Accumulating evidence suggests that the TP53 mutation, intratumoral microbiome, and tumour microenvironment (TME) are closely linked to tumourigenesis, yet the biological mechanisms underlying these connections remain unclear. To explore this, we collected multi-omics data-including genome, transcriptome, and tumour microbiome data-from a wide range of cancer types in The Cancer Genome Atlas (TCGA). Through a pan-cancer analysis, we identified significant correlations between intratumoral microbiota diversity and TP53 mutation status, particularly in hepatocellular carcinoma (HCC) and endometrial cancer (EC). Despite notable differences in microbiota composition between these two cancer types, we consistently observed that TP53 mutations were associated with reduced alpha-diversity. Additionally, we found that TP53 mutation status significantly influenced stromal components within the TME, such as a strong correlation between decreased endothelial cell abundance and TP53 mutation. Our integrated approach reveals the complex interplay between TP53 and factors regulating the host TME, offering new insights into cancer progression and potential therapeutic targets for future research.

The evolutionarily conserved Integrator complex, which is composed of over 10 subunits, orchestrates diverse RNA-processing events such as 3'-end maturation of small nuclear RNAs (snRNAs), transcription termination of RNA Polymerase II, and DNA damage response signaling pathways; however, the functional roles of individual Integrator complex subunits in lung adenocarcinoma (LUAD) remain poorly characterized, and this study aimed to systematically investigate the potential oncogenic functions and prognostic values of these subunits in LUAD. To achieve this goal, the expression profiles of Integrator complex subunits were profiled using transcriptomic data from the The Cancer Genome Atlas (TCGA) database, survival analyses (including Kaplan-Meier and Cox regression models) were performed to evaluate the correlations between subunit expression levels and patient survival outcomes (overall survival (OS) and disease-free survival (DFS)), co-expression network analysis was conducted to annotate the potential biological functions of key subunits, and functional validation was performed using CCK-8 assays and flow cytometry to assess the impact of INTS7 depletion on cell proliferation and cycle progression in LUAD cell lines. The findings of this study showed that Integrator complex subunits were significantly overexpressed in LUAD tissues compared to normal lung parenchyma; among these subunits, INTS7 expression was most strongly associated with shortened OS and DFS, indicating its pivotal role in LUAD pathogenesis, while bioinformatics analyses revealed that INTS7 is involved in regulating critical biological processes including cell cycle progression, transcriptional regulation, and RNA metabolism, and loss-of-function experiments demonstrated that genetic silencing of INTS7 significantly inhibited cell proliferation and induced cell cycle arrest in LUAD cells. Ultimately, this study provides the first evidence that INTS7, a core component of the Integrator complex, serves as a functional and prognostic regulator in LUAD, highlighting its potential as a therapeutic target for this malignancy.

Exosomes are involved in intracellular communication and mediate the radiation-induced bystander effect (RIBE). We assessed the ability of exosomes to modify the radiation response of PC3 and DU145 prostate cancer cells exposed to X-rays. Irradiated cells were analyzed using clonogenic survival and apoptosis assays, while exosome-stimulated cells were evaluated for γH2AX immunostaining, immunoblotting, and apoptosis. Exosomes were isolated via size exclusion chromatography (SEC), characterized by nanoparticle tracking analysis (NTA) and immunoblotting, and ranged from 130 to 137 nm, containing CD63 and CD81. We found that exposure to ionizing radiation (IR) resulted in increased apoptosis and necrosis. To assess exosomes impact on radiation response, exosomes were transferred to non-irradiated and irradiated recipient cells. Non-irradiated PC3 cells stimulated by exosomes released from irradiated PC3 and DU145 cells showed more apoptosis and necrosis than those stimulated by exosomes released from non-irradiated cells. Non-irradiated PC3 cells co-incubated with exosomes from irradiated PC3 and DU145 cells exhibited more γH2AX foci than non-irradiated PC3 cells. Our results confirmed that DU145 cells are more radioresistant than PC3 cells and exosomes isolated from these cells may contribute to radiation resistance in prostate cancer. Thus, studying exosome functions, particularly in radiation resistance, is crucial for understanding carcinogenesis and optimizing radiotherapeutic methods.

This clinical trial is registered on ClinicalTrials.gov (NCT06428045). The authors confirm that all ongoing and related trials for this intervention are registered.

Mitotic cell cycle (MCC) is a critical process in cell growth and division, and dysregulation of MCC genes may contribute to tumorigenesis. In this study, to identify diagnostic and prognostic value of MCC genes, differentially expressed MCC genes between HCC and normal tissues were identified and subjected to machine learning methods. SVM-RFE and RF-RFE were employed to select the most informative diagnostic genes. The SVM-RFE model demonstrated high performance in TCGA (AUC = 1.0), and generalizability across GSE77509 (AUC = 0.95) and GSE144269 (AUC = 0.879), outperforming RF-RFE. Permutation testing confirmed that these AUCs were outside the null distribution for all datasets. Nine genes, CDKN3, TRIP13, RACGAP1, FBXO43, EZH2, SPDL1, E2F1, TUBE1 and CDC6, were common in SVM-RFE and RF-RFE and showed robust individual diagnostic performance across datasets (AUCs > 0.81). Univariate Cox regression followed by LASSO Cox regression was used for identification of prognostic gene signature consisted of eight MCC genes, BCAT1, DPF1, CDKN2B, CDKN2C, TUBA3C, IGF1, CDC14B and SMARCA2, that predicted overall survival of HCC patients. The risk score was shown to be an independent prognostic factor for HCC and its combination with AJCC stage improved prognostic value. Kaplan-Meier analysis showed that high-risk score was associated to poorer survival across clinical subgroups; stage, grade, age, and gender. Additionally, risk score was significantly higher in patients with advanced-stage and high-grade tumors. In conclusion, diagnostic biomarker candidates classifying HCC patients and healthy controls, and a novel prognostic gene signature predicting overall survival of HCC patients were identified by using machine learning approaches.

BACKGROUND Immunotherapy has seen an exponential increase recently, as has the study of its associated adverse effects. Although a wide range of reactions to immunotherapy has been described, reports of immune-mediated focal pancreatitis remain rare. Autoimmune pancreatitis related to immune checkpoint inhibitors occurs because of the hyperactivation of T lymphocytes, which act against pancreatic cells, causing inflammation. CASE REPORT This case report describes a previously healthy 41-year-old man with a diagnosis of metastatic melanoma with inguinal lymph node metastasis. The patient underwent 1 year of adjuvant treatment with nivolumab and had excellent tolerance. After a 1-year suspension of this treatment, nodal and peritoneal recurrence occurred, leading to the initiation of combined therapy with ipilimumab and nivolumab, followed by maintenance nivolumab, resulting in a complete response. After 10 cycles of nivolumab, PET-CT and MRI identified a lesion in the head of the pancreas, which was suspected to be a primary neoplasm. The patient was asymptomatic, with normal tumor markers and elevated amylase and lipase levels. An endoscopic ultrasound-guided biopsy was performed to rule out primary pancreatic cancer, revealing moderately active chronic inflammation associated with immunotherapy. Nivolumab treatment was interrupted for 2 weeks, during which pancreatic enzyme levels improved. Treatment was resumed thereafter. The patient continued with monthly nivolumab applications, maintaining a complete response. without changes in imaging or laboratory test results. CONCLUSIONS This case is atypical for autoimmune pancreatitis owing to the absence of corticosteroid intervention, self-limiting nature of inflammation, and lack of inflammatory recurrence despite the continued use of immunotherapy.

In this review, the historical development of tumor response criteria is examined and an interview was conducted with one of the original researchers behind the original study. This study, published nearly five decades ago, assessed tumor size through palpation and measurements of simulated tumor masses ("balls under mattresses"). The methodology used in that early study as well as in subsequent research that has influenced modifications of the current response evaluation criteria was critically evaluated.

Fibrolipomatous hamartomas (FLHs) are rare pathologies almost exclusively involving the median nerve. Rarer is extra-median involvement of FLH, especially in nerves outside of the upper extremity. In this case report, we detail the case of a 48-year-old male with FLH involving his right tibial nerve-the first in reported literature in this nerve distribution to our knowledge- and perform a review of the existing case reports on extra-median FLH within the English-based literature.

The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary fibrous tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to soft tissue sarcomas. SFTs can arise throughout the body and are usually managed surgically. However, 30-40% of SFTs will relapse local-regionally or metastasize. There are no systemic therapies with durable activity for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the NAB2 and STAT6 loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolsters the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2's co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The limitations of conventional therapies, namely severe side effects and the emergence of drug resistance, underscore the urgent need for novel and more effective treatment strategies. Natural products, including bioactive compounds derived from scorpion venom (SV), have demonstrated promising anticancer properties in various studies. This study aimed to investigate the potential chemopreventive and therapeutic effects of Leiurus quinquestriatus venom (LQV) and Androctonus bicolor venom (ABV) against chemically induced CRC in a rat model. Male rats were randomly assigned to four groups: Group 1 (Gp1) (control), Gp2 (CRC induced using 40 mg/kg 1,2-dimethylhydrazine (DMH), administered subcutaneously for 4 weeks), and Gp3 and 4 (DMH-induced CRC treated intraperitoneally with 0.025 mg/kg LQV and 0.05 mg/kg ABV, respectively, for 11 weeks). At the end of the experimental period, colon tissues were collected for histopathological examination, tumor biomarker analysis, gene expression profiling, cell cycle distribution, and apoptotic assays. Both LQV and ABV significantly reduced the number of aberrant crypt foci (ACF) and mucin-depleted foci (MDF) while enhancing the number of goblet cells in colonic mucosa. Treatment also resulted in a marked downregulation of proliferating cell nuclear antigen (PCNA) and cyclin D1 and upregulation of the tumor suppressor gene PTEN. Moreover, flow cytometry analysis revealed an increase in late apoptotic cells and cell cycle arrest at sub-G1 and G0 phases in venom-treated groups. These findings suggest that LQV and ABV possess notable anti-CRC activity through modulation of proliferation, apoptosis, and gene regulation, highlighting their potential as candidates for alternative CRC therapies.

Intrahepatic biliary neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells in the intrahepatic bile ducts. Patients often present without hormone-related symptoms but are admitted due to jaundice or abdominal pain.

Colorectal cancer is the third most common cancer worldwide, with 15-25% of patients presenting synchronous liver metastases (UICC stage IV). Surgical resection remains crucial, but the optimal sequence for managing synchronous metastases is debated. This study evaluates the impact of different surgical strategies on survival in colorectal cancer patients with liver-only metastases (CRLM) and identifies factors influencing mortality.

The relationship between chronic liver disease and liver cancer remains poorly understood, and treatment options for advanced liver disease remain limited. This study aims to elucidate the dynamic evolution of cellular and molecular alterations from normal liver to diseased liver.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Spindle- and kinetochore-associated complex 1 (SKA1) participates in the regulation of mitosis, playing an essential role in regulating cancer progression. Therefore, this study aims to explore the effects of knocking down SKA1 on HCC. The bioinformatics analysis approaches were adopted to predict SKA1 expression in HCC, the role of SKA1 on the survival rate and prognosis of HCC patients, and the associations between SKA1 expression and gene mutation and immune cell infiltration. The single-cell transcriptome sequencing analysis was employed to explore the cell-cell communications and molecular interactions. The CCK-8, wound healing, Transwell, flow cytometry, and qRT-PCR approaches were used to determine the cell viability, invasion, migration, cell cycle, apoptosis, and SKA1 mRNA expression level of SMMC7721 cells. The tumor volume and weight were measured. The Western blot was applied to determine the protein expression levels of SKA1, survivin, Bax, Bad, Bcl-2, caspase-3, and caspase-9 in SMMC7721 cells and tumor tissue. The bioinformatics analysis results indicated that highly expressed SKA1 was related to a low survival rate and poor prognosis of HCC patients and was involved in the TP53 mutation and multiple immune cell infiltrations. The single-cell transcriptome sequencing analysis affirmed that malignant cells were associated with hepatocytes, ILC, and granulocytes. Meanwhile, various pathways and ligand-receptor pairs were enriched in the cell subpopulation with high SKA1 expression, especially for the Protease-Activated Receptors (PARs) pathway and MDK-SDC1 pair associated with the apoptosis signaling. Knocking down SKA1 reduced the cell viability, invasion, and migration, arrested the cell cycle in the S period, promoted the apoptosis in vitro, decreased the tumor volume and weight in vivo, and down-regulated the survivin and Bcl-2 protein expression levels and up-regulated the caspase 3, caspase 9, Bax, and Bad in vivo and in vitro. Taken together, knocking down SKA1 inhibited HCC progression by promoting the apoptosis signaling pathway.

Pancreatic cancer (PC) is a common malignant tumor with high morbidity and mortality and a very poor prognosis, highlighting the urgent need to identify molecular therapeutic targets. Monocyte chemotactic protein-inducible protein-1 (MCPIP1) is a common inflammatory protein associated with the pathogenesis of a variety of cancers, although a comprehensive understanding of its function and the underlying mechanisms involved in PC remains unclear.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited treatment options. PARP inhibitors (PARPi) have shown promise in treating PDAC with homologous recombination deficiency (HRD), but rapid acquisition of resistance limits their efficacy. Our objective is to investigate mechanisms of resistance to PARPi in BRCA2-mutant PDAC cells and identify potential therapeutic targets to modulate this resistance. We developed olaparib- and talazoparib-resistant Capan-1 cell lines and characterised their resistance profiles using viability assays, RNA sequencing and metabolomic profiling. We also developed a cisplatin-resistant Capan-1 cell line to compare resistance mechanisms between PARPi and platinum agents. Both olaparib- and talazoparib-resistant cells showed cross-resistance to other PARPi and oxaliplatin, but not to gemcitabine or 5-FU. Talazoparib-resistant cells exhibited a similar resistance profile to cisplatin-resistant cells, including decreased PARP1 expression and altered metabolomic profiles. RNA sequencing and metabolomic profiling revealed significant enrichment of metabolic pathways, including oxidative phosphorylation and glycolysis, in resistant cells. Our study highlights the complexity of resistance mechanisms to PARPi in PDAC and identifies potential therapeutic targets in metabolism. The differences in the resistance profiles between olaparib and talazoparib suggest that PARP-trapping potency may play a role in resistance development. Further research is needed to validate these findings and explore novel therapeutic strategies to overcome resistance to PARPi in PDAC.

Leydig cell tumours (LCTs) are uncommon stromal neoplasms of the testis, accounting for less than 3% of all gonadal cancers. Most of them are benign, but the malignant ones are very aggressive without specific effective treatment. Several studies reported pharmacologic insight into the use of statins as anti-tumour agents, but their efficacy on LCTs has not been investigated. Previously, we emphasised the central role of insulin-like growth factor 1 (IGF1)/insulin-like growth factor 1 receptor (IGF1R) signalling in Leydig cell tumorigenesis; here, we showed that simvastatin reduces cell proliferation, determines cell cycle arrest at the G1 phase, and induces reactive oxygen species (ROS) accumulation and apoptosis in R2C and LC540 rat Leydig tumour cells. Furthermore, it prevents isoprenoid farnesyl pyrophosphate (FPP) formation and decreases IGF1R expression, leading to the breakdown of the IGF1R signalling pathway. Importantly, we observed that simvastatin synergised with cisplatin in reducing tumour cell proliferation. Collectively, these data suggest that simvastatin is a potential anticancer drug capable of counteracting LCT growth, and it could be proposed as an adjuvant for chemotherapy in LCT treatment.

Drug repurposing offers a cost-effective and time-efficient strategy for identifying new cancer therapies. Sertraline, a widely prescribed selective serotonin reuptake inhibitor (SSRI), has shown promising anticancer properties through modulation of key pathways involved in tumor survival, stress adaptation, and therapeutic resistance. This scoping review systematically evaluates the current evidence on sertraline's anticancer mechanisms, efficacy, and translational potential. A systematic search of PubMed, EMBASE, Scopus, and Web of Science was conducted in accordance with PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, mechanisms, assays, and outcomes were extracted and synthesized. Of 97 screened articles, 67 met inclusion criteria, comprising 56 preclinical studies, nine population-based studies, and two mixed-methods reports. Sertraline induces apoptosis via mitochondrial dysfunction, caspase activation, and Bcl-2 downregulation, disrupts autophagy and the unfolded protein response, and impairs serine/glycine metabolism through SHMT inhibition. It also suppresses oncogenic signaling via mTOR and TCTP modulation. In vivo studies confirmed tumor growth inhibition in various cancer models, including breast, lung, glioblastoma, and liver. Sertraline enhances the efficacy of chemotherapy, radiotherapy, and targeted therapies by sensitizing resistant cells, modulating immune responses, and impairing metabolic recovery. Retrospective studies suggest no increased cancer risk with SSRI use and hint at protective associations in select malignancies. While current evidence is predominantly preclinical, sertraline's multi-targeted action and established safety profile support its candidacy for repurposing. Further translational research and biomarker-driven clinical trials are warranted to validate its therapeutic niche and optimize its integration into oncology.

IntroductionTreatment of soft tissue sarcomas can profoundly impact on patients' clinical and functional outcomes, and quality of life (QoL). In this study, we aimed to investigate the factors affecting oncological and functional outcomes in surgically treated lower extremity soft tissue sarcoma patients.MethodsThis retrospective study analyzed 52 patients with lower extremity soft tissue sarcoma treated between 2016 and 2022. All patients underwent surgical excision and radiotherapy, either in the neoadjuvant (n:32, 28 Gy over 10 days) or adjuvant (20 patients, 45 Gy 5 week) setting. QoL was assessed using the QLQ-C30 score, while functional outcomes were evaluated with the Musculoskeletal Tumor Society (MSTS) and Toronto Extremity Salvage Score (TESS) scales. Additionally, factors such as tumor location, histological subtype, surgical margins, tumor volume, and oncologic status were analyzed in relation to functional and QoL outcomes.ResultsPatients who received adjuvant radiotherapy had significantly higher mean MSTS and TESS scores compared to those who received neoadjuvant radiotherapy (P = 0.032, P = 0.010, respectively). Patients who received adjuvant radiotherapy had also significantly higher total QLQ-C30 scores and subscale scores for Physical Functioning, Role Functioning, and Social Functioning compared to those who underwent neoadjuvant treatment (P = 0.033, P = 0.005, P = 0.005, P<0.001, respectively). Five-year overall survival was 72%, and local control was 69%. Mortality rate was higher in patient with pelvic tumors and metastatic disease. In the multivariate analysis, only the presence of metastasis was found to have a significant effect on overall survival (P < 0.05).ConclusionOur study highlights that tumor location, particularly pelvic involvement, and the presence of metastases are associated with poorer oncologic outcomes in patients with lower extremity soft tissue sarcomas. Additionally, adjuvant radiotherapy, delivered using a conventional fractionation scheme, is linked to better functional outcomes and improved QoL compared to neoadjuvant radiotherapy, which is administered in a hypo-fractionated regimen.

Colon cancer persists as a major global health burden due to therapy resistance and metastasis, with tumor-associated macrophages (TAMs) in the microenvironment driving progression through immune evasion and angiogenesis. This review highlights plant-derived therapeutics targeting TAMs to disrupt protumor signaling. Key phytochemicals (e.g., Curcumin, Cucurbitacin B, Astragaloside IV) suppress M2 polarization via NF-κB/STAT3 inhibition, block VEGF/HIF-1α-mediated angiogenesis, and enhance antitumor immunity by downregulating PD-L1. Cannabidiol, Hydroxygenkwanin regulate TAM metabolism. Dietary agents like sulforaphane and β-glucans modulate TAM-gut microbiome crosstalk. Nanoparticle-encapsulated phytochemicals enhance TAM-targeted delivery, while clinical translation requires standardized phytopreparations and biomarker-guided trials. We propose integrating validated botanical adjuvants (e.g., Fucoidan for TLR4 inhibition, dihydroisotanshinone I for CCL2 suppression) with immunotherapies to remodel immunosuppressive niches. Phytotherapy offers a multifaceted strategy to overcome TAM-driven therapeutic barriers in colon cancer, emphasizing plant-based precision medicine to augment conventional treatments.