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Human papillomaviruses (HPVs) infect epithelial cells of human beings, and their replication cycle is associated with epithelial differentiation. More than 200 genotypes of HPVs were identified, and each of these HPVs shows distinct specificity for tissues and infection. HPV infection was involved in the development of lesions on the feet, genital warts and hands. The evidence of HPV infection revealed the role of HPVs in neck and head squamous cell carcinoma, esophageal cancer, cervical cancer, head and neck cancer, brain and lung tumours. The independent traditional risk factors, various clinical outcomes, and increased prevalence among certain populations and geographical regions have led increasing interest in HPV infection. The mode of HPVs transmission remains unclear. Moreover, in recent years, vertical transmission of HPVs was reported. This review concludes present knowledge about HPV infection, virulence strains, clinical significance of HPVs, and mode of transmission, and vaccination strategies.

Lung cancer stands as one of the most lethal diseases and is the foremost cause of cancer-related mortalities worldwide. The pathophysiology of lung cancer is multifaceted, and it includes multiple cell signaling pathways and other complex factors such as oxidative stress and genetics. The association of HPV with lung carcinogenesis was first proposed in 1979, and since then, scientists worldwide have been putting forward several hypotheses to establish a relationship between this virus and lung cancer. Although studies have reported the presence of HPV in lung cancer, the exact mechanism of entry and the route of transmission have not been elucidated clearly till date. Numerous studies across the globe have detected differentially expressed HPV oncoproteins in lung cancer patients and found their association with the critical cell signaling pathways that leads to the development and progression of lung cancer. Many reports have also provided evidence stating the involvement of HPV in determining the survival status of lung cancer patients. The present review recapitulates the studies evincing the association of HPV and lung cancer, its route of transmission and mechanism of action; the detection of the virus and treatment opportunities for HPV-positive lung cancer; and the severity associated with this disease. Therefore, this will provide an explicit idea and would help to develop preventive measures and specific as well as effective treatment for HPV-associated lung carcinogenesis., 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 Inc. All rights reserved.)

Oncogenic viruses contribute to 15% of global human cancers. To achieve that, virus-encoded oncoproteins deregulate cellular transcription, antagonize common cellular pathways, and thus drive cell transformation. Notably, adenoviruses were the first human viruses proven to induce cancers in diverse animal models. Over the past decades, human adenovirus (HAdV)-mediated oncogenic transformation has been pivotal in deciphering underlying molecular mechanisms. Key adenovirus oncoproteins, encoded in early regions 1 (E1) and 4 (E4), co-ordinate these processes. Among the different adenovirus species, the most extensively studied HAdV-C5 displays lower oncogenicity than HAdV-A12. A complete understanding of the different HAdV-A12 and HAdV-C5 oncoproteins in virus-mediated cell transformation, as summarized here, is relevant for adenovirus research and offers broader insights into viral transformation and oncogenesis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality. In this review, we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

Human primary cells, including urine-derived cells (UCs), are an excellent source for generation of pluripotent stem cells (iPSCs) to model disease. However, replicative senescence starts early and shortens the time window for generation of iPSCs. We addressed the question whether combinations of transgenes allows efficient immortalization of UCs, iPSC generation, and differentiation into hepatocyte-like cells (HLCs). Retroviral transfer of three gene cassettes HPVE6E7 (H), hTERT/p53DD (T), cyclinD1/CDK4R24C (C) encoding five genes was established in primary UCs. Long-term cell proliferation was observed in cells carrying transgenes H, HT, HC, and HCT, whereas cells carrying transgenes C, T and CT showed early senescence similar to UCs. iPSCs could be exclusively generated from immortalized UCs transduced with transgenes HCT and HC. iPSC colonies appeared however later and in smaller number as compared to UCs. Using an established hepatic differentiation protocol, HLCs were obtained with high efficacy. Of note, a high expression of individual transgenes was observed in immortalized UCs, which was down-regulated after reprogramming in four out of five genes. One transgene was re-expressed in HLCs as compared to iPSCs. Our data suggest that individual transgene combinations result in advanced growth rates of immortalized cells and do not prevent iPSC formation and HLC differentiation. Retroviral transgene expression is mostly silenced in iPSCs but can be rarely re-expressed after hepatic differentiation. An extended time window for iPSC establishment can be proposed that allows straightforward functional analyses of differentiated cells.

Ewing's sarcoma (ES) is an aggressive malignant tumor commonly affecting adolescents. The standard of care includes surgical treatment and systemic therapies, although ES patients often develop drug resistance, leading to disease progression. Tumorigenesis in Ewing's sarcoma has unique characteristics that allow for the development of targeted therapeutics. New data on the role of oncogenic drivers in ES tumorigenesis, particularly in relation to treatment-induced stress, offers new therapeutic opportunities. This review summarizes the latest information on the clinically relevant oncogenes found in Ewing's sarcoma, their biological roles, and candidate targets for improving ES patient outcomes.

Background: PALB2 (BRCA2 partner and localizer) is a BRCA2-interacting protein that is required for BRCA2 genome caretaker tasks and interacts with BRCA1. Women with PALB2 mutation have a 40% to 60% higher risk of breast cancer, almost equivalent to women who have BRCA mutations. PALB2 mutation may also increase the risk of pancreatic cancer. New guidelines for PALB2 mutation in breast cancer advise pancreatic cancer screening, which includes M.R.I.s of the pancreas as well as endoscopic ultrasonography, for women who have a family history of pancreatic cancer. Using the Cancer Genome Atlas (TCGA) and The Human Protein Atlas we examined genes that co-express with PALB2 in breast and pancreatic cancer. Methods: We used cBioPortal for Cancer Genomics to analyze data in TCGA. cBioPortal provides visualization, analysis and download of large-scale cancer genomics data sets. We used the UCSC Xena Browser to additionally analyze gene expression in TCGA. Results: Six genes, EARS2, ARL6IP1, DNAJA3, KNOP1, RPUSD1, and TMEM186, significantly coexpressed with PALB2 in both breast and pancreatic cancer. Glutamyl-tRNA synthetase 2 (EARS2) was the only gene coexpressing with PALB2 in the breast and pancreatic cancer subjects that was significantly related to pancreatic cancer survival. Elevated PALB2 and EARS2 gene expression are both significantly associated with the PAM50 Luminal B subtype and high risk of recurrence, suggesting why these women may need active intervention, such as prophylactic mastectomy. Conclusions: EARS2 expression might be a risk factor for pancreatic cancer in breast cancer patients with PALB2 mutations. By assessing EARS2 expression in breast tumors, the clinician might obtain a second piece of information that, with family history of pancreatic cancer, could inform the decision to perform pancreatic cancer screening.

DNA chains with sequential guanine (G) repeats can lead to the formation of G-quadruplexes (G4), which are found in functional DNA and RNA regions like telomeres and oncogene promoters. The development of molecules with adequate structural features to selectively stabilize G4 structures can counteract cell immortality, highly described for cancer cells, and also downregulate transcription events underlying cell apoptosis and/or senescence processes. We describe here, the efficiency of four highly charged porphyrins-phosphonium conjugates to act as G4 stabilizing agents. The spectrophotometric results allowed to select the conjugates P2-PPh 3 and P3-PPh 3 as the most promising ones to stabilize selectively G4 structures. Molecular dynamics simulation experiments were performed and support the preferential binding of P2-PPh 3 namely to MYC and of P3-PPh 3 to KRAS. The ability of both ligands to block the activity of Taq polymerase was confirmed and also their higher cytotoxicity against the two melanoma cell lines A375 and SK-MEL-28 than to immortalized skin keratinocytes. Both ligands present efficient cellular uptake, nuclear co-localization and high ability to generate 1 O 2 namely when interacting with G4 structure. The obtained data points the synthesized porphyrins as promising ligands to be used in a dual approach that can combine G4 stabilization and Photodynamic therapy (PDT)., Competing Interests: Declaration of competing interest Catarina IV Ramos reports financial support was provided by Foundation for Science and Technology. Nuno MM Moura reports financial support was provided by Foundation for Science and Technology. Helena Oliveira reports financial support was provided by Foundation for Science and Technology. Diana Salvador reports financial support was provided by Foundation for Science and Technology. If there are other authors, they 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.)

Methyl cellosolve (MC) is used in production of textile, paints, stains, inks, surface coatings, and anti-icing additive in hydraulic fluids and jet fuel. Consequently, the present study investigated its effect on renal cells, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of MC for a period of 7, 14, and 21 days. Following 7 days of administration of MC, there was a significant increase in the levels of K-Ras, c-Myc, TNF-α, IL-6 and NO, while GSH level and SOD activity were significantly reduced compared with control. At the end of 14 days exposure, RKW, GSH, NO, and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GPx activity were significantly increased compared with control. After 21 days of MC administration, RKW, GSH, NO, IL-10 and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GST activity were significantly increased compared with control. Exposures to MC in any way should be strictly avoided as it could trigger renal damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in the world. It has been reported that HCC is closely related to the changes of histone modifications. However, finding histone modification patterns in key genes which related to HCC is still an important task. In our study, the patterns of 11 kinds of histone modifications in the promoter regions for the different types of genes were analyzed by hierarchical screening for hepatocyte (normal) cell line and HepG2 (tumor) cell line. The important histone modifications and their key modification regions in different types of genes were found. The results indicate that these important genes may play a pivotal role in the occurrence of HCC. By analyzing the differences of histone modifications and gene expression levels for these important genes between the two cell lines, we found that the signals of H3K4me3, H3K27ac, H3K9ac, and H3K4me2 in HCC are significantly stronger. The changed regions of important histone modifications in 17 key genes were also identified. For example, the H3K4me3 signals increased 150 times in regions (−1500, −500) bp and (0, 1000) bp of ARHGAP5 in tumor cell line than in normal cell line. Finally, a prognostic risk scoring model was constructed, and the effects of key genes on the prognosis of HCC were verified by the survival analysis. Our results may provide a more precise potential therapeutic targets for identifying key genes and histone modifications in HCC as new biomarkers.

Introduction: Alterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap with diagnoses of advanced oncogene-driven NSCLC. Guidelines for cytotoxic agents and pregnancy are well established. Nevertheless, accessible data on targeted lung cancer therapy during pregnancy or egg retrieval has not been collated previously, nor have the issues of reproduction in the setting of specific oncogene-addicted advanced NSCLC been widely discussed., Methods: We performed a narrative review of ex vivo placenta perfusion studies, pharmacologic characteristics, mutagenicity, animal embryo-fetal development studies, and case reports of pathways to motherhood, pregnancies, and egg retrieval while on EGFR-, ALK-, or ROS1-targeted therapy., Results: EGFR inhibitors may reduce female fertility while on therapy owing to decrease in corpora lutea. Odds of pregnancy in women on EGFR and ALK inhibitors may be reduced owing to potential increase in postimplantation loss found in animals. Crizotinib and entrectinib exhibit in vitro mutagenic potential. Several effects on human pregnancies have been noted; however, 11 EGFR and ALK tyrosine kinase inhibitor-exposed infants have been documented free of substantial adverse health effects by ages 4 months to 2 years. Successful gestational surrogacy has been reported in two women treated with crizotinib. Adoption and termination approaches have also been undertaken by some patients., Conclusions: Reproduction may not be out of reach for some patients with advanced NSCLC. Additional explorations of the impact and optimal timing of targeted therapy in egg capture and pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC is warranted., Competing Interests: Disclosure Dr. Simons reports receiving honorarium from Sanofi and Janssen. Dr. Camidge reports receiving honoraria from AbbVie, Anheart, Appolomics, AstraZeneca/Daiichi, Beigene, Dizal, Elevation, Eli Lilly, EMD Serono, Hengrui, Hummingbird, Imagene, Immunocore, Janssen, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Prelude, Regeneron, Roche, Sanofi, Seattle Genetics, Takeda, Theseus, Valence, and Xcovery; and having clinical trials (institutional) sponsored by AbbVie, AstraZeneca, Blueprint, Dizal, Inhibrx, Karyopharm, Nuvalent, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point, and Verastem., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to investigate the expression of EGFR and HER-2 oncogenes using an experimental two stage chemically induced carcinogenesis protocol on the dorsal skin in FVB/N mice. Forty female FVB/N mice 4 weeks old, were grouped into one control (n = 8) and two experimental groups (Group A: n = 16, Group B: n = 16) following a randomization process. Two-stage carcinogenesis protocol, was implicated, including an initial treatment with 97.4 nmol DMBA on their shaved dorsal skin and subsequent treatments of 32.4 nmol TPA applications after 13 weeks for Group A and after 20 weeks for Group B. The control group C, received no treatment. Skin was examined weekly for tumor development. Post-experiment, animals were euthanized for tissue analysis. The histological status of the skin lesions in the experimental groups corresponded well with tumour advancement (from dysplasia to poorly-differentiated carcinoma). Tumour sections were evaluated histologically and immunohistochemically. EGFR expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 008 respectively), while tended to be higher in benign tumours (p = 079), compared to normal histology. Moreover, mean percentage of EGFR positive expression in malignant tumours was significantly higher than in benign tumours (p < 001). HER-2 expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 015 respectively), while tended to be higher in benign tumours (p = 085), compared to normal histology. Furthermore, mean percentage of HER-2 positive expression in malignant tumours was significantly higher than in benign tumours (p = 005). The study demonstrated that in FVB/N mice subjected to a two-stage chemically induced carcinogenesis protocol, there was a significant increase in the expression of EGFR and HER-2 oncogenes in precancerous and malignant skin lesions compared to normal tissue. This suggests a potentially early role of these oncogenes in the progression of skin tumours in this model., Competing Interests: Declaration of competing interest The authors report no competing interests regarding this study., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Our study identified a novel long noncoding RNA, LINC01322, that acts as an oncogene in lung adenocarcinoma progression. Cytoplasmic and nuclear RNA purification assays indicated that LINC01322 was localized in the cytoplasm and nucleus. Gene set enrichment analysis revealed the involvement of LINC01322 in the regulation of cell proliferation, migration, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. LINC01322 may promote lung adenocarcinoma proliferation and migration through the Janus kinase/signal transducer and activator of transcription signaling pathway. In vitro experiments demonstrated that the knockdown of LINC01322 significantly suppressed lung adenocarcinoma cell proliferation, migration, and activation of the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, whereas overexpression had the opposite effects. Inhibition of the Janus kinase 2/signal transducer and activator of transcription 3 pathway activity partially reversed the enhancement of cell proliferation and migration caused by LINC01322 overexpression. In vivo experiments further verified the oncogene role of LINC01322. Altogether, our findings suggest that LINC01322 promotes lung adenocarcinoma progression by activating the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway and that it could be a therapeutic target., 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 Ltd. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is the most frequent subtype of head and neck cancer, generally with a poor prognosis and limited therapeutic options due to its highly heterogeneous malignancy. In this study, we screened functional splicing regulatory RNA binding proteins (RBPs) that were closely related with the prognosis of HNSCC patients and showed significant expression differences between HNSCC tumors and normal tissues. Based on this finding, we chose six candidate genes (HNRNPC, ZCRB1, RBM12B, SF3A2, SF3B3, and SRSF11) to generate a prognostic prediction model and validated the accuracy of the prognostic model for predicting patient survival outcomes. We found that the risk score predicted by our model can serve as an independent prognostic predictor. Notably, HNSCC tumors showing higher expression of SF3B3, HNRNPC, or ZCRB1 possessed higher risk scores in the discovered prediction model. The investigation of the underlying mechanism validated that knockdown of SF3B3, HNRNPC, and ZCRB1 separately induced a substantial impairment of HNSCC cell survival. Conversely, overexpression of each of the three genes promoted tumor cellular proliferation. High throughput RNA sequencing analysis revealed that changes in the expression of SF3B3 and HNRNPC remarkably affected alternative splicing of genes related to cell cycle regulation, whereas the depletion of ZCRB1 contributed to aberrant splicing events involving in DNA damage response. In addition, the prognostic prediction model's risk score was demonstrated to be related with the immune infiltration score. Particularly, SF3B3 has a negative correlation with CD8A expression. Therefore, our findings provide promising prognosis predictors and potential therapeutic targets for better treatment efficacy of HNSCC., 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.)

Star-PAP is a non-canonical poly(A) polymerase that is down regulated in breast cancer. While Star-PAP down regulation impairs target mRNA polyadenylation, paradoxically, we see up regulation of a large number of oncogenes on Star-PAP knockdown. Using two breast cancer cells (MCF7 with high Star-PAP, and MDA-MB-231 with negligible Star-PAP level), we discover that Star-PAP negatively regulates oncogene expression and subsequently cellular proliferation. This regulation is compromised with Star-PAP mutant of 3'-end processing function (serine 6 to alanine, S6A phospho-mutation). Concomitantly, xenograft mice model using MDA-MB-231 cells reveals a reduction in the tumour formation on ectopic Star-PAP expression that is ameliorated by S6A mutation. We find that Star-PAP control of target oncogene expression is independent of Star-PAP-mediated alternative polyadenylation or target mRNA 3'-end formation. We demonstrate that Star-PAP regulates target oncogenes through cellular miRNAs (miR-421, miR-335, miR-424, miR-543, miR-205, miR-34a, and miR-26a) that are down regulated in breast cancer. Analysis of various steps in miRNA biogenesis pathway reveals that Star-PAP regulates 3'-end formation and synthesis of primary miRNA (host) transcripts that is dependent on S6 phosphorylation thus controlling mature miRNA generation. Using mimics and inhibitors of two target miRNAs (miR-421 and miR-424) after Star-PAP depletion in MCF7 or ectopic expression in MDA-MB-231 cells, we demonstrate that Star-PAP controls oncogene expression and cellular proliferation through targeting miRNAs that regulates tumour formation. Our study establishes a novel mechanism of oncogene expression independent of alternative polyadenylation through Star-PAP-mediated miRNA host transcript polyadenylation that regulates breast cancer progression., Competing Interests: Declaration of competing interest We declare that we 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.)

Ethylene glycol monomethyl ether (EGME) has been used in many products usually handled by humans including inks, paints, polishes, brake fluids and so on. This present study therefore, investigated its effect on lung, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for a period of 7, 14, and 21 days. Following 7 days of oral exposure to EGME, activities of GPx and SOD were significantly increased, as well as levels of K-Ras, c-Myc, p53, caspase-3, TNF-α and, IL-6, while NO level and GST activity were significantly reduced compared with control. At the end of 14 days exposure, GSH level was significantly decreased, while levels of K-Ras, c-Myc, p53, caspase-3, TNF-α, IL-6, NO and the activities of SOD and GPx were significantly elevated with respect to control. After 21 days of EGME administration, levels of Bcl-2, IL-10, GSH and NO as well as GST activity were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, IL-6, IL-1β, TNF-α, as well as GPx, CAT, and SOD activities were significantly elevated compared with control. Lung histopathology revealed chronic disseminated alveolar inflammation, bronchiolitis, severe alveolar and bronchi hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels as a result of EGME exposures. Exposures to EGME could trigger lung damage via the disorganization of the antioxidant system, eliciting the up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

2-methoxyethanol (2-ME) is an organic solvent widely used in the manufacture of brake fluids, paints, resins, varnish, nail polish, acetate cellulose, wood coloring, and as a plasticizer in plastics manufacturing. We therefore, investigated its effect on the liver, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of 2-ME for a period of 7, 14, and 21 days. Following 7 days of administration of 2-ME, there was a significant increase in the level of Bax, c-Myc, K-Ras, TNF-α, IL-1β, IL-6, MDA and GPx activity, while the levels of Bcl-2, NO and GSH were significantly reduced compared with control. At the end of 14 days exposure, Bcl-2, and GSH levels, as well as GST activity, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. After 21 days of 2-ME administration, Bcl-2, IL-10, and GSH levels, as well as SOD and GST activities, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, p53, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. Lastly, liver histopathology confirmed and corroborated the biochemical findings reported above. We therefore, advised that exposures to 2-ME should be strictly avoided as it could trigger hepatic damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Salivary Gland carcinomas (SGCs) are rare tumors accounting for less than 1% of all cancers with 21 histologically diverse subtypes. The rarity of the disease presents a challenge for clinicians to conduct large size randomized controlled trials. Surgery and radiotherapy remain the only curative treatment for localized disease, whereas treatments for recurrent and metastatic disease remain more challenging with very disappointing results for chemotherapy. The different histological subtypes harbor various genetic alterations, some pathognomonic with a diagnostic impact for pathologists in confirming a difficult diagnosis and others with therapeutic implications regardless of the histologic subtype. Current international guidelines urge pathologists to identify androgen receptor status, HER-2 expression that could be determined by immunohistochemistry, and TRK status in patients with non-adenoid cystic salivary gland carcinoma that are eligible to initiate a systemic treatment, in order to offer them available targeted therapies or refer them to clinical trials based on their mutational profile. A more advanced molecular profiling by next generation sequencing would offer a larger panel of molecular alterations with possible therapeutic implications such as NOTCH, PI3K, BRAF, MYB, and EGFR. In the following review, we present the most common genetic alterations in SGCs as well as actionable mutations with the latest available data on therapeutic options and upcoming clinical trials., 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 Ltd. All rights reserved.)

Breast cancer has become a severe public health concern and one of the leading causes of cancer-related death in women worldwide. Several genes and mutations in these genes linked to breast cancer have been identified using sophisticated techniques, despite the fact that the exact cause of breast cancer is still unknown. A commonly used feature for identifying driver mutations is the recurrence of a mutation in patients. Nevertheless, some mutations are more likely to occur than others for various reasons. Sequencing analysis has shown that cancer-driving genes operate across complex networks, often with mutations appearing in a modular pattern. In this work, as a retrospective study, we used TCGA data, which is gathered from breast cancer patients. We introduced a new machine-learning approach to examine gene functionality in networks derived from mutation associations, gene-gene interactions, and graph clustering for breast cancer analysis. These networks have uncovered crucial biological components in critical pathways, particularly those that exhibit low-frequency mutations. The statistical strength of the clinical study is significantly boosted by evaluating the network as a whole instead of just single gene effects. Our method successfully identified essential driver genes with diverse mutation frequencies. We then explored the functions of these potential driver genes and their related pathways. By uncovering low-frequency genes, we shed light on understudied pathways associated with breast cancer. Additionally, we present a novel Monte Carlo-based algorithm to identify driver modules in breast cancer. Our findings highlight the significance and role of these modules in critical signaling pathways in breast cancer, providing a comprehensive understanding of breast cancer development. Materials and implementations are available at: [https://github.com/MahnazHabibi/BreastCancer]., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Cancer remains a significant global public health issue. There is growing proof that Ring Finger Protein 186 (RNF186) may play a function in pan-cancer, however, this has not yet been thoroughly determined. This study aims to analyze RNF186 with potential implications in progression and prognosis in human cancer., Materials and Methods: A comprehensive bioinformatics approaches combined with experimental verification were used across 33 types of cancers in this study to conduct a pan-cancer investigation of RNF186 from the perspectives of gene expression, prognosis, genomic alterations, immunological markers, gene set, and function., Key Findings: RNF186 is a valuable prognostic biomarker in several cancer types, especially breast invasive carcinoma (BRCA) and uterine corpus endometrial carcinoma (UCEC). The levels of RNF186 promoter methylation and genetic alterations may be responsible for some cancers' abnormal expression. Furthermore, RNF186 expression was determined to be associated with immune checkpoint genes. Analysis of RNF186-related genes revealed that proteasome and PI3K-AKT signaling pathway were primarily involved in the cellular function of RNF186. Additionally, our research first confirmed that RNF186 may function as an oncogene and contribute to cancer proliferation, migration and invasion in UCEC. In contrast, RNF186 may play an inhibitory role in BRCA progression. This function depends on the ligase activity of RNF186., Significance: This study suggests that RNF186 is a novel critical target for tumor progression in BRCA and UCEC. It reveals that RNF186 may be associated with tumor immunotherapy, which may provide an effective predictive evaluation of the prognosis of immunotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastric cancer (GC) has emerged as one of the most common malignancies in gastrointestinal system. Inducible T-cell costimulator ligand (ICOSLG) was found to be highly expressed in various cancers, which contributes to disease progression. This study aims to investigate the role of ICOSLG and its potential mechanism of action in dictating the aggressiveness of GC cell. ICOSLG and miR-331-3p expression patterns in cancerous and para-cancerous tissues from GC patients were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The miRNAs targeting ICOSLG were predicted by "miRDB", "starBase," and "TargetScan" databases. The interplay of ICOSLG and miR-331-3p in dictating the aggressiveness and glycolysis of GC cells was investigated by CCK-8 proliferation assay and Transwell migration/invasion assays, as well as the detection of glucose uptake, lactate production and ATP levels. The tumorigenesis of GC cells after ICOSLG silencing was examined in the nude mice. ICOSLG was highly expressed in GC tissues, and GC patients with high ICOSLG expression showed a poorer prognosis than the low-expression group. Further, high ICOSLG level was correlated with more advanced TNM stages, more lymph-node metastases, and poorer tumor differentiation. ICOSLG knockdown inhibited the proliferation, migration, invasion and tumor formation of GC cells, which was concomitant with reduced glucose consumption, lactate production, and ATP levels. In contrast, ICOSLG overexpression enhanced the aggressiveness of GC cells, and this effect was abrogated after the treatment with glycolysis inhibitor. We further found that miR-331-3p was a negative regulator of ICOSLG4, and miR-331-3p overexpression reduced ICOSLG4 expression and suppressed the aggressive phenotype induced by ICOSLG4 in GC cells. Together, these findings indicate that ICOSLG4, as an oncogene, is upregulated to promote glycolysis and the malignant phenotype in GC cells. miR-331-3p, which is downregulated in GC tissues, functions as a negative regulator of ICOSLG4. Targeting miR-331-3p/ICOSLG4 axis could potentially suppress GC progression., Competing Interests: Declaration of competing interest All authors have declared no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Small cell lung cancer (SCLC) is one of the deadliest forms of lung cancer, but few information exists regarding the role of genetics, particularly on Genome Wide Association Studies (GWAS). The aim of the study is to explore the evidence available obtained through GWAS studies for SCLC using a systematic review. We performed a literature search in the main databases until July 31st, 2023. We included all human based studies on GWAS for lung cancer which presented results for SCLC. Only studies with participants diagnosed of SCLC with anatomopathological confirmation were included. Fourteen studies were identified; 8 studies showed a relationship between ASCL1 overexpression and SCLC, which may regulate CHRNA5/A3/B4 cluster, producing a consequent nAChR overexpression. Nine papers, including 8 of the previous, found a positive association between SNPs located in chromosome 15 and SCLC. The most important cluster of genes found is CHRNA5/A3/B4 but the mechanism for the role of these genes is unclear. Kyoto Encyclopaedia of Genes and Genome (KEGG) shows that these receptors were found to be overexpressed where nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-Nitrosonornicotine (NNN) acts, involving different routes in SCLC carcinogenesis., Competing Interests: Disclosure Karl Kelsey is a founder and scientific advisor to Cellintec, which had no role in this research. The other authors declare not to have any conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer is one of the most extensive diseases with the highest mortality rate, accounting for almost 10 million deaths in 2020. The most common cancers are breast, lung, colon and rectum and prostate cancers. Of these, lung cancer, accounted for about 1.8 million of all cancer deaths (25%) in 2020. Detection of cancer relies on presence of biomarkers such as DNA molecules, proteins and metabolites released by cancerous cells into the circulation. Carcinoembryonic antigen (CEA) is one of the biomarkers that has been used for the detection of lung cancer. However, CEA is not specific to lung cancer since it is also manifested in gastric cancer, pancreatic cancer, colorectal cancer, and breast cancer. Recently, v-YES1 Yamaguchi sarcoma viral oncogene homolog 1 (YES1) was described as a specific biomarker for lung cancer. The detection of both CEA and YES1 would give more precise and authentic information for detecting lung cancer. This is because detection of a single tumor marker usually limits the precision in tumor diagnosis, due to the fact that several cancers have more than one marker linked with their prevalence. Whereas traditional methods have been used for the detection of CEA, electrochemical immunosensors have attracted considerable attention owing to their profound advantages, including fast response, miniaturization, high selectivity, low sample requirements and magnificent sensitivity. The fabrication of a multiplex and simultaneous immunosensor is met with challenge of preparation of distinguishable immunoprobes with different redox activities. This can be addressed by incorporation of electroactive Nano metals into the sensing platform. In this study, gold nanoparticles were used for the fabrication of an ultrasensitive sandwich electrochemical multiplex immunosensor for simultaneous detection of CEA and YES1. Under optimized conditions, the electrochemical immunosensor detection limit for YES1 and CEA was found to be 0.0022 and 0.0034 ng/mL respectively within a linear range of 0.1-50 ng/mL. The proposed immunosensor proved to be stable for up to 2 weeks and had negligible cross reactivity towards various interfering compounds in human plasma. This study reports that gold nanoparticles can be bio synthesized using shade dried Mangifera indica leaves extract. The bio-synthesized gold nanoparticles coupled with thiolated protein G can be used for fabrication of a multiplex immunosensor for detection of CEA and YES1. The proposed immunosensor can provide a new approach for early diagnosis of circulating cancer biomarkers and holds great promise for application in clinical diagnosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:LUCIA KIIO reports equipment, drugs, or supplies was provided by Universidad de Navarra, Center for Applied Medical Research. Lucia Kiio, D. Mbui, J. Onyatta, P. Ndangili, L. Montuenga has patent #KE/P/2022/4341 issued to Kenya Industrial Property Institute|., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancers are diseases caused by genetic and non-genetic environmental factors. Epigenetic alterations, some attributed to non-genetic factors, can lead to cancer development. Epigenetic changes can occur in tumor suppressors or oncogenes, or they may contribute to global cell state changes, making cells abnormal. Recent advances in gene editing technology show potential for cancer treatment. Herein, we will discuss our current knowledge of epigenetic alterations occurring in cancer and epigenetic editing technologies that can be applied to developing therapeutic options., (Copyright © 2024. Published by Elsevier Inc.)

Background: Obtaining sufficient tumor tissue for genomic profiling is challenging in pancreaticobiliary cancer (PBCA). We determined the utility of molecular barcoding (MB) of liquid biopsies (bile, duodenal fluid, and plasma) for highly sensitive genomic diagnosis and detection of druggable mutations for PBCA., Methods: Two in-house panels of 60 genes (non-MB panel) and 21 genes using MB (MB panel) were used for the genomic analysis of 112 DNA samples from 20 PBCA patients. We measured the yield of DNA and compared the genomic profiles of liquid samples obtained using the non-MB panel and the MB panel. The utility of the panels in detecting druggable mutations was investigated., Results: A significantly greater amount of DNA was obtained from bile supernatants and precipitates compared to tumor samples (P < 0.001 and P = 0.001, respectively). The number of mutations per patient was significantly higher using the MB panel than using the non-MB panel (2.8 vs. 1.3, P = 0.002). Tumor-derived mutations were detected more frequently using the MB panel than the non-MB panel (P = 0.023). Five drug-matched mutations were detected in liquid samples., Conclusions: Liquid biopsy with MB may have utility in providing genomic information for the prognosis of patients with PBCA., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroshi Ohyama reports financial support was provided by Japan Society for the Promotion of Science. Yosuke Hirotsu reports financial support was provided by Japan Society for the Promotion of Science. Rintaro Mikata reports financial support was provided by Japan Society for the Promotion of Science. Hiroshi Ohyama reports financial support was provided by the Pancreas Research Foundation of Japan. Hiroshi Ohyama reports financial support was provided by the Chiba Foundation for Health Promotion and Disease Prevention. Yosuke Hirotsu reports financial support was provided by Yasuda Memorial Medical Foundation. Yosuke Hirotsu reports financial support was provided by Uehara Memorial Foundation. Yosuke Hirotsu reports financial support was provided by The Takeda Foundation. Yosuke Hirotsu reports financial support was provided by Genome Research Project from Yamanashi Prefecture. Masao Omata reports financial support was provided by Genome Research Project from Yamanashi Prefecture., (Copyright © 2023. Published by Elsevier Inc.)

Ethylene glycol monomethyl ether (EGME) is a major component of paints, lacquers, inks, and automobile brake fluids. As a result, exposures to humans are inevitable. We therefore, investigated in this study, its effect on testicular cells in a time-course manner in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for duration of 7, 14, and 21 days. Following 7 days of the administration, levels of NO and GSH were significantly reduced, while levels of c-Myc, K-Ras, caspase-3, IL-6, TNF-α, and IL-1β were significantly increased compared with control. At the end of 14 days exposure, GPx, and SOD activities, as well as IL-10 level were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1β, and GST activity were significantly elevated compared with control. After 21 days of EGME administration, Bcl-2, IL-10, and NO levels were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1β, MDA and GST activity were significantly increased compared with control. After 7, 14, and 21 days of EGME administrations, testis histopathology showed severe loss of seminiferous tubules, the seminiferous epithelium revealed very few spermatocytes, spermatids, spermatogonia, spermatozoa, and Sertoli cells, while the interstitial tissue is eroded, with scanty abnormal Leydig cells, compared with the control that appeared normal. We therefore, concluded that EGME-induced testicular toxicity as a result of EGME administration could be via the disorganization of the endogenous antioxidant systems as well as up-regulation of pro-inflammatory, apoptotic and oncogenic mediators in rats.

Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.

Previous studies revealed that some bioactive food components have anti-cancer effects. However epigenetic effects of dietary compound resveratrol are largely unknown in breast cancer cells (M.A. Dawson, T. Kouzarides, 2012) [1]. Here we provide novel data and comparisons of DNA methylation status of promoter gene regions in response to resveratrol treatment at 24 h and 48 h versus untreated MDA-MB-231 breast cancer cells. DNA methylation changes were measured using Array-PRIMES method (aPRIMES) followed by whole-genome hybridization using human DNA methylation promoter microarray NimbleGen HG18 Refseq Promoter 3×720 K array. Our data were associated to corresponding changes in mRNA expression in a set of cancer-related genes. Using gene ontology analysis we also identify cancer-related cellular processes and pathways that can be epigenetically reprogramed by resveratrol. Data in this article are associated to the research articles “Methylation Landscape of Human Breast Cancer Cells in Response to Dietary Compound Resveratrol”. Medina Aguilar et al., PLoS ONE 11(6): e0157866. doi:10.1371/journal.pone.0157866 2016 (A.R. Medina, P.C. Pérez, L.A. Marchat, P. Gariglio, M.J. García, C.S. Rodríguez, G.E. Ruíz, et al., 2016) [2]; and “Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells” in Oncology Reports. Medina Aguilar et al., 2016 Jun; 35(6):3696-704. doi: 10.3892/or.2016.4728 (A.R. Medina, P. Gariglio, M.J. García, O.E. Arechaga, S.N. Villegas, C.M. Martínez et al., 2016) [3].

DNA Methylation is an epigenetic phenomenon in which methyl groups are added to the cytosines, thereby altering the physio-chemical properties of the DNA region and influencing gene expression. Aberrant DNA methylation in a set of genes or across the genome results in many epigenetic diseases including cancer. In this paper, we use entropy to analyze the extent and distribution of DNA methylation in Tumor Suppressor Genes (TSG's) and Oncogenes related to a specific type of cancer (viz.) KIRC (Kidney-renal-clear-cell-carcinoma). We apply various mathematical transformations to enhance the different regions in DNA methylation distribution and compare the resultant entropies for healthy and tumor samples. We also obtain the sensitivity and specificity of classification for the different mathematical transformations. Our findings show that it is not just the measure of methylation, but the distribution of the methylation levels in the genes that are significant in cancer.

Metabolic reprogramming is critical to oncogenesis, but the emergence and function of this profound reorganization remain poorly understood. Here we find that cooperating oncogenic mutations drive large-scale metabolic reprogramming, which is both intrinsic to cancer cells and obligatory for the transition to malignancy. This involves synergistic regulation of several genes encoding metabolic enzymes, including the lactate dehydrogenases LDHA and LDHB and mitochondrial glutamic pyruvate transaminase 2 (GPT2). Notably, GPT2 engages activated glycolysis to drive the utilization of glutamine as a carbon source for TCA cycle anaplerosis in colon cancer cells. Our data indicate that the Warburg effect supports oncogenesis via GPT2-mediated coupling of pyruvate production to glutamine catabolism. Although critical to the cancer phenotype, GPT2 activity is dispensable in cells that are not fully transformed, thus pinpointing a metabolic vulnerability specifically associated with cancer cell progression to malignancy.

Constitutive mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activity drives survival of malignant lymphomas addicted to chronic B-cell receptor signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. Although MALT1 scaffolding induces NF-κB-dependent survival signaling, MALT1 protease function is thought to augment NF-κB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-κB transcriptional responses but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and nonenzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data suggest that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces posttranscriptional upregulation of many genes including NFKBIZ/IκBζ, NFKBID/IκBNS, and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on an mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives posttranscriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in MALT lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and posttranscriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease-selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Extrachromosomal DNA (ecDNA), derived from chromosomes, is a cancer-specific circular DNA molecule. EcDNA drives tumor initiation and progression, which is associated with poor clinical outcomes and drug resistance in a wide range of cancers. Although ecDNA was first discovered in 1965, tremendous technological revolutions in recent years have provided crucial new insights into its key biological functions and regulatory mechanisms. Here, we provide a thorough overview of the methods, bioinformatics tools, and database resources used in ecDNA research, mainly focusing on their performance, strengths, and limitations. This study can provide important reference for selecting the most appropriate method in ecDNA research. Furthermore, we offer suggestions for the current bioinformatics analysis of ecDNA and provide an outlook to the future research., Competing Interests: Declaration of competing interest All authors of this manuscript have directly participated in planning and execution of this review. The contents of this manuscript have not been copyrighted or published previously. The contents of this manuscript are not now under consideration for publication elsewhere. The contents of this manuscript will not be copyrighted, submitted, or published elsewhere while acceptance by “Computers in Biology and Medicine”. We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Methods, bioinformatics tools and databases in ecDNA research: An overview”., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Tumor antigenicity and efficiency of antigen presentation jointly influence tumor immunogenicity, which largely determines the effectiveness of immune checkpoint blockade (ICB). However, the role of altered antigen processing and presentation machinery (APM) in breast cancer (BRCA) has not been fully elucidated., Methods: A series of bioinformatic analyses and machine learning strategies were performed to construct APM-related gene signatures to guide personalized treatment for BRCA patients. A single-sample gene set enrichment analysis (ssGSEA) algorithm and weighted gene co-expression network analysis (WGCNA) were combined to screen for BRCA-specific APM-related genes. The non-negative matrix factorization (NMF) algorithm was used to divide the cohort into different clusters and the fgsea algorithm was applied to investigate the altered signaling pathways. Random survival forest (RSF) and the least absolute shrinkage and selection operator (Lasso) Cox regression analysis were combined to construct an APM-related risk score (APMrs) signature to predict overall survival. Furthermore, a nomogram and decision tree were generated to improve predictive accuracy and risk stratification for individual patients. Based on Tumor Immune Dysfunction and Exclusion (TIDE) method, random forest (RF) and Lasso logistic regression model were combined to establish an APM-related immunotherapeutic response score (APMis). Finally, immune infiltration, immunomodulators, mutational patterns, and potentially applicable drugs were comprehensively analyzed in different APM-related risk groups. IHC staining was used to assess the expression of APM-related genes in clinical samples., Results: In this study, APMrs and APMis showed favorable performances in risk stratification and therapeutic prediction for BRCA patients. APMrs exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. APMrs was closely associated with distinct mutational patterns, immune cell infiltration and immunomodulators expression. Furthermore, the two APM-related gene signatures were independently validated in external cohorts with prognosis or immunotherapeutic responses. Potential applicable drugs and targets were mined in the APMrs-high group. APM-related genes were further validated in our in-house samples., Conclusion: The APM-related gene signatures established in our study could improve the personalized assessment of survival risk and guide ICB decision-making for BRCA patients., 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 © 2023. Published by Elsevier Inc.)

The therapies targeting mutations of driver genes in cancer have advanced into clinical trials for a variety of tumors. In glioblastoma (GBM), epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene, and targeting EGFR has been widely investigated as a promising direction. However, the results of EGFR pathway inhibitors have not been satisfactory. Limited blood-brain barrier (BBB) permeability, drug resistance, and pathway compensation mechanisms contribute to the failure of anti-EGFR therapies. This review summarizes recent research advances in EGFR-targeted therapy for GBM and provides insight into the reasons for the unsatisfactory results of EGFR-targeted therapy. By combining the results of preclinical studies with those of clinical trials, we discuss that improved drug penetration across the BBB, the use of multi-target combinations, and the development of peptidomimetic drugs under the premise of precision medicine may be promising strategies to overcome drug resistance in GBM., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2023. Published by Elsevier B.V.)

Background: Preoperative immunotherapy has shed light on the management of resectable non-small cell lung cancer (NSCLC). However, whether neoadjuvant immunotherapy benefits patients with oncogene-positive NSCLC remains unknown., Methods: Data were retrieved from 4 institutions in the period from August 2018 to May 2021. Eligible patients were aged ≥18 years with histologically confirmed stage IIA to stage IIIB (T1-2 N1-2 or T3-4 N0-2) NSCLC that was deemed to be surgically resectable. The neoadjuvant regimen included immune checkpoint inhibitors alone or in combination with platinum-based doublets. Surgical resection was performed 4 to 6 weeks after the first day of the last cycle of treatment. The primary end point was major pathologic response (MPR; ≤10% viable tumor cells). Analyses were categorized according to the patients' oncogene (EGFR, ALK, KRAS, MET, BRAF, ROS1, RET) status., Results: Overall, 137 patients were identified; 46 (33%) patients had nonsquamous cell cancer, and 114 (83%) had stage IIIA/B disease. Oncogene alterations were identified in 22 (16%) patients, of whom only 2 patients (2/22 [9%]) had an MPR compared with 65 (65/115 [56.5%]) in the oncogene-negative population (P < .001). Similar results were retained after propensity score matching for age, sex, smoking status, histologic type, stage, and cycles of neoadjuvant treatment. Squamous cell carcinoma (odds ratio, 2.54; 95% CI, 1.08-5.99) and positive oncogene status (odds ratio, 0.13; 95% CI, 0.03-0.64) were found to be indicators for MPR by logistic regression. The 1-year event-free survival rate was 75.4% in the oncogene-positive group, which was not significantly different from 85.5% in the oncogene-negative population (P = .23)., Conclusions: Patients with stage II-III oncogene-positive NSCLCs respond less than patients with oncogene-negative NSCLCs after neoadjuvant immunotherapy., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Inorganic complexes of iron and sulfur, that is, iron-sulfur [FeS] clusters, have played a fundamental role in life on Earth since the prebiotic period. These clusters were involved in elementary reactions leading to the emergence of life and, since then, gained function in processes, such as respiration, replication, transcription, and the immune response. We discuss how three [FeS] proteins involved in the innate immune response play a role in oncogene expression/function and oncometabolism. Our analysis highlights the importance of future research into understanding the [FeS] clusters' roles in cancer progression and proliferation. The outcomes of these studies will help identify new targets and develop new anticancer therapeutics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kourosh H. Ebrahimi reports financial support was provided by The Royal Society. Kourosh H. Ebrahimi, Hoang Thao Nghi reports financial support was provided by King's College London. Hoang Thao Nghi reports financial support was provided by Vietnamese Government Scholarship. Sayeh Shahmohammadi reports financial support was provided by Hungarian Scientific Research Council., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ultimate goal of this study is to analyze the gene regulation between FAM111B and p53 in lung adenocarcinoma using Boolean networks. Recent studies have shown that downregulation of FAM111B enhances the G2/M cell cycle checkpoint in the respective cell lines. Upregulation of p53 directly downregulates FAM111B, which is directed to affect cell cycle controllers Cdc25C and Cdk1/CyclinB, thereby controlling G2/M cell cycle arrest. As for apoptosis, down-regulation of FAM111B by p53 directly regulates the BAG3/Bcl-2 axis, which triggers apoptotic cell death. However, the molecular mechanisms involving p53 and FAM111B in G2/M checkpoint regulation are still unknown. Thus, we present a Boolean model of the G2/M checkpoint considering the effect of p53 and FAM111B. Our model indicates that the cell fate between the two cellular phenotypes, arrest, and apoptosis, at the G2/M checkpoint is non-deterministic and is controlled by p53. The model was compared with the experimental data involving gain- or loss-of-function genes and achieved a fair agreement. The model predicts a positive circuit involving p53/FAM111B/BAG3. Our circuit perturbation analysis suggests that this circuit may be essential for controlling cell-fate decisions at the G2/M checkpoint. Our model supports that FAM111B is an engaging target for drug development in lung adenocarcinoma., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate’s phosphorylation, rather than SUMOylation, and binding to RNF4’s arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.