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Objective: To investigate the mechanism and clinical value of zinc finger protein 492 (ZNF492) gene mutation in ovarian cancer, and to provide a theoretical basis for the diagnosis and treatment of ovarian cancer. Methods: The transcriptome data of ZNF492 mutant samples were downloaded by TCGA, and the samples were divided into two groups: ZNF492 mutant and non-mutant groups. The R package DESeq2 was used to analyze the differential genes between the two groups. The differentially expressed genes were analyzed by kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA). The age, tumor stage and differentiation of ovarian cancer patients were obtained, and the Nomogram model was constructed and evaluated by multivariate COX regression prediction model of ZNF492 expression and clinical characteristics of ovarian cancer patients. Results: There were 100 up -regulated genes and 971 down-regulated genes in the differential genes between the ZNF492 mutant group (n=377) and the non-mutant group (n=2). The pathway enrichment analysis of differential genes between the two groups and 100 up-regulated genes in the ZNF492 mutant group showed that they were enriched transforming growth factor -β (TGF -β) signal path. The results of multivariate COX regression prediction model showed that higher age (≥65 years old), the higher tumor stage (Ⅲ-Ⅳ stage) and differentiation (G3) might be related to the poor overall survival (HR>1), while high expression of ZNF492 (≥0.672) was related to the better prognosis (HR＜1), among which the higher age patients (≥65 years old) had a poor prognosis (P＜0.01). Based on the above four factors, further construct the Nomogram prediction model. The model validation results showed that the C index was 0.593, the area under the curve (AUC) (0.610 and 0.566) of three-year and five-year ROC curves, and the clinical decision curve analysis (DCA) suggested that patients can take bold measures when the 3-year or 5-year survival rate was greater than 18% and less than 82% . Conclusions: Mutated ZNF492 may affect the occurrence and development of ovarian cancer by regulating TGF -β pathway and anti -apoptosis potential mechanism, and has strong clinical practical value in predicting prognosis. ZNF492 mutation is expected to be a marker of circulating tumour DNA and therapeutic target for ovarian cancer. [ABSTRACT FROM AUTHOR]

Aims: Identification of recurrent genetic alterations in JAK2 , MPL and CALR remains crucial in the diagnosis of Philadelphia-negative myeloproliferative neoplasms (MPNs). Current laboratory testing algorithms may entail batching and/or sequential testing, involving multiple testing modalities and sometimes send-out testing that increase the technical and economic demands on laboratories while delaying patient diagnoses. To address this gap, an assay based on PCR and high-resolution melting (HRM) analysis was developed for simultaneous evaluation of JAK2 exons 12-14, MPL exon 10 and CALR exon 9, embodied in the HemeScreen® (hereafter 'HemeScreen') MPN assay., Methods: The HemeScreen MPN assay was validated with blood and bone marrow samples from 982 patients with clinical suspicion for MPN. The HRM assay and Sanger sequencing were performed in independent Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories with Sanger sequencing (supported by droplet digital PCR) serving as the gold standard., Results: HRM and Sanger sequencing had an overall concordance of 99.4% with HRM detecting 133/139 (96%) variants confirmed by sequencing (9/10 MPL, 25/25 CALR, 99/104 JAK2), including 114 single nucleotide variants and 25 indels (3-52 bp). Variants consisted of disease-associated (DA) variants (89%), variants of unclear significance (2%) and non-DA variants (9%) with a positive predictive value of 92.3% and negative predictive value of 99.5%., Conclusions: These studies demonstrate the exquisite accuracy, sensitivity and specificity of the HRM-based HemeScreen MPN assay, which serves as a powerful, clinically applicable platform for rapid, simultaneous detection of clinically relevant, somatic disease variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tumorigenesis arises from the dysfunction of cancer genes, leading to uncontrolled cell proliferation through various mechanisms. Establishing a complete cancer gene catalogue will make precision oncology possible. Although existing methods based on graph neural networks (GNN) are effective in identifying cancer genes, they fall short in effectively integrating data from multiple views and interpreting predictive outcomes. To address these shortcomings, an interpretable representation learning framework IMVRL-GCN is proposed to capture both shared and specific representations from multiview data, offering significant insights into the identification of cancer genes. Experimental results demonstrate that IMVRL-GCN outperforms state-of-the-art cancer gene identification methods and several baselines. Furthermore, IMVRL-GCN is employed to identify a total of 74 high-confidence novel cancer genes, and multiview data analysis highlights the pivotal roles of shared, mutation-specific, and structure-specific representations in discriminating distinctive cancer genes. Exploration of the mechanisms behind their discriminative capabilities suggests that shared representations are strongly associated with gene functions, while mutation-specific and structure-specific representations are linked to mutagenic propensity and functional synergy, respectively. Finally, our in-depth analyses of these candidates suggest potential insights for individualized treatments: afatinib could counteract many mutation-driven risks, and targeting interactions with cancer gene SRC is a reasonable strategy to mitigate interaction-induced risks for NR3C1, RXRA, HNF4A, and SP1., (© The Author(s) 2024. Published by Oxford University Press.)

Accurate classification of genetic variants is crucial for clinical decision-making in hereditary cancer. In Spain, genetic diagnostic laboratories have traditionally approached this task independently due to the lack of a dedicated resource. Here we present SpadaHC, a web-based database for sharing variants in hereditary cancer genes in the Spanish population. SpadaHC is implemented using a three-tier architecture consisting of a relational database, a web tool and a bioinformatics pipeline. Contributing laboratories can share variant classifications and variants from individuals in Variant Calling Format (VCF) format. The platform supports open and restricted access, flexible dataset submissions, automatic pseudo-anonymization, VCF quality control, variant normalization and liftover between genome builds. Users can flexibly explore and search data, receive automatic discrepancy notifications and access SpadaHC population frequencies based on many criteria. In February 2024, SpadaHC included 18 laboratory members, storing 1.17 million variants from 4306 patients and 16 343 laboratory classifications. In the first analysis of the shared data, we identified 84 genetic variants with clinically relevant discrepancies in their classifications and addressed them through a three-phase resolution strategy. This work highlights the importance of data sharing to promote consistency in variant classifications among laboratories, so patients and family members can benefit from more accurate clinical management. Database URL: https://spadahc.ciberisciii.es/., (© The Author(s) 2024. Published by Oxford University Press.)

Motivation: Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited., Results: Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes., Availability and Implementation: DISHyper is freely available for download at https://github.com/genemine/DISHyper., (© The Author(s) 2024. Published by Oxford University Press.)

A Variant of Uncertain Significance (VUS) is a difference in the DNA sequence with uncertain consequences for gene function. A VUS in a hereditary cancer gene should not change medical care, yet some patients undergo medical procedures based on their VUS result, highlighting the unmet educational needs among patients and healthcare providers. To address this need, we developed, evaluated, and refined novel educational materials to explain that while VUS results do not change medical care, it remains important to share any personal or family history of cancer with family members given that their personal and family medical history can guide their cancer risk management. We began by reviewing the prior literature and transcripts from interviews with six individuals with a VUS result to identify content and design considerations to incorporate into educational materials. We then gathered feedback to improve materials via a focus group of multidisciplinary experts and multiple rounds of semi-structured interviews with individuals with a VUS result. Themes for how to improve content, visuals, and usefulness were used to refine the materials. In the final round of interviews with an additional 10 individuals with a VUS result, materials were described as relatable, useful, factual, and easy to navigate, and also increased their understanding of cancer gene VUS results.

Aims: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs., Methods: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes., Results: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes., Conclusions: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

CLLU1, a disease-specific gene associated with chronic lymphoid leukemia (CLL), is located on chromosome 12q22. Previous studies considered CLLU1 to be a non-coding RNA; however, recent research has discovered that its coding sequence region possesses the potential to encode a short peptide similar to interleukin-4. Remarkably, abnormally elevated expression of CLLU1 has only been detected in chronic lymphoid leukemia among all hematological cancers. High CLLU1 expression often indicates more malignant pathological features and an unfavorable prognosis for patients. Importantly, the expression level of CLLU1 remains unaffected by the passage of time or therapeutic interventions, thus rendering it a novel prognostic marker. This article provides a comprehensive summary of relevant research findings on CLLU1 in the context of CLL prognosis and clinical applications, aiming to guide subsequent theoretical and clinical investigations in this field., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

We report a case of a middle-aged woman with a rapidly growing abdominal mass that was diagnosed as myxoid pleomorphic liposarcoma, a recently recognised, rare and aggressive subtype of liposarcoma. The tumour exhibits a combination of histological features from both myxoid liposarcoma and pleomorphic liposarcoma. Genetic analysis revealed mutations in TP53 and RB1, along with widespread loss of heterozygosity. However, no DDIT3 gene translocation or MDM2/CDK4 gene amplification was detected. These genetic characteristics can be used to distinguish this type of liposarcoma from others. Two unusual gene fusion/rearrangements, CREB5::TERT fusion and ETV1::LFNG rearrangement, were identified. The patient underwent complete removal of the tumour without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 18 months., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Tumor-associated neutrophils (TANs) can promote tumor progression. This study aimed to investigate the molecular signature that predict the prognosis and immune response of breast cancer (BRCA) based on TAN-related gene (TANRG) expression data. The RNA-seq data of BRCA were gathered from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) datasets. Univariate Cox regression analysis and the least absolute shrinkage and selection operator for selecting prognostic genes. A neo-TAN-related risk signature was constructed by multivariate Cox regression analysis. Time-dependent receiver operating characteristic (ROC) curve analyses and Kaplan-Meier analyses were performed to validate the signature in GEO cohorts and the triple-negative breast cancer (TNBC) subtype. We constructed an independent prognostic factor model with 11 TANRGs. The areas under the ROC curve (AUCs) of the TCGA training cohorts for 3-, 5-, and 7-year overall survival were 0.72, 0.73, and 0.73, respectively. The AUCs of the GEO test cohorts for 3-, 5-, and 7-year overall survival were 0.83, 0.89, and 0.94 (GSE25066) and 0.67, 0.69, and 0.73 (GSE58812), respectively. The proportion of immune subtypes differed among the different risk groups. The IC50 values differed significantly between risk groups and can be used as a guide for systemic therapy. The prognostic model developed by TANRGs has excellent predictive performance in BRCA patients. In addition, this feature is closely related to the prediction of survival, immune activity and treatment response in BRCA patients., (© 2024. The Author(s).)

The fusogenic membrane glycoprotein (FMG) derived from the human endogenous retrovirus-W (HERV-W) exhibits fusogenic properties, making it a promising candidate for cancer gene therapy. When cells are transfected with HERV-W FMG, they can fuse with neighboring cells expressing the receptor, resulting in the formation of syncytia. These syncytia eventually undergo cell death within a few days. In addition, it has been observed that an HERV-W env mutant, which is truncated after amino acid 483, displays increased fusogenicity compared to the wild-type HERV-W env . In this study, we observed syncytium formation upon transfection of HeLa and TE671 human cancer cells with plasmids containing the HERV-W 483 gene. To explore the potential of a semi-replication-competent retroviral (s-RCR) vector encoding HERV-W 483 for FMG-mediated cancer gene therapy, we developed two replication-defective retroviral vectors: a gag-pol vector encoding HERV-W 483 (MoMLV-HERV-W 483) and an env vector encoding VSV-G (pCLXSN-VSV-G-EGFP). When MoMLV-HERV-W 483 and pCLXSN-VSV-G-EGFP were co-transfected into HEK293T cells to produce the s-RCR vector, gradual syncytium formation was observed. However, the titers of the s-RCR virus remained consistently low. To enhance gene transfer efficiency, we constructed an RCR vector encoding HERV-W 483 (MoMLV-10A1-HERV-W 483), which demonstrated replication ability in HEK293T cells. Infection of A549 and HT1080 human cancer cell lines with this RCR vector induced syncytium formation and subsequent cell death. Consequently, both the s-RCR vector and RCR encoding HERV-W 483 hold promise as valuable tools for cancer gene therapy.

Background: Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients., Methods: A case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing -log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation., Results: Glycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 ( HAX1 ) and hyaluronan-mediatedmotility receptor ( HMMR ), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis., Conclusions: Combining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The exploration of tumor target genes holds paramount importance for the prevention and treatment of cervical cancer. In this study, we outline the steps involved in the identification of a tumor target gene FAM83A in cervical cancer. First, the Cancer Genome Atlas dataset was employed to validate the expression and prognostic significance of FAM83A in women. A small interfering RNA (siRNA) was used for knockdown of the FAM83A gene in HeLa and C33a cells. Next, 5-ethynyl-2'-deoxyuridine (EdU) staining was conducted to determine the effects on the proliferation capabilities of the tumor cells. Wound healing and porous membrane insert assays were performed to evaluate tumor cell migration and invasion abilities. Western blotting was used to quantify apoptosis-related protein levels. JC-1 staining was employed to evaluate mitochondrial function alterations. Furthermore, cisplatin (diaminedichloroplatinum, DDP) intervention was used to assess the therapeutic potential of the target gene. Flow cytometry and colony formation assays were conducted to further validate the anticancer characteristics of the gene. As a result, FAM83A knockdown was shown to inhibit the proliferation, migration, and invasion of cervical cancer cells and sensitize these cells to cisplatin. These comprehensive methodologies collectively validate FAM83A as a tumor-associated target gene, holding promise as a potential therapeutic target in the prevention and treatment of cervical cancer.

The V-set and transmembrane domain containing 2A ( VSTM2A) gene is located on chromosome 7. In the physiological state, VSTM2A regulates preadipocyte cell differentiation. VSTM2A is highly expressed in normal human brain tissue and minimally expressed in other normal tissues. Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a distinct renal tumour subtype with signature chromosomal copy number alterations and an indolent outcome in the majority of cases. VSTM2A overexpression is highly enriched in this renal cancer subtype and has been shown to have potential diagnostic value in distinguishing MTSCC from renal tumours with overlapping histological appearances., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of pulmonary adenocarcinoma. Due to its rarity, few pathological and molecular studies have been performed on PEAC. We herein conducted clinicopathological, immunohistochemical and molecular analyses of PEAC with a focus on its differentiation from invasive mucinous adenocarcinoma (IMA)., Methods: We examined the clinicopathological features of 16 cases of PEAC and performed a genetic analysis using next-generation sequencing (NGS). The results obtained were compared with those for IMA., Results: The average age of patients with PEAC (seven men and nine women) was 72.9 years. A comparison of clinical data on PEAC and IMA revealed no significant differences in age, sex or smoking history. Fifteen PEAC cases had dirty necrosis. Immunohistochemically, the positive rates for each antibody in PEAC were as follows: CK7, 88% (14/16); CK20, 81% (13/16); CDX2, 88% (14/16); p53, 69% (11/16); MUC1, 100% (16/16); MUC2, 19% (3/16); MUC5AC, 69% (11/16); MUC6, 19% (3/16). The positive rates for these antibodies in IMA were 100%, 87%, 0%, 7%, 93%, 0%, 100% and 80%, respectively. EGFR mutations, the MET exon 14 skipping mutation, BRAF mutations, the ALK fusion gene and ROS-1 fusion gene were not detected in any cases of PEAC or IMA. Among PEAC cases, NGS identified KRAS mutations in seven (44%, 7/16) and TP53 mutations in nine (56%, 9/16). Among IMA cases, the most commonly mutated gene was KRAS (90%)., Conclusions: The rates of dirty necrosis, immunopositivity for CDX2 and TP53 mutations were significantly higher, while that of KRAS mutations was significantly lower in PEAC cases than in IMA cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Ferroptosis-related cancer therapy is limited by insufficient Fe 2+ /Fe 3+ redox pair and hydrogen peroxide (H 2 O 2 ) for producing lethal hydroxyl radicals (·OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine is developed for responsive LIP release and H 2 O 2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated antitumor effects. A glutathione(GSH)/pH dual activatable fluorinated and cross-linked polyethyleneimine (PEI) with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX (CA IX)) plasmids (FP@MC) are developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids are constructed to knockdown CA IX and translate KillerRed-SOD recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidifies the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generates H 2 O 2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravate cancer ferroptosis and suppress tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy., (© 2023 Wiley-VCH GmbH.)

Replication-competent oncolytic adenovirus (TOA2) gene therapy is a recently introduced anti-tumor treatment regimen with superior results. The biodistribution studies of virus vector-based medicine seem more cautious and have been given much attention recently in terms of its quality and safety in preclinical trials. The current study determined the biodistribution and safety of a replication-competent adenovirus in different organs to predict its toxicity threshold. The present study has used TOA2, while biodistribution analysis was performed in human lung carcinoma A549-induced tumor-bearing nude mice model. Intratumoral injection was applied onto tumor-bearing mice with the adenovirus (3×10 10 VP per mouse). Mice were sacrificed at the end of the experiment and the organs were dissected. Biodistribution analysis was done with complete hexon gene detection in each organ using quantitative real-time polymerase chain reaction (qRT-PCR). The biodistribution and concentration profiles showed that the TOA2 is well distributed in the entire tumor tissue. After dose 3 at day 11, the concentration of the virus has increased in the tumor tissue from 2240.54 (± 01.69) copies/100 ng genome to 13,120.28 (± 88.21) copies/100 ng genome on the 18th day, which eventually approached 336.45 (± 23.41) copies/100ng genome on the day 36. On the contrary, the concentration of the same decreased in the order of the liver, kidney, spleen, lung, and heart over time but no distributional traces in gonads. But the concentration found decreased dramatically in blood and other organs, while at the end of the experiment no detectable distribution was seen besides tumor tissue. The study confirms that adenovirus-based tumor therapy using conditionally replicating competent oncolytic TOA2 exhibited great efficiency with no toxicity at all., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines., Methodology: The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal., Results: This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8 + and TCD8 + CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors., Conclusion: The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The use of nucleic acid to control the expression of genes relevant to tumor progression is a key therapeutic approach in cancer research. Therapeutics based on nucleic acid provide novel concepts for untreatable targets. Nucleic acids as molecular medications must enter the target cell to be effective and obstacles in the systemic delivery of DNA or RNA limit their use in a clinical setting. The creation of nucleic acid delivery systems based on nanoparticles in order to circumvent biological constraints is advancing quickly. The ease of synthesis and surface modification, biocompatibility, biodegradability, cost-effectiveness and high loading capability of nucleic acids have prompted the use of mesoporous silica nanoparticles (MSNs) in gene therapy. The unique surface features of MSNs facilitate their design and decoration for high loading of nucleic acids, immune system evasion, cancer cell targeting, controlled cargo release, and endosomal escape. Reports have demonstrated successful therapeutic outcomes with the administration of a variety of engineered MSNs capable of delivering genes to tumor sites in laboratory animals. This comprehensive review of studies about siRNA, miRNA, shRNA, lncRNA and CRISPR/Cas9 delivery by MSNs reveals engineered MSNs as a safe and efficient system for gene transfer to cancer cells and cancer mouse models., Competing Interests: Declaration of competing interest All authors have read and approved this paper and have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Gene therapy for lung cancer has emerged as a novel tumor-combating strategy for its superior tumor specificity, low systematical toxicity and huge clinical translation potential. Especially, the applications of microRNA shed led on effective tumor ablation by directly interfering with the crucial gene expression, making it one of the most promising gene therapy agents. However, for lung cancer therapy, the microRNA treatment confronted three bottlenecks, the poor tumor tissue penetration effect, the insufficient lung drug accumulation and unsatisfied gene transfection efficiency. To address these issues, an inhalable RGD-TAT dual peptides-modified cationic liposomes loaded with microRNA miR-34a and gap junction (GJ) regulation agent all-trans retinoic acid (ATRA) was proposed, which was further engineered into dry powder inhalers (DPIs)., Results: Equipped with a rough particle surface and appropriate aerodynamic size, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs were expected to deposit into the deep lung and reach lung tumor lesions guided by targeting peptide RGD. Assisted by cellular transmembrane peptides TAT, the RGD-TAT-CLPs/ARTA@miR-34a was proven to be effectively internalized by cancer cells, enhancing gene transfection efficiency. Then, the GJ between tumor cells was upregulated by ARTA, facilitating the intercellular transport of miR-34a and boosting the gene expression in the deep tumor., Conclusion: Overall, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could enhance tumor tissue penetration, elevate lung drug accumulation and boost gene transfection efficiency, breaking the three bottlenecks to enhancing tumor elimination in vitro and in vivo. We believe that the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could serve as a promising pulmonary gene delivery platform for multiple lung local disease treatments., (© 2023. The Author(s).)

New tumour types are being described at increasing frequency, and most new tumour types are now identified via retrospective review of next-generation sequencing data. This contrasts with the traditional, morphology-based method of identifying new tumour types, and while the sequencing-based approach has accelerated progress in the field, it has also introduced novel and under-recognised biases. Here, we discuss tumour types identified based on morphology, including superficial CD34-positive fibroblastic tumour, pseudoendocrine sarcoma and cutaneous clear cell tumour with melanocytic differentiation and ACTIN::MITF fusion. We also describe tumour types identified primarily by next-generation sequencing, including epithelioid and spindle cell rhabdomyosarcoma, round cell neoplasms with EWSR1::PATZ1 fusion, cutaneous melanocytic tumour with CRTC1::TRIM11 fusion, clear cell tumour with melanocytic differentiation and MITF::CREM fusion and GLI1 -altered mesenchymal neoplasms, including nested glomoid neoplasm., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The FOXL2 (forkhead box L2) gene is located on chromosome 3 and encodes for forkhead box (FOX) family of transcription factors which play a critical role in various biological processes. Germline FOXL2 mutations have been identified in blepharophimosis/ptosis/epicanthus inversus syndrome. The somatic missense mutation in FOXL2 ( FOXL2 C134W) is now known to be the defining molecular feature of adult-type granulosa cell tumour of the ovary, present in over 90% of cases of this tumour type. Immunohistochemistry for FOXL2 is used as a marker of sex cord-stromal differentiation. However, expression is not restricted to lesions harbouring FOXL2 mutations, and it is positive in a variety of sex cord-stromal proliferations other than adult-type granulosa cell tumour., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The gene mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) mainly occur in astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma and secondary glioblastoma. The IDH1/2 gene mutation can alter proteinase function, consume α-ketoglutarate and nicotinamide adenine dinucleotide phosphate-reduced (NADPH) and thus produce carcinogenic metabolite, 2-hydroxyglutarate. The intracellular accumulation of 2-hydroxyglutarate will induce a series of downstream effects which may result in the development of gliomas mentioned above. Both IDH1/2 mutations and other concomitant hereditary variations are biomarkers for differential diagnosis and IDH1/2 mutations are also independent factors for the prognosis of gliomas. The molecular targeting therapy for IDH1/2 mutations has become the research focus of glioma treatment. This review summarizes the recent progress of this field. DOI: 10.3969/j.issn.1672-6731.2015.11.017

Importance: The biological processes that underlie the association of neighborhood environment with chronic diseases, such as cancer, remain poorly understood., Objective: To determine whether differences in breast tissue DNA methylation are associated with neighborhood deprivation among Black and White women with breast cancer., Design, Setting, and Participants: This cross-sectional study collected breast tissue from women undergoing surgery for breast cancer between January 1, 1993, and December 31, 2003. Participants were recruited through the University of Maryland Medical Center, with additional collection sites at Baltimore-area hospitals. Data analysis was performed from March 1 through December 1, 2022., Exposure: Year 2000 census tract-level socioeconomic deprivation measured via neighborhood deprivation index (NDI) as a standardized score, with Black and White race being ascertained through self-report., Main Outcome and Measures: The primary outcome was tissue DNA methylation using genome-wide measurements. The secondary outcome was tissue gene expression., Results: Participants included 185 women with breast cancer (110 Black [59.5%], 75 White [40.5%]). Mean (SD) age at surgery was 56.0 (14.1) years. Neighborhood deprivation was higher for Black women than for White women (Mean [SD] NDI, 2.96 [3.03] for Black women and -0.54 [1.91] for White women; difference, -3.50; 95% CI, -4.22 to -2.79; P < .001). In unstratified analysis, 8 hypomethylated CpG sites were identified as associated with the NDI, including sites in 2 tumor suppressor genes, LRIG1 and WWOX. Moreover, expression of the 2 genes inversely correlated with neighborhood deprivation. In the race-stratified analysis, the negative correlation between the LRIG1 gene body CpG site cg26131019 and the NDI remained significant in Black women. A neighborhood deprivation-associated decrease in gene expression was also observed for LRIG1 and WWOX in tumors from Black women., Conclusions and Relevance: In this study, high neighborhood deprivation was associated with differences in tissue DNA methylation and gene expression among Black women. These findings suggest that continued investment in public health interventions and policy changes at the neighborhood level may help to remedy biological alterations that could make minoritized populations more susceptible to chronic diseases.

Leptomeningeal involvement among non-small cell lung cancer (NSCLC) patients is an aggressive form of disease that requires quick and efficient treatment. In this case report, we describe a woman in her 40s with a presenting symptom of headache that ultimately was diagnosed as leptomeningeal spread from NSCLC adenocarcinoma. We identified EGFR mutation in less than 48 hours from the biopsy using imagene-artificial intelligence's real-time algorithmic solution on the pathological diagnostic slide., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients., (© 2023. Springer Nature Limited.)

The tumor microenvironment is a very complex and dynamic ecosystem. Although a variety of pH-responsive peptides have been reported to deliver nucleic acid drugs for cancer treatment, these responses typically only target the acidic microenvironment of the tumor or the lysosome, and the carrier suffers from issues such as low transfection efficiency and poor lysosomal escape within the cell. To address this problem, we have developed an ultra pH-responsive peptide nanocarrier that can efficiently deliver siRNA, pDNA, and mRNA into cancer cells by performing progressive dynamic assembly in response to pH changes in the acidic tumor microenvironment (pH 6.5-6.8) and the acidic intracellular lysosomal environment (pH 5.0-6.0). The maximum transfection efficiency was 87.1% for pDNA and 74.9% for mRNA, which is higher than that of peptide-based nanocarrier reported to date. In addition, the targeting sequence on the surface allows the peptide@siRNA complex to efficiently enter cancer cells, causing 96% of cancer cell mortality. The carrier has high biocompatibility and low cytotoxicity, making it highly promising for application in immunotherapy and gene therapy of tumors.

Aims: The aim of this quality improvement project was to improve the turnaround time of B-raf proto-oncogene (BRAF) mutation testing in patients with malignant melanoma to support oncologists in making timely treatment decisions., Methods: This is a prospective in-house verification of the Idylla BRAF test as compared with DNA panel next-generation sequencing (NGS) performed at an external laboratory., Results: The Idylla BRAF test had an overall concordance of 95% compared with NGS. This was considered sufficiently good for use in patients with a poor performance status who were at risk of rapid clinical deterioration. Reliable results can be generated using the Idylla BRAF test in tissue sections with tumour neoplastic cell content below 50%. We present a multidisciplinary clinical care algorithm to support dual testing., Conclusions: The Idylla BRAF test has the potential to make a significant positive impact on progression-free survival of malignant melanoma patients due to its rapid turnaround time. The Idylla BRAF test can be used as an adjunct to NGS for timely management of patients, particularly those with a poor performance status at presentation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)