Oncogenic Processes Research Articles

Single-Sample Networks Reveal Intra-Cytoband Co-Expression Hotspots in Breast Cancer Subtypes

Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this study, we employed single-sample gene co-expression network analysis to investigate the structural and functional genomic alterations across breast cancer subtypes (Luminal A, Luminal B, Her2-enriched, and Basal-like) and compared them with normal breast tissue. We utilized RNA-Seq gene expression data to infer gene co-expression networks. The LIONESS algorithm allowed us to construct individual networks for each patient, capturing unique co-expression patterns. We focused on the top 10,000 gene interactions to ensure consistency and robustness in our analysis. Network metrics were calculated to characterize the topological properties of both aggregated and single-sample networks. Our findings reveal significant fragmentation in the co-expression networks of breast cancer subtypes, marked by a change from interchromosomal (TRANS) to intrachromosomal (CIS) interactions. This transition indicates disrupted long-range genomic communication, leading to localized genomic regulation and increased genomic instability. Single-sample analyses confirmed that these patterns are consistent at the individual level, highlighting the molecular heterogeneity of breast cancer. Despite these pronounced alterations, the proportion of CIS interactions did not significantly correlate with patient survival outcomes across subtypes, suggesting limited prognostic value. Furthermore, we identified high-degree genes and critical cytobands specific to each subtype, providing insights into subtype-specific regulatory networks and potential therapeutic targets. These genes play pivotal roles in oncogenic processes and may represent important keys for targeted interventions. The application of single-sample co-expression network analysis proves to be a powerful tool for uncovering individual-specific genomic interactions.

EHD1 promotes breast cancer metastasis through upregulating HIF2a expression via activating mTOR pathway

AbstractThe multistep dynamic process of metastasis is the primary cause of breast cancer deaths. C‐terminal Eps15‐homology domain‐containing protein 1 (EHD1), a translocator associated with endocytic recycling, has been implicated in various oncogenic processes. However, the precise molecular mechanisms of EHD1‐induced breast cancer metastases remain largely unexplored. Here we found that the upregulation of EHD1 in breast cancer was positively associated with distant lymph node metastasis in patients. Meanwhile, EHD1 promoted epithelial‐mesenchymal transition (EMT), invasion, and metastasis of breast cancer cells in both two‐dimensional (2D) and three‐dimensional (3D) culture models in vitro, as well as in vivo. Remarkably, EHD1 can activate the AKT–mTOR pathway to upregulate the protein expression of hypoxia‐inducible factor 2α (HIF2α) under normoxic conditions and subsequently enhance the invasive and metastatic breast cancer. Our findings indicated EHD1 as a new regulator of HIF2α and a potential therapeutic target for inhibiting breast cancer metastasis.

EXTH-83. CHARACTERIZATION OF SPLICING ABERRATIONS INDUCED BY PRMT5 INHIBITION IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) are lethal tumors with limited treatment options, with a high unmet need for novel therapies. PRMT5, an arginine methyltransferase that regulates several histone and non-histone targets, is overexpressed in cancers including GBM and is a promising therapeutic target given its role in promoting oncogenic processes. Here, we characterized the effects of pharmacological inhibition of PRMT5 by the brain-penetrant, orally bioavailable inhibitors, PRT811 and PRT808 on treatment-induced splicing aberrations using a panel of patient-derived glioma stem cells (GSC) and organotypic human glioma slice cultures. Changes in protein expression upon PRMT5 inhibition were assessed using reverse phase protein array (RPPA) analysis. Additionally, splicing aberrations due to PRMT5 inhibition in were tested in several GSCs using RNA-seq. We observed a potent reduction of symmetrical dimethylation of arginine (SDMA protein marks by both PRMT5 inhibitors across various GSC lines and ex-vivo brain tumor tissue slices. Notably, GSCs with both mutant and wild-type p53 displayed similar sensitivity to PRMT5 inhibition, independent of MTAP status. Moreover, PRMT5 inhibition elicited reduced cell proliferation, altered cell survival pathways, and apoptosis. RNA-seq analysis revealed that splicing alterations affecting numerous oncogenes and regulatory factors, encompassing 42 cancer driver genes, 80 splicing factors, and 42 transcriptional factors across these GSC lines, with specific splicing events observed in nuclear and cytoplasmic subcellular compartments. Additional analysis is ongoing to determine which of the aberrant transcripts are translated to yield tumor specific neoantigens that can be potential targets for tumor specific immune strategies. These results underscore the efficacy of pharmacological PRMT5 inhibition in genetically and epigenetically diverse GSCs, and highlight its potential for developing novel immune and non-immune therapeutic strategies against GBM.

MiRNA Profiling of Areca Nut-Induced Carcinogenesis in Head and Neck Cancer

Background: While miRNAs are increasingly recognized for their role in tumorigenesis, their involvement in head and neck cancer (HNC) remains insufficiently explored. Additionally, the carcinogenic mechanisms of areca nut, a major habitual carcinogen in Southeast Asia, are not well understood. Methods and results: This study adopts a systematic approach to identify miRNA profiles associated with areca nut-induced HNC. Using miRNA microarray analysis, we identified 292 miRNAs dysregulated in areca nut-treated HNC cells, with 136 upregulated and 156 downregulated. Bioinformatic analysis of the TCGA-HNSC dataset uncovered a set of 692 miRNAs relevant to HNC development, comprising 449 overexpressed and 243 underexpressed in tumor tissues. Integrating these datasets, we defined a signature of 84 miRNAs, including 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs), highlighting their pivotal role in areca nut-induced carcinogenesis. MultiMiR analysis identified 740 genes cross-regulated by eight hub TsmiRs, significantly impacting key cancer-related pathways (p53, PI3K-AKT, MAPK, and Ras) and critical oncogenic processes. Moreover, we validated miR-499a-5p as a vital regulator, demonstrating its ability to mitigate areca nut-induced cancer progression by reducing cell migration, invasion, and chemoresistance. Conclusions: Thus, this miRNA signature addresses a crucial gap in understanding the molecular underpinnings of areca nut-induced carcinogenesis and offers a promising platform for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies.

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma

AbstractRhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive the majority of the clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details of PAX3-FOXO1 epigenetic mechanisms, including interactions with, and dependence on, other chromatin and transcription factors, are incompletely understood. We previously identified a novel disease-promoting epigenetic axis in RMS, involving the histone demethylase KDM3A and the ETS1 transcription factor, and demonstrated that this epigenetic axis interfaces with PAX3-FOXO1 both phenotypically and transcriptomically, including co-regulation of biological processes and genes important to FP-RMS progression. In this study, we demonstrate that KDM3A and ETS1 colocalize with PAX3-FOXO1 to enhancers of important disease-promoting genes in FP-RMS, including FGF8, IL4R, and MEST, as well as PODXL, which we define herein as a new FP-RMS-promoting gene. We show that ETS1, which is induced by both PAX3-FOXO1 and KDM3A, exists in complex with PAX3-FOXO1, and augments PAX3-FOXO1 chromatin occupancy. We further show that the PAX3-FOXO1/ETS1 complex can be disrupted by the clinically relevant small molecule inhibitor YK-4-279. YK-4-279 displaces PAX3-FOXO1 from chromatin and interferes with PAX3-FOXO1-dependent gene regulation, resulting in potent inhibition of growth and invasive properties in FP-RMS, along with downregulation of FGF8, IL4R, MEST and PODXL expression. We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

Synergistic effects of anlotinib and DDP on breast cancer: targeting the VEGF/JAK2/STAT3 axis.

Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms. BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model. Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice. This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.

Harnessing the role of aberrant cell signaling pathways in glioblastoma multiforme: a prospect towards the targeted therapy.

Glioblastoma Multiforme (GBM), designated as grade IV by the World Health Organization, is the most aggressive and challenging brain tumor within the central nervous system. Around 80% of GBM patients have a poor prognosis, with a median survival of 12-15months. Approximately 90% of GBM cases originate from normal glial cells via oncogenic processes, while the remainder arise from low-grade tumors. GBM is notorious for its heterogeneity, high recurrence rates, invasiveness, and aggressive behavior. Its malignancy is driven by increased invasive migration, proliferation, angiogenesis, and reduced apoptosis. Throughout various stages of central nervous system (CNS) development, pivotal signaling pathways, including Wnt/β-catenin, Sonic hedgehog signaling (Shh), PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, STAT3, NF-КB, TGF-β, and Notch signaling, orchestrate the growth, proliferation, differentiation, and migration of neural progenitor cells in the brain. Numerous upstream and downstream regulators within these signaling pathways have been identified as significant contributors to the development of human malignancies. Disruptions or aberrant activations in these pathways are linked to gliomagenesis, enhancing the invasiveness, progression, and aggressiveness of GBM, along with epithelial to mesenchymal transition (EMT) and the presence of glioma stem cells (GSCs). Traditional GBM treatment involves surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ). However, most patients experience tumor recurrence, leading to low survival rates. This review provides an overview of the major cell signaling pathways involved in gliomagenesis. Furthermore, we explore the signaling pathways leading to therapy resistance and target key molecules within these signaling pathways, paving the way for the development of novel therapeutic approaches.

In silico and pharmacological evaluation of GPR65 as a cancer immunotherapy target regulating T-cell functions.

The success of cancer immunotherapies such as immune checkpoint inhibitors, CAR T-cells and immune cell engagers have provided clinicians with tools to bypass some of the limitations of cancer immunity. However, numerous tumour factors curtail the immune response against cancer and limit the efficiency of immuno-oncology (IO) therapies. Acidification of the extra-cellular tumour environment consecutive to aberrant cancer cell metabolism is a well-known promoter of oncogenic processes that also acts as an immune regulator. Yet, the suppressive mechanisms of low extra-cellular pH on anti-cancer immunity remain poorly understood. Recent reports have suggested that GPR65, a Gαs-coupled proton-sensing GPCR broadly expressed in the immune system, may act as an immune suppressant detrimental to anti-tumour immunity. So far, the immuno-regulatory properties of GPR65 in acidic milieux have mostly been documented in macrophages and myeloid cells. Our computational evaluation of GPR65's transcriptomic expression profile and potential as an IO target using public datasets prompted us to further investigate its functions in human T-cells. To this end, we identified and validated GPR65 small molecule inhibitors active in in vitro cellular assays and we showed that GPR65 inhibition promoted the killing capacity of antigen-specific human T-cells. Our results broaden the scope of GPR65 as an IO target by suggesting that its inhibition may enhance T-cell anti-tumour activity and provide useful pharmacological tools to further investigate the therapeutic potential of GPR65 inhibition.

Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome

In cancer genome analysis, identifying pathogenic alterations and assessing their effects on oncogenic processes is important. Although whole exome sequencing (WES) can effectively detect such changes, driver alterations could not be identified in 27.8% of the cases, according to a previous study. The objectives of the present study were to evaluate the utility of whole genome sequencing (WGS) and clarify its differences with WES in terms of driver alteration detection. For this purpose, WGS analysis was conducted on 177 driverless WES samples, selected from 5,480 fresh frozen samples derived from 5,140 Japanese patients with cancer. These samples were selected as primary tumor, both WES and transcriptome profiling were performed, estimated tumor content of ≥ 30%, and no driver alterations were identified by WES. WGS identified driver and likely driver alterations in 68.4 and 22.6% of the samples, respectively. The most frequent alteration type was oncogene amplification, followed by tumor suppressor gene deletion and small variants located outside the coding region. In the remaining 9.0% of samples, no such signals were identified; therefore, further investigations are required. The current study clearly demonstrated the role and utility of WGS in identifying genomic alterations that contribute to tumorigenesis.

CISD3 is a prognostic biomarker and therapeutic target in pan-cancer.

Recent studies indicate that CISD3 is crucial in mitochondrial function and tumorigenesis. Using various databases, we systematically analyzed its expression, prognostic value, and immune activity. Our findings show CISD3 is mainly expressed in tumor cells across cancers, with higher mRNA but lower protein levels, degraded post-translationally via the lysosomal pathway. In certain cancers, CISD3 expression is positively correlated with tumor-infiltrating immune cells. Prognostic analysis suggests dual roles as both protective and risk factors, notably an independent prognostic predictor in renal cell carcinoma (RCC). CISD3 copy number variations are linked to homologous recombination defects and tumor-specific neoantigens, negatively correlated with methylation levels. Pathway analysis reveals CISD3 involvement in oncogenic processes, such as proliferation inhibition and epithelial-mesenchymal transition. Protein interactions underline its role in mitochondrial metabolism and redox balance. Experiments confirm low CISD3 expression in cancers, with overexpression reducing proliferation, migration, invasion, and tumor growth in mice. Mechanistic studies indicate CISD3 overexpression disrupts mitochondrial function, increases ROS levels, decreases GSH/GSSG ratios and mitochondrial membrane potential, inhibiting antioxidant activity and promoting cell damage and ferroptosis, thus impeding cancer progression. This study highlights CISD3's potential as a prognostic biomarker and therapeutic target.

The Prognostic Significance of CTSV Expression in Patients with Hepatocellular Carcinoma.

Cathepsin V (CTSV) is a cysteine protease peptidase, which is typically upregulated in cancer and is associated with various oncogenic processes, such as angiogenesis, proliferation, apoptosis, and invasion. The study explored the role of CTSV in hepatocellular carcinoma (HCC) and its potential as a potential biomarker. This study collected tumor and peritumoral archived specimens from 180HCC patients who underwent surgical resection at Zhongshan Hospital, Fudan University (Shanghai, China) between 2009 and 2010. We extracted data from the TCGA and GEO databases and conducted differential expression analysis, univariate Cox regression, and Kaplan-Meier analysis. Ultimately, we determined that CTSV may emerge as a potential biomarker. Then, immunohistochemical staining for CTSV was performed on tumors and adjacent tissues of HCC patients, and a Cox proportional hazards model was constructed to evaluate the prognostic significance of CTSV expression levels. Applied functional enrichment analysis to reveal the underlying molecular mechanisms. Utilized ssGSEA enrichment analysis and TIMER2.0 algorithm to explore the correlation between CTSV expression and immune cells in HCC. In vitro and in vivo experiments were conducted using human liver cancer cell lines to further validate the clinical application value of CTSV. In this study, we observed that CTSV expression was notably elevated in HCC (P < 0.001), and identified a significant association between elevated CTSV expression and reduced overall survival rates in patients. In vitro and in vivo experiments indicated that CTSV knockdown could significantly inhibit the proliferation, migration, and invasion of liver cancer cells, and it was found that the combination of CTSV knockdown with PD-1 inhibitors might enhance the therapeutic effect of PD-1 inhibitors in HCC. CTSV serves as a standalone negative prognostic indicator and possesses clinical significance in HCC.

Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived Model

Background & AimsHepatitis B virus (HBV)-DNA integration into the host genome contributes to hepatocellular carcinoma (HCC) development. KMT2B is the second most frequent locus of HBV-DNA integration in HCC, however its role and function remain unclear. We aimed to clarify the impact of HBV-KMT2B integration in HCC development using a human genome-edited induced pluripotent stem cells (iPSCs) model. MethodsBased on the genetic information on HBV-KMT2B integration in HCC, we determined its complete DNA sequence and transcript variants. To exclude the effect of other oncogenic mutations, we reproduced HBV integration in healthy donor iPSCs with an intact genome and analyzed its effects using iPSC-derived hepatic progenitor cells (HPCs) and hepatocytes (iPS-Heps). ResultsThe reproduced HBV-KMT2B integration significantly upregulated the proliferation of hepatic cells. Comprehensive transcriptional and epigenetic analyses revealed enhanced expression of cell cycle-related genes in hepatic cells with HBV-KMT2B integration based on perturbation of histone 3 lysine 4 tri-methylation(H3K4me3), mimicking that in the original HCC sample. Long-read RNA-sequence detected the common KMT2B transcript variants in the HCC sample and HPCs. Overexpression of the truncated variant significantly enhanced proliferation of hepatic cells, whereas HBV-KMT2B fusion transcripts did not enhance proliferation. HBV-KMT2B-integrated HPCs exhibited replication stress and DNA damage, indicating that our model initiated the process of hepatocarcinogenesis due to abnormally promoted KMT2B function. ConclusionsOur disease model using genetically engineered iPSCs provides the first insight into both the KMT2B function in HCC development and the oncogenic processes by HBV-KMT2B integration. We clarified the novel oncogenic mechanism in HBV-related HCC due to aberrant KMT2B function.

Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells.

Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway. Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.

Immune-Mediated Inflammatory Diseases and Cancer - a dangerous liaison.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

C-Myc, AKT, Hsc70, and the T-Box Transcription Factor TBX3 Form an Important Oncogenic Signaling Axis in Breast Cancer.

Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer.

CXCR4 as a therapeutic target in acute myeloid leukemia.

Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML's oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and Treg cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.

COVID-19, Long COVID, and Gastrointestinal Neoplasms: Exploring the Impact of Gut Microbiota and Oncogenic Interactions

Background: The impact of COVID-19 and long-term COVID-19 on gastrointestinal neoplasms remains underexplored. The current review investigates the potential link between these conditions and the role of gut microbiota in mediating oncogenic processes. Dysbiosis, characterized by alterations in gut microbial composition, may exacerbate inflammation and immune dysregulation, contributing to cancer development. Methods: A comprehensive literature review was conducted using databases including PubMed, Scopus, Embase, SciELO, and Web of Science. Inclusion criteria encompassed studies published between 2020 and 2024 that explored the intersection of COVID-19, long-term COVID-19, and gastrointestinal cancers. The articles were critically appraised for quality and relevance, and data were synthesized to elucidate common mechanisms and outcomes. Results: The review identifies several mechanisms by which gut microbiota may influence cancer risk in COVID-19 patients. Persistent inflammation, oxidative stress, and immune dysfunction observed in Long COVID were associated with dysbiosis. Specific microbial metabolites, such as secondary bile and short-chain fatty acids, were implicated in promoting tumorigenesis. Comparative analysis of studies suggests that SARS-CoV-2-induced dysbiosis may heighten susceptibility to gastrointestinal cancers, particularly in patients with prolonged post-infection symptoms. Conclusion: The findings underscore the need for further research to clarify the role of gut microbiota in cancer development among COVID-19 patients. These mechanisms could inform preventative strategies and therapeutic interventions, particularly for those experiencing COVID. The review highlights gaps in current knowledge and advocates for longitudinal studies to assess the long-term effects of COVID-19 on gastrointestinal health.

Posttransplant complications: molecular mechanisms and therapeutic interventions.

Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft-versus-host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.

Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

Leveraging single-cell RNA-seq for uncovering naïve B cells associated with better prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.