ambiguous and overlapping cancer subtypes during clustering. In this study, we propose a novel contrastive-learning-based approach to address this issue. The proposed end-to-end deep learning method can extract crucial information from the multi-omics features by self-supervised learning for patient clustering., Results: By applying our method to nine public cancer datasets, we have demonstrated superior performance compared to existing methods in separating patients with different survival outcomes (p < 0.05). To further evaluate the impact of various omics data on cancer survival, we developed an XGBoost classification model and found that mRNA had the highest importance score, followed by DNA methylation and miRNA. In the presented case study, our method successfully clustered subtypes and identified 14 cancer-related genes, of which 12 (85.7%) were validated through literature review., Conclusions: Our findings demonstrate that our method is capable of identifying cancer subtypes that are both statistically and biologically significant. The code about COLCS is given at: https://github.com/Mercuriiio/COLCS ., (© 2024. International Association of Scientists in the Interdisciplinary Areas.)

Tumors pose a major threat to human health, accounting for nearly one-sixth of global deaths annually. The primary treatments include surgery, radiotherapy, chemotherapy, and immunotherapy, each associated with significant side effects. This has driven the search for new therapies with fewer side effects and greater specificity. Nanotechnology has emerged as a promising field in this regard, particularly nanomolecular machines at the nanoscale. Nanomolecular machines are typically constructed from biological macromolecules like proteins, DNA, and RNA. These machines can be programmed to perform specialized tasks with precise instructions. Recent research highlights their potential in tumor diagnostics-identifying susceptibility genes, detecting viruses, and pinpointing tumor markers. Nanomolecular machines also offer advancements in tumor therapy. They can reduce traditional treatment side effects by delivering chemotherapy drugs and enhancing immunotherapy, and they support innovative treatments like sonodynamic and phototherapy. Additionally, they can starve tumors by blocking blood vessels, and eliminate tumors by disrupting cell membranes or lysosomes. This review categorizes and explains the latest achievements in molecular machine research, explores their models, and practical clinical uses in tumor diagnosis and treatment. It aims to broaden the research perspective and accelerate the clinical adoption of these technologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The current constraints associated with cancer diagnosis and molecular profiling, which rely on invasive tissue biopsies or clinical imaging, have spurred the emergence of the liquid biopsy field. Liquid biopsy involves the extraction of circulating tumor cells (CTCs), circulating free or circulating tumor DNA (cfDNA or ctDNA), circulating cell-free RNA (cfRNA), extracellular vesicles (EVs), and tumor-educated platelets (TEPs) from bodily fluid samples. Subsequently, these components undergo molecular characterization to identify biomarkers that are critical for early cancer detection, prognosis, therapeutic assessment, and post-treatment monitoring. These innovative biosources exhibit characteristics analogous to those of the primary tumor from which they originate or interact. This review comprehensively explores the diverse technologies and methodologies employed for processing these biosources, along with their principal clinical applications.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 10 9 /L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; p  < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival ( p  < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; p  = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

Rationale & Objective: Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear., Study Design: Two-sample Mendelian randomization (MR)., Setting & Participants: Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329)., Exposure: eGFR and UACR., Outcome: Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence., Analytical Approach: Univariable and multivariable MR conducted for all outcomes., Results: The mean eGFR and median UACR were 91.4mL/min/1.73m 2 and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m 2 and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR., Limitations: To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification., Conclusions: Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death., Plain-Language Summary: Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian randomization analysis. Mendelian randomization uses the random assignment of genetic variants at birth to investigate causal relationships without confounding from measured and unmeasured confounders. We found that there is no evidence of a causal relationship between reduced kidney function and cancer., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have been helpful in identifying genetic variants predicting cancer risk and providing new insights into cancer biology. Increasing use of genetically informed care, as well as genetically informed prevention and treatment strategies, have also drawn attention to some of the inherent limitations of cancer genetic data. Specifically, genetic endowment is lifelong. However, those recruited into cancer studies tend to be middle-aged or older people, meaning the exposure most likely starts before recruitment, as opposed to exposure and recruitment aligning, as in a trial or a target trial. Studies in survivors can be biased as a result of depletion of the susceptibles, here specifically due to genetic vulnerability and the cancer of interest or a competing risk. In addition, including prevalent cases in a case-control study will make the genetics of survival with cancer look harmful (Neyman bias). Here, we describe ways of designing GWAS to maximize explanatory power and predictive utility, by reducing selection bias due to only recruiting survivors and reducing Neyman bias due to including prevalent cases alongside using other techniques, such as selection diagrams, age-stratification, and Mendelian randomization, to facilitate GWAS interpretability and utility., (© 2024 Wiley Periodicals LLC.)

Tumor cell-derived extracellular vesicles (TEVs) contain numerous cellular molecules and are considered potential biomarkers for non-invasive liquid biopsy. However, due to the low abundance of TEVs secreted by tumor cells and their phenotypic heterogeneity, there is a lack of sensitive and specific methods to quantify TEVs. Here, we developed a dual-aptamer proximity ligation-coupled hybridization chain reaction (HCR) method for tracing TEVs, exploiting CRISPR to achieve highly sensitive detection. Taking advantage of the high binding affinity of aptamers, the two aptamers (Apt EpCAM , Apt HER2 ) exhibited the high selectivity for TEVs recognition. HCR generated long-repeated sequence containing multiple crRNA targetable barcodes, and the signals were further amplified by CRISPR upon recognizing the HCR sequences, thereby enhancing the sensitivity. Under optimal conditions, the developed method demonstrated a favorable linear relationship in the range of 2 × 10 3 -10 7 particles/μL, with a limit of detection (LOD) of 3.3 × 10 2 particles/μL. We directly applied our assay to clinical plasma analysis, achieving 100 % accuracy in cancer diagnosis, thus demonstrating the potential clinical applications of TEVs. Due to its simplicity and rapidity, excellent sensitivity and specificity, this method has broad applications in clinical medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer remains a major global health concern with high mortality rates mainly due to late diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression in human cancer, functioning through various mechanisms including as competing endogenous RNAs (ceRNAs) and indirectly regulating miRNA expression. LncRNAs have been found to have both oncogenic and tumor-suppressive roles in cancer, with the former promoting cancer cell proliferation, migration, invasion, and poor prognosis. Recent research has shown that lncRNAs are expressed in various immune cells and are involved in cancer cell immune escape and the modulation of the tumor microenvironment, thus highlighting their potential as targets for cancer immunotherapy. Targeting lncRNAs in cancer or immune cells could enhance the anti-tumor immune response and improve cancer immunotherapy outcomes. However, further research is required to fully understand the functional roles of lncRNAs in cancer and the immune system and their potential as targets for cancer immunotherapy. This review offers a comprehensive examination of the multifaceted roles of lncRNAs in human cancers, with a focus on their potential as targets for cancer immunotherapy. By exploring the intricate mechanisms underlying lncRNA-mediated regulation of cancer cell proliferation, invasion, and immune evasion, we provide insights into the diverse therapeutic applications of these molecules., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions., Competing Interests: Competing interests: M.D. is co-inventor of patents held by the Buck Institute for Research on Aging and by Cleara Biotech. M.D. is the scientific cofounder of Cleara Biotech and consultant for Oisin Biotechnologies. The M.D. laboratory currently receives research funding from Ono Pharmaceuticals. J.H.E. holds equity in Unity Biotechnology and Aegeria Soft Tissue and is an adviser for Tessera Therapeutics, HapInScience, and Font Bio., (© 2024. Springer Nature Limited.)

Clinical data from over two decades, involving more than 3000 treated patients, demonstrate that adeno-associated virus (AAV) gene therapy is a safe, effective, and well-tolerated therapeutic method. Clinical trials using AAV-mediated gene delivery to accessible tissues have led to successful treatments for numerous monogenic disorders and advancements in tissue engineering. Although the US Food and Drug Administration (FDA) has approved AAV for clinical use, systemic administration remains a significant challenge. In this review, we delve into AAV biology, focusing on current manufacturing technologies and transgene engineering strategies. We examine the use of AAVs in ongoing clinical trials for ocular, neurological, and hematological disorders, as well as cancers. By discussing recent advancements and current challenges in the field, we aim to provide valuable insights for researchers and clinicians navigating the evolving landscape of AAV-based gene therapy., (© 2024 International Union of Biochemistry and Molecular Biology.)

Diagnosis is the most important step in different diseases, especially in cancers and blood malignancies. There are different methods in order to better diagnose of cancer, but many of them are invasive and also, some of them are not useful for immediate diagnosis. Cell-free DNA (cfDNA) or liquid biopsy easily accessible in peripheral blood is one of the non-invasive prognostic biomarkers in various areas of cancer management. In fact, amounts of cfDNA in serum or plasma can be used for diagnosis. In this review, we have considered some cancers such as hepatocellular carcinoma, lung cancer, breast cancer, and hematologic malignancies to compare the various methods of cfDNA diagnosis., Competing Interests: Declarations Conflict of Interests The authors declare that there are no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Next-generation sequencing (NGS) identifies genetic variants to inform personalized treatment plans. Insufficient evidence of cost-effectiveness impedes the integration of NGS into routine cancer care. The complexity of personalized treatment challenges conventional economic evaluation. Clearly delineating challenges informs future cost-effectiveness analyses to better value and contextualize health, preference-, and equity-based outcomes., Areas Covered: We conducted a scoping review to characterize the applied methods and outcomes of economic evaluations of NGS in oncology and identify existing challenges. We included 27 articles published since 2016 from a search of PubMed, Embase, and Web of Science. Identified challenges included defining the evaluative scope, managing evidentiary limitations including lack of causal evidence, incorporating preference-based utility, and assessing distributional and equity-based impacts. These challenges reflect the difficulty of generating high-quality clinical effectiveness and real-world evidence (RWE) for NGS-guided interventions., Expert Opinion: Adapting methodological approaches and developing life-cycle health technology assessment (HTA) guidance using RWE is crucial for implementing NGS in oncology. Healthcare systems, decision-makers, and HTA organizations are facing a pivotal opportunity to adapt to an evolving clinical paradigm and create innovative regulatory and reimbursement processes that will enable more sustainable, equitable, and patient-oriented healthcare.

Cellular plasticity refers to the ability of cells to change their identity or behavior, which can be advantageous in some cases (e.g., tissue regeneration) but detrimental in others (e.g., cancer metastasis). With a better understanding of cellular plasticity, the complexity of cancer cells, their heterogeneity, and their role in metastasis is being unraveled. The plasticity of the cells could also prove as a nemesis to their characterization. In this review, we have attempted to highlight the possibilities and benefits of using multiomics approach in characterizing the plastic nature of cancer cells. There is a need to integrate fragmented evidence at different levels of cellular organization (DNA, RNA, protein, metabolite, epigenetics, etc.) to facilitate the characterization of different forms of plasticity and cell types. We have discussed the role of cellular plasticity in generating intra-tumor heterogeneity. Different omics level evidence is being provided to highlight the variety of molecular determinants discovered using different techniques. Attempts have been made to integrate some of this information to provide a quantitative assessment and scoring of the plastic nature of the cells. However, there is a huge gap in our understanding of mechanisms that lead to the observed heterogeneity. Understanding of these mechanism(s) is necessary for finding targets for early detection and effective therapeutic interventions in metastasis. Targeting cellular plasticity is akin to neutralizing a moving target. Along with the advancements in precision and personalized medicine, these efforts may translate into better clinical outcomes for cancer patients, especially in metastatic stages., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ankyrin repeat domain 52 (ANKRD52) is a regulatory component of the protein phosphatase 6 (PP6) holoenzyme. Evidence has emerged to suggest involvement of ANKRD52 in tumor metastases and cancer cell escape from T cell-mediated elimination and immunotherapy but there has been no research across different cancer types. The current study explored the biological functions of ANKRD52 by combining data from many databases. The aim was to expose new diagnostic or treatment biomarkers for malignant tumors. The roles of ANKRD52 with respect to immunotherapy in 33 human cancer types were analyzed by combining data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), UCSC Xena, the Tumor Immune Estimation Resource (TIMER), TISIDB and Cellminer. Bioinformatics methods were used to analyze the association between ANKRD52 expression and prognosis, immunological indicators (immune cell infiltration, ESTIMATE scores and tumor microenvironment (TME) signatures), tumor mutational burden (TMB), microsatellite instability (MSI) and drug sensitivity. ANKRD52 expression was generally higher in 24 tumor tissues than in normal tissues and was associated with poor prognosis, especially in kidney chromophobe (KICH). Lower expression was observed in advanced cancer. ANKRD52 expression was strongly linked to major immunological indicators, such as immune cell infiltration, ESTIMATE scores, TME signatures, as well as expression of immune and tumor-related genes. Expression was also associated with indicators of immunotherapy efficacy and outcome, such as TMB in 7 cancer types and MSI in 12. In addition, ANKRD52 expression was linked to sensitivity to a number of anticancer drugs. ANKRD52 had a distinct immune function in breast invasive carcinoma (BRCA) that correlated negatively with most immune indicators. Expression was enriched in proliferation-, differentiation- and metabolism-related pathways and linked to other immune cells and TME signatures. A nomogram to predict 3- or 5-year overall survival (OS) of patients with BRCA was constructed. ANKRD52 may have utility as an oncological and immunological biomarker. New insights into oncogenesis are presented and the development of ANKRD52-targeting to increase the therapeutic efficacy of immunotherapy combined with chemotherapy explored., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long non-coding RNAs (lncRNAs), although incapable of encoding proteins, play crucial roles in multiple layers of gene expression regulation, epigenetic modifications, and post-transcriptional regulation. Zinc finger antisense 1 (ZFAS1), a lncRNA located in the 20q13 region of the human genome, exhibits dual functions as an oncogene or tumor suppressor in various human malignancies. ZFAS1 plays a crucial role in cancer progression, metastasis, invasion, apoptosis, cell cycle regulation, and drug resistance through complex molecular mechanisms. Additionally, ZFAS1 has a long half-life of over 16 h, demonstrating exceptional stability, and making it a potential biomarker. This review integrates recent studies on the role and molecular mechanisms of ZFAS1 in malignancies and summarizes its clinical significance. By summarizing the role of ZFAS1 in cancer, we aim to highlight its potential as an anti-cancer biomarker and therapeutic target., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1 , and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

Background: One of the ailments with the greatest fatality rates in the 21st century is cancer. Globally, molecular methods are widely employed to treat cancer-related disorders, and the body of research on this subject is growing yearly. A thorough and critical summary of the data supporting molecular methods for illnesses linked to cancer is required., Objective: In order to guide clinical practice and future research, it is important to examine and summarize the systematic reviews (SRs) that evaluate the efficacy and safety of molecular methods for disorders associated to cancer., Methods: We developed a comprehensive search strategy to find relevant articles from electronic databases like PubMed, Google Scholar, Web of Science (WoS), or Scopus. We looked through the literature and determined which diagnostic methods in cancer genetics were particularly reliable. We used phrases like 'cancer genetics', genetic susceptibility, Hereditary cancer, cancer risk assessment, 'cancer diagnostic tools', cancer screening', biomarkers, and molecular diagnostics, reviews and meta-analyses evaluating the efficacy and safety of molecular therapies for cancer-related disorders. Research that only consider treatment modalities that don't necessitate genetic or molecular diagnostics fall under the exclusion criteria., Results: The results of this comprehensive review clearly demonstrate the transformative impact of molecular methods in the realm of cancer genetics.This review underscores how these technologies have empowered researchers and clinicians to identify and understand key genetic alterations that drive malignancy, ranging from point mutations to structural variations. Such insights are instrumental in pinpointing critical oncogenic drivers and potential therapeutic targets, thus opening the door for methods in precision medicine that can significantly improve patient outcomes., Limitation: The search does not specify a timeframe for publication inclusion, it may have missed recent advancements or changes in the field's landscape of molecular methods for cancer. As a result, it may not have included the most recent developments in the field., Conclusion: After conducting an in-depth study on the molecular methods in cancer genetics, it is evident that these cutting-edge technologies have revolutionized the field of oncology, providing researchers and clinicians with powerful tools to unravel the complexities of cancer at the genetic level. The integration of molecular methods techniques has not only enhanced our understanding of cancer etiology, progression, and treatment response but has also opened new avenues for personalized medicine and targeted therapies, leading to improved patient outcomes.

Circular RNAs (circRNAs) are endogenous covalently closed single-stranded RNAs produced by reverse splicing of pre-mRNA. Emerging evidence suggests that circRNAs contribute to cancer progression by modulating the oncogenic STAT3 signaling pathway, which plays key roles in human malignancies. STAT3 signaling-related circRNAs expression appears to be extensively dysregulated in diverse cancer types, where they function either as tumor suppressors or oncogenes. However, the biological effects of STAT3 signaling-related circRNAs and their associations with cancer have not been systematically studied before. Given this, shedding light on the interaction between circRNAs and STAT3 signaling pathway in human malignancies may provide several novel insights into cancer therapy. In this review, we provide a comprehensive introduction to the molecular mechanisms by which circRNAs regulate STAT3 signaling in cancer progression, and the crosstalk between STAT3 signaling-related circRNAs and other signaling pathways. We also further discuss the role of the circRNA/STAT3 axis in cancer chemotherapy sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mosaic variegated aneuploidy (MVA) is a rare condition in which abnormal chromosome counts (that is, aneuploidies), affecting different chromosomes in each cell (making it variegated) are found only in a certain number of cells (making it mosaic). MVA is characterized by various developmental defects and, despite its rarity, presents a unique clinical scenario to understand the consequences of chromosomal instability and copy number variation in humans. Research from patients with MVA, genetically engineered mouse models and functional cellular studies have found the genetic causes to be mutations in components of the spindle-assembly checkpoint as well as in related proteins involved in centrosome dynamics during mitosis. MVA is accompanied by tumour susceptibility (depending on the genetic basis) as well as cellular and systemic stress, including chronic immune response and the associated clinical implications., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Liquid biopsy is considered a complementary and recently also an alternative method to surgical biopsy. It allows for the acquisition of valuable information regarding the potential presence of tumors, particularly through the analysis of circulating tumor DNA (ctDNA). CtDNA is a fraction of circulating free DNA (cfDNA) that can be extracted from various tissues, with blood being the most readily available., Results: To maximize the yield of plasma separation, specific Streck tubes are recommended for blood collection. The MagPurix CFC DNA Extraction Kit can be used for cfDNA extraction, and the TWIST Library Preparation protocol can be optimized for further analysis. Next-generation sequencing (NGS) can be employed to compare somatic and germline lineages, enabling the identification of somatic variants with a Variant Allele Frequency (VAF) of 5 % or higher, which are absent in the germline lineage., Conclusion: This analysis helps in the assessment of recurrence, analysis, and monitoring of cancer tissue., Competing Interests: Declaration of competing interest The authors of this scientific article often publish together, being part of the same group and/or scientific society. The scientific journal designated to publish this article has a specific policy to ensure the optimal handling of these situations. The journal’s policy ensures that the peer review process is kept independent by selecting reviewers independent of the authors of the article. All affiliations of the authors with private companies have been declared to make clear the position regarding the interests of these companies. The authors are affiliated with private companies for which there could be a possible conflict of interest. The authors state that the research was conducted in the absence of any commercial relationship that could be construed as a possible direct conflict of interest avoiding mention of any products or services sold by private companies related to the authors. The authors of this article are reported to be patents inventors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)