Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.

Progestin and adipoQ receptor family member 4 (PAQR4) gene is a recently discovered seven-transmembrane protein-coding gene that belongs to the PAQR family. An increasing amount of evidence suggests that PAQR4 is upregulated in multiple tumors and participates in tumor progression and chemotherapy resistance via different signaling pathways; PAQR4 regulates cellular ceramide homeostasis by influencing sphingolipid metabolism and glycerol metabolism, and plays a significant role in adipose tissue remodeling. Meanwhile, it is known that the differential expression of PAQR4 is associated with the occurrence of various diseases and is a potential biomarker and therapeutic target. This article conducts a systematic review of the subcellular localization of PAQR4, its topological structure characteristics, and its functions in cancer occurrence, metabolic diseases, and fertility, and provides clues for the future research and translational application of PAQR4.

Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.

Cancer development is driven by genetic alterations, particularly cancer driver mutations (CDMs), which are associated with aggressive phenotypes and shorter survival. In contrast, higher mutation loads caused by microsatellite instability (MSI) or mismatch repair deficiency (MMRd) can induce anti-cancer immunity, leading to tumor shrinkage and improved responses to immune checkpoint inhibitor (ICI) therapies. However, understanding how CDMs and MSI/MMRd influence cancer evolution remains limited. We opted uterine corpus endometrial carcinoma (UCEC) as a model in this study due to its MSI-high/MMRd characteristics. Somatic mutation screening revealed that UCEC has a significantly higher mutation rate in cancer driver genes compared to ovarian cancer (OVCA) and cervical squamous cell carcinoma (CSCC), despite these cancers arising from histologically connected organs in the reproductive tract. Interestingly, these CDMs did not necessarily drive tumor progression. Using a cutoff of 7.0 (mutations/Mb) for tumor mutation burden (TMB), we classified UCEC patients into two groups with distinct clinical features, genetic profiles, and drug sensitivities. Among the known CDMs, TP53 mutations and their functional networks emerged as key drivers in UCEC progression, while mutations in CTNNB1, PTEN, and ARID1A may enhance anti-tumor immunity, correlating with longer overall survivals. Drug screening using GDSC and CTRPv2 databases suggested that GSK-3 inhibitor IX may be effective for treating aggressive UCEC patients with a non-MSI phenotype. Curcumin showed efficacy for UCEC patients with MSI, especially with ICI therapy. Our study highlights the importance of immune regulation and tolerance over CDMs in cancer development, particularly in those with an MSI-high/MMRd phenotype. We propose that TMB could serve as a valuable screening method alongside molecular and histopathological classifications to guide treatment strategies for UCEC patients.

Pancreatic cancer is one of the most deadly with poor prognosis and overall survival rate due to the dense stroma in the tumors which often is challenging for the delivery of drug to penetrate deep inside the tumor bed and usually results in the progression of cancer. The conventional treatment such as chemotherapy, radiotherapy or surgery shows a minimal benefit in the survival due to the drug resistance, poor penetration, less radiosensitivity or recurrence of tumor. There is an urgent demand to develop molecular-level targeted therapies to achieve therapeutic efficacy in the pancreatic ductal adenocarcinoma (PDAC) patients. The precision oncology focuses on the unique attributes of the patient such as epigenome, proteome, genome, microbiome, lifestyle and diet habits which contributes to promote oncogenesis. The targeted therapy helps to target the mutated proteins responsible for controlling growth, division and metastasis of tumor in the cancer cells. It is very important to consider all the attributes of the patient to provide the suitable personalized treatment to avoid any severe side effects. In this review, we have laid emphasis on the precision medicine; the utmost priority is to improve the survival of cancer patients by targeting molecular mutations through transmembrane proteins, inhibitors, signaling pathways, immunotherapy, gene therapy or the use of nanocarriers for the delivery at the tumor site. It will become beneficial therapeutic window to be considered for the advanced stage pancreatic cancer patients to prolong their survival rate.

Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.

Identifying genetic mutations contributing to solid tumors by altering the biological pathways related to tumor formation and development is essential for the development of targeted therapies. This study aimed to identify commonly mutated genes and altered pathways in canine solid tumors. Four dogs with different types of naturally occurring neoplasias (urothelial carcinoma, adenocarcinoma, rhabdomyosarcoma, and chondrosarcoma) were randomly selected and classified into carcinoma and sarcoma groups based on histopathological findings. Tumor tissues were analyzed using whole-genome sequencing, and significant variants shared within each tumor group were identified. Gene set enrichment analyses were conducted to compare the biological and functional pathways altered by the mutations in each carcinoma and sarcoma group. Forty-three and fifty-eight genes were identified in the carcinoma and sarcoma groups, respectively. Distinctions between the two tumor groups were noted for mutations related to tumor metastatic function. Mutations were identified in genes encoding cell adhesion molecules in the carcinoma group, whereas significant variations in extracellular matrix-related molecules were evident in the sarcoma group. This study revealed mutations and modified pathways associated with immune and tumor metastatic functions in canine carcinoma and sarcoma, indicating their significant relevance to the development and progression of each tumor group. Additionally, the distinctions indicated that different therapeutic approaches were required for each tumor group.

Cuproptosis, a novel form of copper (Cu)-dependent programmed cell death, is induced by directly binding Cu species to lipoylated components of the tricarboxylic acid (TCA) cycle. Since its discovery in 2022, cuproptosis has been closely linked to the field of materials science, offering a biological basis and bright prospects for the use of Cu-based nanomaterials in various disease treatments. Owing to the unique physicochemical properties of nanomaterials, Cu delivery nanosystems can specifically increase Cu levels at disease sites, inducing cuproptosis to achieve disease treatment while minimizing the undesirable release of Cu in normal tissues. This innovative nanomaterial-mediated cuproptosis, termed as "nanocuproptosis", positions at the intersection of chemistry, materials science, pharmaceutical science, and clinical medicine. This review aims to comprehensively summarize and discuss recent advancements in cuproptosis across various diseases, with a particular focus on cancer. It delves into the biochemical basis of nanomaterial-mediated cuproptosis, the rational design for cuproptosis inducers, strategies for enhancing therapeutic specificity, and cuproptosis-centric synergistic cancer therapeutics. Beyond oncology, this review also explores the expanded applications of cuproptosis, such as antibacterial, wound healing, and bone tissue engineering, highlighting its great potential to open innovative therapeutic strategies. Furthermore, the clinical potential of cuproptosis is assessed from basic, preclinical to clinical research. Finally, this review addresses current challenges, proposes potential solutions, and discusses the future prospects of this burgeoning field, highlighting cuproptosis nanomedicine as a highly promising alternative to current clinical therapeutics.

Vascular dementia (VaD) is the second most common cause of dementia. Few bioinformatic analysis has been done to explore its biomarkers. This study aimed to excavate potential biomarkers for VaD using bioinformatic analysis and validate them at both animal and patient levels. Based on microarray data of GSE122063, bioinformatic analysis revealed 502 DEGs in the frontal and 674 DEGs in the temporal cortex of VaD patients. Afterward, the hub genes between two regions, including C1QA, C1QB, C1QC, and C5AR1, were dugout. Interestingly, compared with sham mice or controls, the above four complements were highly expressed in the cortices of VaD animals and in the peripheral serum of VaD patients. Moreover, receiver operating characteristic curve analysis conformed to good diagnostic powers of these complements, with C1QB having the most prominent capacity (AUC = 0.799, 95%CI 0.722-0.875). That means the complements, especially subunits of C1Q, might be used as specific early VaD diagnostic biomarkers.

Background/Objectives: Recently, many researchers have evaluated various viruses, including polyomaviruses (JCV, BKV) and EBV, as potential factors playing a role in the development and/or progression of prostate cancer (PCa), one of the most common cancers in men. Therefore, we aimed to assess the frequency of the JCPyV DNA in tissue collected from PCa patients. Methods: We detected the presence of viral DNA (PCR) in 49.6% of clinical samples, including 71.9% with single EBV infection and 28.1% with EBV/JCV co-infection. We did not detect BKV or a single JCV infection. Therefore, we compared patients with EBV mono-infection with EBV/JCV co-infected patients in the context of risk group, Gleason score, and TNM classification. Results: Our results showed differences in clinicopathological features between single EBV infection and EBV/JCV co-infection. In the group of patients with single EBV infection, most patients were classified as medium/high risk, while in the group with EBV/JCV co-infection, most patients were classified as low risk. Conclusions: Among patients with single EBV infection, a more advanced stage of cancer was observed than in EBV/JCV co-infection. Moreover, the level of anti-EBVCA and anti-EBNA antibodies as well as EBV load was higher in the case of single infection compared to EBV/JCV co-infection. Higher antibody levels were detected in more advanced tumor stages in single EBV infection. Does JCV only "reside" in prostate cells or is it a co-factor in EBV infection? In light of these studies, there is a need to clarify the role of JCV virus in the development and/or progression of prostate cancer.

Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution. To address these gaps, we performed mutation accumulation experiments using clonal populations of patient-derived tumoroids from seven CIN, microsatellite-stable colorectal cancers (CRCs), and one microsatellite-unstable CRC. Each tumor exhibited a distinctive mutation rate footprint that was conserved among different clones from the same ancestor. In contrast, mutation rates diverged markedly across different tumors, with variations in magnitude within microsatellite-stable tumors as prominent as those distinguishing them from microsatellite-unstable tumors. New mutations reflected mutational processes associated with defective DNA replication and repair, which were not detected in normal tissues. Last, both mutation accumulation assays and high-depth whole-exome sequencing of subclonal variants showed higher mutation rates in metastatic lesions compared with matched primary tumors, suggesting positive selection for cells with increasing mutability during cancer dissemination. By providing an empirical assessment of mutation rates in human cancer, our data delineate heterogeneity, heritability, and progression-associated evolvability of DNA mutational instability as hallmarks of microsatellite-stable CRC.

Cancers are increasingly common and significantly impact patients' quality of life and longevity. The role of macrophages in tumorigenesis is critical, and natural compounds have long been recognized as valuable sources of bioactive agents for treating this condition. However, no systematic review has been performed on the role of phytochemicals impacting tumorigenesis by M1/M2 macrophage polarization. The aim of this study is to systematically review phytochemicals that relieve tumorigenesis by impacting M1/M2 macrophage polarization and investigate related signaling pathways. This systematic review adheres to PRISMA 2020 guidelines and statements. Scientific databases, MEDLINE, Scopus, and Web of Science, have been searched from inception to October 2023. This review includes English original articles on the role of phytochemicals, whole plant extracts, and polyherbal formulas in ameliorating tumorigenesis through M1/M2 polarization while excluding non-English articles, non-original research, and unrelated studies according to title, abstract, and full-text screening. Shreds of evidence were gathered from cellular and animal studies about the beneficial impacts of phytochemicals against tumorigenesis by impacting M1/M2 macrophage polarization. Critical assessment of in vitro and in vivo studies was performed by the CRIS and ARRIVE guidelines. Due to the high level of heterogeneity of the collected data, only a narrative synthesis was performed. Of 741 collected articles, only 35 remained. Polyphenols are the most highlighted group. Phytochemicals affect cytokines related to M1, such as CD80, CD86, CD64, and iNOS, and M2, like CXCR-1, CXCR-2, and TGF-β, in various cancer models. Together, these compounds exerted protective effects against tumorigenesis in preclinical cancer models. Furthermore, high-quality clinical experiments are recommended to cover the limitations of the current study, which are reliance on preclinical evidence, lack of clinical trials, and exclusion of non-English and grey literature.

Cuproposis is a new-found mechanism of cell death, and the role of cuproposis-related genes (CRGs) in pancreatic cancer prognosis remains uncertain.

DECRGs were identified from TCGA and GTEx databases. Five OS-associated hub genes were screened using Cox regression and LASSO analyses. A prognostic model was constructed and validated by survival analysis. GSEA, gene mutation, small-molecule drugs, immune-infiltrating and TF/miRNA/mRNA network were investigated to determine the underlying mechanism of 5-CRGs. In addition, RT-qPCR, and WB were applied to validate the expression of 5-CRGs. CCK8, colony formation and transwell assays were used to prove the function of LIPT1 in PC.

PDP1, DLAT, DBT, LIAS, and LIPT1 were screened as hub genes. 5-CRGs prognostic model established the low-risk population has a longer OS. There was a high the risk score value for the prediction in clinicopathological features. The forest plots showed that age, N stage and the RiskScore were the significant independent risk indicators. T cells CD4 memory resting and Mast cells are the amplest immune cell subpopulations in the high-score individuals. The expression of 5 CRGs exhibited significant differences in PC cell lines and tissues, LIPT1-knockdowning inhibited proliferation and invasion of pancreatic cancer cell lines.

Five CRGs relevant to pancreatic cancer prognosis were identified. Meanwhile, a new and accurate five CRGs prognostic model of pancreatic cancer was constructed. In addition, LIPT1 may promote proliferation, invasion and migration of pancreatic cancer cell lines. This may have a specific guiding value for future development of precise anti-cancer treatment strategies.

Enzyme-linked immunosorbent assay (ELISA) has been widely used in cancer diagnostics due to its specificity, sensitivity and high throughput. However, conventional ELISA is semiquantitative and has an insufficiently low detection limit for applications requiring ultrahigh sensitivity. In this study, we developed an α-hemolysin-nanopore-based ELISA for detecting cancer biomarkers. After forming the immuno-sandwich complex, peptide probes carrying enzymatic cleavage sites are introduced, where they interact with enzymes conjugated to the detection antibodies within the complex. These probes generate distinct current signatures when translocated through the nanopore after enzymatic cleavage, enabling precise biomarker quantification. This approach offers a low detection limit of up to 0.03 fg ml-1 and the simultaneous detection of six biomarkers, including antigen and antibody biomarkers in blood samples. Overall, the nanopore-based ELISA demonstrates high sensitivity and multiplexing capability, making it suitable for next-generation diagnostic and point-of-care testing applications.

Cancers are complex diseases that have heterogeneous genetic drivers and varying clinical outcomes. A critical area of cancer research is organizing patient cohorts into subtypes and associating subtypes with clinical and biological outcomes for more effective prognosis and treatment. Large-scale studies have collected a plethora of omics data across multiple tumor types, providing an extensive dataset for stratifying patient cohorts. Network-based stratification (NBS) approaches have been presented to classify cancer tumors using somatic mutation data. A challenge in cancer stratification is integrating omics data to yield clinically meaningful subtypes. In this study, we investigate a novel approach to the NBS framework by integrating somatic mutation data with RNA sequencing data and investigating the effectiveness of integrated NBS on three cancers: ovarian, bladder, and uterine cancer.

We show that integrated NBS subtypes are more significantly associated with overall survival or histology. Specifically, we observe that integrated NBS subtypes for ovarian and bladder cancer were more significantly associated with patient survival than single-data type NBS subtypes, even when accounting for covariates. In addition, we show that integrated NBS subtypes for bladder and uterine are more significantly associated with tumor histology than single-data type NBS subtypes. Integrated NBS networks also reveal highly influential genes that span across multiple integrated NBS subtypes and subtype-specific genes. Pathway enrichment analysis of integrated NBS subtypes reveal overarching biological differences between subtypes. These genes and pathways are involved in a heterogeneous set of cell functions, including ubiquitin homeostasis, p53 regulation, cytokine and chemokine signaling, and cell proliferation, emphasizing the importance of identifying not only cancer-specific gene drivers but also subtype-specific tumor drivers.

Our study highlights the significance of integrating multi-omics data within the NBS framework to enhance cancer subtyping, specifically its utility in offering profound implications for personalized prognosis and treatment strategies. These insights contribute to the ongoing advancement of computational subtyping methods to uncover more targeted and effective therapeutic treatments while facilitating the discovery of cancer driver genes.

Extranodal natural killer/T-cell lymphoma (ENKTL) involving the adrenal glands is extremely rare, and only a few cases have been reported. However, the genetic alterations, clinicopathological features and prognosis of these patients have not yet been fully elucidated.

Profiling of tumor mutations in ENKTL patients with adrenal involvement was conducted by whole-genome sequencing, and the predisposing genes and driver mutation gene variants were verified through Sanger sequencing. Immunohistochemical analysis of markers for the diagnosis and tumor microenvironment competent were performed to identify histopathological features. In addition, we searched the Surveillance, Epidemiology, and End Results (SEER), PubMed, Embase, and Scopus databases to perform a population-based study to compare the prognosis between adrenocortical carcinoma (ACC) patients and adrenal ENKTL patients using Kaplan-Meier survival curves and log-rank tests and analyzed the prognostic factors affecting the overall survival (OS) of adrenal ENKTL patients via univariate and multivariate Cox regression analyses.

We screened 15892 somatic single-nucleotide variants (SNVs), 364 somatic insertions and deletions (INDELs), and four driver mutation genes, namely, TET2, STAT3, FAS, and TP53. In addition, immunohistochemical analysis revealed that tumor cells were positive for CD3, CD43, CD56, TIA1, granzyme B, CD2, CD4, and CD7. The immunohistochemistry for detecting components of the tumor microenvironment reveled the infiltration of tumor-associated macrophages (CD68, CD163) and tumor-associated fibroblasts (vimentin, SMA) in the tumor sample. According to our population-based analysis, Kaplan-Meier survival curves revealed that ENKTL patients with adrenal involvement had a significantly poorer prognosis than did patients with ACC (p<0.001), and chemotherapy was a significant prognostic factor for OS in ENKTL patients with adrenal involvement according to Cox multivariate analysis (hazard ratio = 0.318; p=0.027).

The metastasis of ENKTL to the adrenal gland may be due to gene mutations caused by genetic variations, which may provide new therapeutic targets for this disease. The prognosis of adrenal ENKTL patients is markedly worse than that of ACC patients, and chemotherapy may serve as an independent factor of OS in adrenal ENKTL patients. However, our findings still need to be validated in additional studies.

In recent years, cancer research has made huge advances also thanks to the discovery of the role of non-coding RNAs in the control of tumorigenesis, tumor proliferation, migration and metastasis and therefore also in the diagnosis and therapy of tumors. This work aims to review the most recent literature involving the study of miRNAs in ocular tumors affecting adult patients. We will introduce the role of miRNAs in tumorigenesis, and we will focus on summarizing the studies on uveal intraocular melanomas in which a role of microRNAs has been demonstrated. Similarly, we will also cover observations on miRNAs and eyelid cancers, especially sebaceous gland carcinoma, and cancers of the conjunctiva and the retina, excluding retinoblastoma which is typically a pediatric-onset tumor. We will summarize specific miRNAs that could be considered as diagnostic molecules or as therapeutic targets against some ocular cancer diseases, indicating their potentialities and limitations, considering also their administration as nanomedicine for the eye.

The nexus between aging-associated immune deteriorations and tumorigenesis of lung cancers remains elusive. In a mouse model with Med23 depletion in T cells (Med23 -/-), it is found a strong association between the decline of CD103+ T cells and spontaneous alveolar epithelial type II cell (AT2 cell)-originated lung adenocarcinomas. The reduction of CD103+ T cells in the lung results in an accumulation of AT2 cells bearing oxidative damages, which appears to be the major origin of the lung adenocarcinoma. Functional experiments reveal CD103+ T cells can eradicate oxidative-damage-bearing AT2 cells as well as ROS-dependent, KRAS (G12D)-driven tumorigenesis. In vitro co-cultures prove CD103+ T cells, especially CD103+ CD8+ T cells, exhibit a killing capacity that matches the oxidative stress level in the target cells. In aged animals, it is found the abundance of CD103+ CD8+ T cells in the lung declines with age, accompanied by an accumulation of oxidative-damage-bearing AT2 cells. Collectively, the study establishes the vital function of CD103+ T cells in surveilling epithelial cells under oxidative stress to prevent malignancies, and unravels a potential immuno-dysregulation in the aged lung which contributes to tumorigenesis.

Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability.

Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis.

Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets.

Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.

Malignant transformation of an intracranial epidermoid cyst (EC) into squamous cell carcinoma (SCC) is an exceedingly rare occurrence that is typically diagnosed on postoperative histology. The mechanisms underlying transformation remain poorly understood, with limited characterization of genetic changes associated with progression.

A 55-year-old female presented with a large cerebellopontine angle EC with an enhancing nodule in the left tectum, for which she underwent resection. Three months following surgery, rapid enlargement of the residual tectal component required reoperation, with pathology showing SCC. Paired next-generation sequencing of the EC and SCC revealed multiple shared variants, including a pathogenic TP53 mutation. Additionally, the SCC contained a pathogenic PTEN variant absent in the EC, suggesting a second driver mutation contributing to malignant transformation of an EC (MTEC). Her SCC was resistant to volumetric modulated arc therapy, requiring subsequent chemotherapy and pembrolizumab combined with stereotactic radiosurgery. Despite a favorable initial response, she died 26 months following MTEC diagnosis.

To the authors' knowledge, this represents the first use of paired molecular profiling to link intracranial SCC to an EC precursor, enhancing precision of this rare diagnosis. Additionally, this case identifies specific genetic alterations associated with transformation, providing insight into the largely unknown mechanisms underlying MTEC. https://thejns.org/doi/10.3171/CASE24849.

The hierarchical organization of the eukaryotic genome is crucial for nuclear activities and cellular development. Genetic aberrations can disrupt this 3D genomic architecture, potentially driving oncogenesis. However, current research often lacks a comprehensive perspective, focusing on specific mutation types and singular 3D structural levels. Here, pathological changes from chromosomes to nucleotides are systematically cataloged, including 10 789 interchromosomal translocations (ICTs), 18 863 structural variants (SVs), and 162 769 single nucleotide polymorphisms (SNPs). The multilayered analysis reveals that fewer than 10% of ICTs disrupt territories via potent 3D interactions, and only a minimal fraction of SVs disrupt compartments or intersect topologically associated domain structures, yet these events significantly influence gene expression. Pathogenic SNPs typically show reduced interactions within the 3D genomic space. To investigate the effects of variants in the context of 3D organization, a two-phase scoring algorithm, 3DFunc, is developed to evaluate the pathogenicity of variant-gene pairs in cancer. Using 3DFunc, IGHV3-23's critical role in chronic lymphocytic leukemia is identified and it is found that three pathological SNPs (rs6605578, rs7814783, rs2738144) interact with DEFA3. Additionally, 3DGAtlas is introduced, which provides a highly accessible 3D genome atlas and a valuable resource for exploring the pathological effects of genetic mutations in cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. A key driver of CRC development is microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency and characterized by hypermutability of short-tandem repeat sequences. A significant portion of MSI CRCs do not respond to checkpoint immunotherapy treatments, highlighting an unmet need for improved therapies. Recent studies have revealed that MSI cancer cells require Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for targeting MSI CRCs that are insensitive to standard therapies. Several highly potent small-molecule WRN inhibitors have been developed and exhibited striking in vitro and in vivo activities against MSI cancers. Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.

The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell's adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.

Chromosomal translocations are key events in cancer, driving oncogenesis by disrupting and deregulating critical genes. While specific tumor-associated translocations are well studied, the frequencies and distributions of most remain unknown. Additionally, the role of chromosomal reshuffling in translocations has received little attention. This study presents data on the chromosomal involvement in 59 251 translocations reported in 58 tumor entities, including both benign and malignant tumors. Unlike studies focusing on tumor-specific abnormalities identified at the chromosome band level, this study examines translocations at the chromosomal level, offering a novel perspective on their distribution. This broader approach aims to uncover patterns that do not emerge or are disregarded in studies limited to tumor-specific aberrations. The resulting dataset provides a novel resource for deepening our understanding of the chromosomal origins of translocations in neoplasia. Comparisons of translocation frequency distributions among tumor types, when excluding the characteristic tumor-associated translocations, revealed that the patterns of chromosomal involvement in translocations are largely unique to each tumor entity. Statistical analyses of 241 pairwise comparisons of translocation spectra within hematologic disorders, solid tumors, and between groups of hematologic malignancies and both benign and malignant solid tumors showed insignificant/very weak associations (R2 ≤ 0.3) in 98% of the comparisons. The findings hence demonstrate that different tumor types are characterized by distinct chromosomal translocation signatures, strongly suggesting that most translocations encountered in tumor cells are not merely random events. Consequently, our study highlights the potential of rare translocations to serve as indicators of disease-specific processes.

Precise tumor excision is important but challenging in breast-conserving surgery (BCS). Tumor-specific fluorescence imaging may be used for intraoperative tumor detection and, therefore, to guide precise tumor excision. The aims of this study are to develop a glucose transporter 1 (GLUT1)-targeted near-infrared fluorescence tracer and evaluate its accuracy for breast cancer detection using fresh surgical breast specimens.

Bioinformatic analysis was performed to compare GLUT1 expression between breast cancer and normal breast tissues. A GLUT1-targeted fluorescence imaging tracer WZB117-CY7.5 was developed. In combination with fluorescence imaging (FMI), its binding specificity to GLUT1 was examined in in vitro breast cancer cell experiments, in vivo 4T1 breast tumor-bearing mouse models, and 60 freshly resected human breast tumor tissues. The diagnostic accuracy of WZB117-CY7.5, was evaluated in fresh specimens derived from 60 patients diagnosed with breast cancer.

GLUT1 expression is higher in breast cancer tissues compared with normal tissues. WZB117-CY7.5 specifically bound to breast cancer cells in in vitro cell experiments and accumulated in tumor areas in a 4T1 tumor-bearing mice after intravenous injection by FMI. Moreover, WZB117-CY7.5 specifically bound to freshly resected human breast cancer and demonstrated excellent diagnostic performance in discriminating breast cancer, irrespective of cancer subtype, from normal breast tissue on fresh surgically resected breast tissues.

WZB117-CY7.5 showed high accuracy in intraoperative breast cancer detection, irrespective of the cancer subtype. This highlights its potential for clinical applications as a generic tracer for fluorescence image-guided surgery (FIGS) in BCS and fluorescence image-guided pathology for tissue sampling.

The targeted delivery of therapeutics to internal organs to, for example, promote healing or apoptosis holds promise in the treatment of numerous diseases1-4. Currently, the prevailing delivery modality relies on the circulation; however, this modality has substantial efficiency, safety and/or controllability limitations5-9. Here we report a battery-free, chipless, soft nanofluidic intracellular delivery (NanoFLUID) patch that provides enhanced and customized delivery of payloads in targeted internal organs. The chipless architecture and the flexible nature of thin functional layers facilitate integration with internal organs. The nanopore-microchannel-microelectrode structure enables safe, efficient and precise electroperforation of the cell membrane, which in turn accelerates intracellular payload transport by approximately 105 times compared with conventional diffusion methods while operating under relatively low-amplitude pulses (20 V). Through evaluations of the NanoFLUID patch in multiple in vivo scenarios, including treatment of breast tumours and acute injury in the liver and modelling tumour development, we validated its efficiency, safety and controllability for organ-targeted delivery. NanoFLUID-mediated in vivo transfection of a gene library also enabled efficient screening of essential drivers of breast cancer metastasis in the lung and liver. Through this approach, DUS2 was identified as a lung-specific metastasis driver. Thus, NanoFLUID represents an innovative bioelectronic platform for the targeted delivery of payloads to internal organs to treat various diseases and to uncover new insights in biology.

Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits an immunosuppressive microenvironment coupled with malnutrition status. These features are instrumental in clinical management strategies for PDAC.

Immune-nutrition status of patients was evaluated by integrating systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Individuals were divided into SII-PNI Status positive (SPS+) group and SPS negative (SPS-) group. Morphology of tissues was evaluated by hematoxylin-eosin (H&E) staining. Expression of PD-L1 and p53 was detected using immunohistochemistry (IHC).

In this study, 530 eligible patients (mean ± SD age, 60.5 ± 9.17 years, 296 males [55.8%], 74 SPS+ [14.0%]) were included. These patients exhibited a median survival of 24 months (1-, 3- and 5-year survival rate; 72.9%, 34.7% and 25.1%, respectively). In the multivariate analysis, independent indicators for outcomes were identified as tumor size, lymph node metastasis and SPS (all p <.01). After matching and adjusting, patients with SPS+ exhibited a notably reduced overall survival compared to those with SPS- (14 vs. 25 months, p <.001), with hazard ratio (95% CI) of 1.79 (1.25-2.56). IHC revealed markedly elevated positive cell proportion of PD-L1 in SPS+ group (p <.01) and distinct p53 mutation patterns between SPS+ and SPS- groups (p =.03). Morphology demonstrated a dissimilar trend of differentiation levels between the two groups (p =.08).

The findings suggest poorer outcome, higher PD-L1 expression and distinct p53 mutation status of patients with SPS+. These patterns may contribute to PDAC management and strategic deployment of immunotherapy and targeted therapy.

Neoadjuvant immunochemotherapy is expected to become the standard treatment mode for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to analyze the clinical outcomes and long-term survival of neoadjuvant immunochemotherapy for locally advanced ESCC, and explore the feasibility of using major pathological response (MPR) as a surrogate endpoint.

This real-world retrospective study consecutively included eligible patients with stage II-IVA locally advanced ESCC who received neoadjuvant immunochemotherapy and surgery between 2019 and 2022 at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine.

This study collected a total of 166 patients, and ultimately included 126 patients after screening. The objective response rate (ORR) was 69.8% (88/126). The incidence of grade 3-4 adverse events (AEs) was 13.5% (17/126). MPR was observed in 49 (38.9%) patients, and 24 (19.0%) patients achieved a complete pathological response (pCR). The median progression-free survival (PFS) was 31.7 months and the 3-year PFS rate was 56.3%. The median overall survival (OS) was not reached and the 3-year OS rate was 70.6%. The median PFS of the non-MPR group was 25.0 months, with the MPR group not achieved (hazard ratio [HR], 2.503; 95% CI 1.359-4.610; P = 0.0022). The median OS in the non-MPR group was 31.7 months and not reached in the MPR group (HR, 3.607; 95% CI 1.576-8.254; P = 0.0012). MPR is an independent prognostic factor affecting OS (HR, 2.522; 95% CI 1.018-6.401; P = 0.046).

Neoadjuvant immunochemotherapy is safe and effective for locally advanced ESCC, and can result in certain survival benefits. MPR can serve as a surrogate endpoint for predicting long-term OS.

Mitochondrial sirtuin 3 (SIRT3) is a gene involved in key functions like acetylation, DNA repair, stress response, and tumorigenesis. Several studies have been published that showed the role of SIRT3 in various cancers. Still, few studies have been reported on the genetic and expression variation of the SIRT3 gene in gastric carcinogenesis. This study was designed to explore the involvement of the SIRT3 gene in gastric cancer. In this study, we used two study cohorts, cohort 1 contained 510 gastric cancer (GC) patients and an equal number of age and gender-matched controls. Cohort 2 included 220 GC tissue samples along with adjacent control tissues. Tetra Arms PCR was used to measure the frequency of three selected SNPs of the SIRT3 gene (rs28365927, rs11246029, and rs3817629) in cohort 1. Quantitative PCR and immunohistochemistry were performed to analyze the SIRT3 expression variation in cohort 2 GC patients. The superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured using ELISA, and DNA damage was measured using the LORD-Q assay. Statistical analysis showed the significant increased frequency of mutant allele of selected SNPs (rs28365927 (p < 0.0001); rs11246029 (p < 0.0001); and rs3817629 (p < 0.0001) in GC patients compared to controls. Expression analysis results showed significant downregulation of the SIRT3 gene at mRNA level (P < 0.001) and protein level (P < 0.001) in gastric tumor section vs control tissues. Multivariant Cox regression analysis showed that downregulated SIRT3 expression (p < 0.000001), H. pylori status (p < 0.0001), T-stage (p < 0.008), and N-stage (p < 0.001) act as prognostic markers in GC patients. ROC curve analysis showed the 90% and 100% specificity of the SIRT3 gene as a diagnostic marker in GC at the mRNA level and protein level, respectively. Significant increased oxidative stress (antioxidant enzyme level p < 0.0001; 8-OHdG level p < 0.0001) and lesion frequency/10 kb (p < 0.03) were indicated in the gastric tumor tissue sections vs controls. The result showed the tumor suppressor role of the SIRT3 gene in GC and was found linked with the surge in oxidative stress and damage in GC patients.

Chromosomal rearrangements can drive adaptive evolution; however, whether the rearrangements in non-coding and non-promoter regions can lead to new phenotypes under selective pressures remains unclear. Additionally, highly producing recombinant proteins is a key industrial task but poses stress on host cells. Therefore, it is desirable to investigate the role of chromosomal rearrangement in non-coding and non-promoter regions during high-yield recombinant protein phenotype formation. In this study, we utilize the Kluyveromyces marxianus strain as the host for recombinant protein production, with the recombinant fusion protein comprising leghemoglobin (LBA) and enhanced green fluorescent protein serving as a reporter. Iterative evolution is conducted to select high-yield strains using Cre-loxP mediated chromosomal rearrangement technology and high-throughput fluorescence intensity screening. The evolved strains exhibit ~seven-fold increase in fluorescence intensity and a 1.7-fold improvement in LBA yield, identified with chromosome VIII inversion and chromosomes III and V translocation. Introducing these rearrangements into wild-type strains significantly increase recombinant protein yield to about 1.5-fold. Cascade networks are reconstructed based on RNA-seq analysis to elucidate rearrangements' impact on global metabolic processes. Our study confirms that chromosomal rearrangements in non-coding regions can establish adaptive phenotypes and provides new ways of engineering host cells to improve recombinant protein productivity.

To explore the key molecules and regulatory mechanisms of lymph node metastasis in gastric cancer.

The differential genes and key genes of lymph node metastasis in gastric cancer were analyzed by utilizing multiple data sets. The key genes were analyzed by GSEA analysis, transcription factor analysis, nomogram prediction model construction, immune infiltration analysis, GSVA analysis, drug sensitive analysis and single cell data analysis.

Abnormal expression of key genes including CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4, PKIA and activation of related signaling pathways might be the result of ultraviolet radiation-induced DNA damage, which was closely related to lymph node metastasis in gastric cancer. The key genes were regulated by a variety of transcription factors, which were strongly connected with the invasion of immune cells and the sensitivity of a variety of drugs. The nomogram prediction model, which is based on the key genes associated with lymph node metastasis and the TNM of gastric cancer, demonstrated a high level of predictive efficiency.

CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4 and PKIA may be the key genes affecting lymph node metastasis in gastric cancer, and F2R has higher biological importance.

Liquid biopsy has been developed as an alternative to tissue-based sequencing for detecting genomic alterations in solid tumors. However, the clinical utility of liquid biopsy in patients with solid tumors for whom tissue-based next-generation sequencing (NGS) is infeasible has not been well-characterized, particularly in previously untreated individuals.

This prospective study evaluated the clinical impact of liquid biopsy, focusing on six solid tumor types. Overall, 109 patients were enrolled and underwent liquid biopsy using Guardant360 (Guardant Health, Redwood City, CA, USA). Among these, 94 (86.3%) patients were previously untreated.

The most common cancer type was non-small cell lung cancer (n = 57, 52.3%), followed by pancreatic (n = 35, 32.1%), biliary tract (n = 8, 7.3%), gastric (n = 5, 4.6%), colorectal (n = 3, 2.8%), and triple-negative breast (n = 1, 0.9%) cancers. The success rate of liquid biopsy was 99.1%, and the median turnaround time from blood collection to results was 7 days (range: 5-22 days). Actionable alterations were detected in 31 (28.4%) patients, and 8.3% of them received matched therapy based on alterations identified by liquid biopsy. Among previously untreated patients, actionable mutations were identified in 29.8%, and 8.5% received matched therapy.

In patients with advanced solid tumors for which tissue-based NGS is not feasible, performing upfront liquid biopsy could lead to the detection of actionable alterations and help guide targeted therapies.

UMIN Clinical Trials Registry (UMIN000041722).

Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Liquid biopsy using plasma cfDNA has been established as a tool for informing the management of advanced-stage NSCLC. However, its effectiveness in early lung cancer detection, including the identification of high-risk cases, remains to be determined.

We analyzed plasma cfDNA and matched tumors from 117 stage I-IV lung adenocarcinoma cases and compared the variants identified across all stages using the Oncomine Precision Assay on the GenexusTM next-generation sequencing platform.

Cancer-specific mutations were detected in plasma from approximately 72% (84/117) of cases (all stages), with detection rates increasing by stage. Concordance between cfDNA and tumor tissue also increased with stage 0% (stage I), 19% (stage II), 45% (stage III), and 75% (stage IV). KRAS mutations were concordant in approximately 22% (6/27) of stage II and 46% (11/24) of stage III cases. Clinically important EGFR variants showed concordance in 11% (1/9) of stage II and 80% (8/10) in stage III/IV cases. Actionable mutations, targetable with FDA-approved drugs, were detected in 11% (4/37) of stage II, 27% (12/45) of stage III, and 55% (4/9) of stage IV cases, underscoring the potential of liquid biopsy for early detection of therapeutic targets. Moreover, co-occurring mutations with varying actionability were identified more frequently in plasma than in tumor tissues. Plasma detection of clinically important KRAS and EGFR variants was mostly associated with advanced-stage disease, suggesting the presence of these variants in plasma as a potential indication of disease progression.

Liquid biopsy holds promise for identifying high-risk lung adenocarcinoma cases and serves as a complementary diagnostic tool in advanced stages, enhancing disease management strategies.