Advanced synovial sarcomas are associated with poor outcomes and a lack of efficacious therapeutic agents. The aim of this study was to assess the efficacy and safety of a novel, low-dose, continuous schedule of regorafenib in these patients.

Colorectal cancer (CRC) ranks third in global incidence and second in mortality, with rates increasing among younger populations. The enteric nervous system (ENS) is crucial for gastrointestinal function, and its dysfunction is associated with the progression of CRC. Neurodegeneration may disrupt ENS function and facilitate tumor growth although the mechanisms remain unclear.

The 22-gene Decipher genomic classifier (GC) (22-gene GC) is the only gene expression test with National Comprehensive Cancer Network (NCCN) level 1 evidence for localized prostate cancer (PCa) treatment decision making. It is unclear whether other commercial signatures-Genomic Prostate Score (GPS) or Prolaris (cell cycle progression [CCP])-correlate sufficiently to explain differences in evidence strength. This study assesses correlation between these three classifiers on a per-patient basis by performing a cross-comparison of these signatures in a large cohort of patients diagnosed with PCa.

We previously developed and validated a 15-gene prognostic signature (15G score) in localized clear cell renal cell carcinoma (ccRCC). Given its ability to differentiate aggressive and indolent disease, we sought to apply the 15G score to patients with metastatic ccRCC to evaluate its prognostic performance in this setting.

Esophageal cancer recurrence occurs even in those who have a pathologic complete response (pCR) following neoadjuvant therapy and esophagectomy. The purpose of this study is to identify predictors of overall survival in patients with pCR. Using the National Cancer Database, a retrospective analysis of all adult patients with ypT0N0 esophageal cancer following neoadjuvant chemotherapy and radiation between 2012 and 2020 was performed. The variables analyzed were age, gender, ethnicity, insurance, Charlson-Deyo comorbidity score, clinical stage, and facility type. Cox proportional hazards regression was used to identify predictors of overall survival. Wilcoxon rank sum and chi-square tests were used for continuous and categorical variables, respectively, with a significance level of P < 0.05. There were 2767 patients that met the inclusion criteria, with the mean age of 63; 78% were male and 92% were White. Median survival was 6.6 years (95% confidence interval [CI]: 6.21-7.12). In multivariable analysis, older age (hazard ratio [HR] 2.7 per year, P < 0.0001), male gender (HR 3.3, P = 0.02), Charlson-Deyo score ≥ 2 (HR 3.9, P = 0.01), and advanced clinical stage (Stage IV vs. Stage I, HR 21.93, P < 0.001) predicted worse overall survival. Among patients who achieved pCR, advanced age, male gender, comorbidities, and clinical stage significantly influenced survival. Tumor- and treatment-related factors that impacted overall survival are advanced clinical stage and treatment at community facilities. These findings suggest that patients with advanced-stage esophageal cancer who achieve pCR remain at higher risk for recurrence and future studies should investigate this population further.

Metallic implants are widely used in orthopaedic surgery. These implants may have carcinogenic properties, but the incidence of associated malignancies appears to be low, and to date, only case reports and small case series have been reported. We describe a series of patients with soft-tissue sarcoma adjacent to orthopaedic implant.

The disproportionate burden of obesity among Black women may contribute to disparities in breast cancer survival; yet, associations of body mass index (BMI), a proxy for total adiposity, are inconsistent.

Several landmark studies over the past decade have uncovered a critical role of the CRL3KBTBD4 ubiquitin ligase complex in regulating stability of corepressor of repressor element 1 silencing transcription factor (CoREST) complex proteins and normal hematopoietic stem cell self-renewal. There is now mounting evidence that the CoREST complex plays oncogenic roles, although the contributions of its catalytic versus noncatalytic functions remain unclear. Here, we summarize and discuss mechanisms whereby the CoREST complex coopts tissue-specific transcription factors to elicit pathogenic activity in cancer and neurodegenerative disease. We also identify tumor types with selective dependencies on the scaffolding properties of the CoREST complex. We argue that these tumor types may benefit from a KBTBD4-activating/CoREST complex degrader therapy, which could also enhance antitumor immunity and sensitize resistant tumors to immunotherapy. Overall, understanding how the CoREST complex operates abnormally and differences between its targeting through catalytic inhibitors or protein degraders will help discern all possible applications for targeting therapies now in clinical development.

To systematically investigate the molecular and pathological mechanisms of enhancer RNA (eRNA)-mediated transcriptional regulation in glioma recurrence and progression, transcriptomic, regulatome, and genomic data were integrated to analyze eRNA behavior in lower-grade gliomas (stages II/III) and glioblastomas (stage IV). Most eRNAs exhibited dynamic expression during glioma progression, regulated by master transcription factors (TFs) and affected by genomic mutations. The constructed perturbed TF-mediated eRNA-promoter regulatory landscape revealed that rewiring eRNA-promoter networks contributed to glioma malignancy. Drug response-related eRNAs associated with poor prognosis were identified, highlighting their clinical potential. Overall, integrative analysis highlights the critical role of eRNA-mediated regulatory rewiring in glioma progression, providing valuable insights into transcriptional mechanisms and potential therapeutic targets.

Visceral haemangiosarcoma is considered clinically aggressive in dogs, with perceived poor prognosis often leading to euthanasia at presentation. This study aimed to determine survival times and prognostic factors in dogs with haemangiosarcoma under first-opinion care. Dogs clinically diagnosed with haemangiosarcoma in first-opinion practice in 2019 were identified in VetCompass electronic health records and examined to capture variables potentially associated with survival. Median survival time (MST) from diagnosis was calculated for the whole population, those histopathologically confirmed and based on primary tumour location. Binary logistic regression was used to explore differences between dogs that died on the day of diagnosis and those that survived ≥1 day. Cox proportional hazards modelling explored factors associated with time to death in dogs surviving ≥1 day. Across all cases (n = 788), overall MST was 9.0 days (95%CI:5.0-15.0, range: 0-1789) and proportional 1-year survival was 12.0% (95%CI:9.7-15.0%). Dogs with splenic (MST = 4.0 days, 95%CI 0.0-9.0) and cutaneous haemangiosarcoma (MST = 119.0 days,95%CI:85.0-248.0) had MST greater than 0 days. Of dogs with a histopathological diagnosis of haemangiosarcoma, overall MST was longer at 105 days (95% CI 84-133 days) and additionally, location-specific MST were longer. For both clinically diagnosed cases and histopathologically confirmed cases, increasing tumour size was associated with increased hazard of death while cutaneous location and surgery were associated with reduced hazard of death. A very short survival time was identified for haemangiosarcoma under first-opinion care. Although survival time was longest for cutaneous cases, the actualised prognosis was poor overall for haemangiosarcoma. However, a common prevailing view of extremely poor prognosis for haemangiosarcoma could be promoting frequent euthanasia at presentation and therefore leading to a self-fulfilling prophecy and low survival times. Further exploration of the potential effect of perceived prognosis is warranted. This study provides valuable information for contextualised care and dialogues with clients in first-opinion practice.

FAT1 is a tumor suppressor gene encoding the protocadherin FAT1, which has been found to be mutated in different types of human cancers with the highest frequency in head and neck squamous cell carcinoma (HNSCC). However, through which mechanisms mutations of FAT1 lead to tumor progression is incompletely understood. Here, we report that loss of FAT1 in various tumor cells, including HNSCC cells, resulted in increased protein levels of the transcriptional regulators YAP and TAZ. This was sufficient to lead to increased expression of YAP/TAZ target genes and to increased tumor cell proliferation. We found that elevated YAP/TAZ activity after loss of FAT1 was due to decreased YAP/TAZ protein degradation, which could be rescued by expression of the intracellular part of FAT1. When analyzing the interactome of the cytoplasmic part of FAT1 in tumor cells, we identified the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as an interaction partner. Suppression of MIB2 expression in various tumor cells led to same effects as loss of FAT1 expression, including a decrease in YAP and TAZ ubiquitination, and degradation as well as an increase in YAP/TAZ protein levels and expression of YAP/TAZ target genes. Similarly, Hela cells or HNSCCs with suppressed MIB2 expression resembled FAT1 defective tumor cells showing faster proliferation in vitro as well as increased tumor growth in vivo compared to control cells. Our study identifies a mechanism by which YAP/TAZ levels are kept low through FAT1/MIB2-mediated protein degradation and shows that tumor progression resulting from mutation of tumor suppressor FAT1 involves loss of MIB2-dependent degradation of YAP and TAZ.

Significant advances have been made in image-based determinations of future remnant liver function, in attempts to better predict post-hepatectomy liver failure (PHLF). We have reported time-associated liver functional assessments using magnetic resonance imaging with liver-to-spleen signal intensity ratio increasing rate (LSRi) and LSRi of the future remnant liver region (LSRi-rem) to predict PHLF. This study aimed to investigate the predictability of PHLF by a preoperative liver function assessment index that combined LSRi-rem and future remnant liver volume (FRLV).

Survivin, an inhibitor of apoptosis proteins (IAPs), is more strongly expressed in triple negative-breast cancer (TNBC) than other subtypes of breast cancer and closely associated with aggressiveness characterized by rapid progression and poor prognosis. The main function of survivin is to regulate cell division and prevent apoptosis. However, other survivin mechanisms are complex and not fully understood. The aim of this study was to evaluate the effects of survivin knockout on TNBC progressiveness relating to proliferation, apoptosis, stemness, cellular stress response, and metastasis mechanisms.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, with limited response rates and resistance to targeted therapies and immunotherapies. Pin1, a phosphorylation-specific peptidyl-prolyl isomerase, has been implicated in multiple oncogenic pathways; however, its role in LUAD is not fully understood. We conducted an integrative analysis using public datasets (TCGA, GEO, HPA), LUAD tissue microarrays, malignant pulmonary nodule specimens, and cell line models to investigate the expression and function of PIN1 in LUAD. Functional assays, immunohistochemistry, and in vivo xenograft models were employed to validate the biological effects of PIN1 in LUAD progression and treatment response. PIN1 expression was significantly downregulated in LUAD tissues compared to adjacent normal lung tissues. High PIN1 expression was associated with improved overall survival, increased immune cell infiltration, and enhanced response to immunotherapy. Overexpression of PIN1 inhibited proliferation and migration while promoting apoptosis of LUAD cells in vitro and in vivo. Mechanistically, high PIN1 expression activated downstream pAKT and pMAPK signaling, potentially contributing to EGFR-TKI resistance despite unchanged pEGFR levels. Moreover, functional enrichment analysis and immune profiling revealed that PIN1 is positively associated with antitumor immune responses in LUAD, contrasting its immunosuppressive role in other cancers. PIN1 exhibits tumor-suppressive activity in LUAD and may serve as a promising biomarker for prognosis and therapeutic response. These findings underscore the context-dependent role of PIN1 and support further exploration of its mechanistic involvement in LUAD immunobiology and targeted therapy resistance.

Cerebral cavernous malformations (CCMs) are clusters of thin-walled enlarged blood vessels in the central nervous system that are prone to recurrent hemorrhage and can occur in both sporadic and familial forms. The familial form results from loss-of-function variants in the CCM1, CCM2, or CCM3 gene. Despite a better understanding of CCM pathogenesis in recent years, it is still unclear why CCM3 mutations often lead to a more aggressive phenotype than CCM1 or CCM2 variants. By combining high-throughput differentiation of blood vessel organoids from human induced pluripotent stem cells (hiPSCs) with a CCM1, CCM2, or CCM3 knockout, single-cell RNA sequencing, and high-content imaging, we uncovered both shared and distinct functions of the CCM proteins. While there was a significant overlap of differentially expressed genes in fibroblasts across all three knockout conditions, inactivation of CCM1, CCM2, or CCM3 also led to specific gene expression patterns in neuronal, mesenchymal, and endothelial cell populations, respectively. Taking advantage of the different fluorescent labels of the hiPSCs, we could also visualize the abnormal expansion of CCM1 and CCM3 knockout cells when differentiated together with wild-type cells into mosaic blood vessel organoids. In contrast, CCM2 knockout cells showed even reduced proliferation. These observations may help to explain the less severe clinical course in individuals with a pathogenic variant in CCM2 and to decode the molecular and cellular heterogeneity in CCM disease. Finally, the excellent scalability of blood vessel organoid differentiation in a 96-well format further supports their use in high-throughput drug discovery and other biomedical research studies.

MUC16 ranks among the top three genes exhibiting the highest mutation frequencies in various cancer types. It encodes transmembrane mucins present in the epithelial linings of the ocular, respiratory, gastric and female reproductive systems, serving to protect and maintain mucosal surfaces. Overexpression of MUC16 contributes to the differentiation, proliferation, invasion and metastasis of cancer cells in ovarian, endometrial, pancreatic, colon, breast and non-small-cell lung cancers. In this study, we analysed the structural and functional effects of pathogenic and potentially harmful non-synonymous single nucleotide polymorphisms (nsSNPs) of MUC16, employing a blend of computational algorithms. Initially, SNPs data for MUC16 were gathered from the Ensembl database and refined using computational tools (PROVEAN, SIFT, PolyPhen-2, SNAP-2, MutPred, I-Mutant3.0 and MUpro) to isolate four final pathogenic SNP variants (L151P, Y144N, C111Y and D108Y). Through evolutionary conservation analysis, we determined that these mutational variants originate from a highly conserved and stable domain. Our findings particularly emphasise the Y144N variant as a potentially highly deleterious mutation situated in the SEA5 domain. This variant could significantly impact stability, overall flexibility, compactness, expansion, glycosylation ability and metastatic potential when compared to both the wild-type and other mutant variants. In summary, these findings shed light on missense mutational variants, providing insights into the vast array of disease susceptibilities associated with MUC16's glycosylation process. This understanding could aid in the development of effective drugs for diseases linked with these mutations.

Breast cancer patients undergoing mastectomy are not well represented in studies evaluating the omission of completion axillary lymph node dissection (cALND) due to sentinel lymph node (SLN) metastases.

The complexity of lung cancer, driven by multifactorial causes such as genetic, environmental and lifestyle factors, underscores the necessity for tailored treatment strategies informed by recent advancements. Studies highlight a significant association between the lung microbiome and lung cancer, with dysbiosis potentially contributing to disease development via inflammation, immune response alterations and bacterial metabolite production. Furthermore, exposure to airborne bacteria may influence lung health by introducing pathogenic species or altering the human microbiome, thereby implicating certain dominant airborne bacteria in lung diseases, including the exacerbation of lung cancer. Extracellular vesicles (EVs) facilitate cell‑to‑cell communication, penetrating mucosal barriers to impact various organs, notably the lung. Epidemiological evidence suggests a strong relationship between the presence of microbial EVs (MEVs) in the air and chronic pulmonary diseases, with indications of a potential risk for lung cancer. MEVs play a significant role in pulmonary disease development by inducing airway inflammation and affecting lung function. The microbiome and MEVs offer considerable potential as novel tools in precision medicine for lung cancer. Biological data analysis and artificial intelligence technology advancements are pivotal for fully realizing their diagnostic and therapeutic capabilities. These developments can potentially shape the future landscape of lung cancer diagnostics, therapeutics and prevention strategies.

Peroxiredoxin (PRDX) is a large and highly conserved family of peroxidases, which can maintain the dynamic balance of intracellular oxidative stress levels based on the degradation of the hydrogen peroxide, peroxynitrite and lipid peroxides, among others. Additionally, PRDXs are expressed with varying levels in almost all tumor tissues and cells, and they can regulate the downstream signaling cascades by modulating intracellular peroxide levels in tumor cells, alongside the participation during the modulation of gene expression, cell proliferation, apoptosis, migration, differentiation and other cellular biological behaviors. It has been revealed that the PRDXs family exhibits crucial functions in the occurrence, development, diagnosis and prognosis of gastrointestinal cancer, but a systematic summary was lacking in relevant studies. Therefore, the present study aims at probing into the underlying mechanisms of the PRDXs family in the occurrence and development of gastrointestinal cancer, providing new insights into the clinical diagnosis, treatment and prognosis monitoring.

Brain tumours are in the spotlight of oncology research due to their intractability and resistance to conventional treatments. High‑risk craniotomies must be performed on patients during tumour resection surgeries due to the specificity of the brain structure, and the complexity of the brain structure also leads to the fact that brain tumours usually cannot be removed completely. Besides, the inability of foreign small molecules to cross the blood‑brain barrier has led to the inability of conventional drug therapy to reach the tumour location in the brain. Furthermore, the damage to healthy brain tissue caused by conventional radiotherapy cannot be ignored. Therefore, brain tumours represented by gliomas are in urgent need for a novel therapeutic approach. Glioma is the most common brain tumour, accounting for 81% of malignant tumours in the central nervous system, and is characterized by high morbidity, recurrence, mortality and low cure rate. In recent years, natural killer (NK) cell immunotherapy for gliomas has gradually emerged and numerous studies have shown surprising therapeutic effects. NK cells have been demonstrated to traverse the blood‑brain barrier and numerous studies have confirmed their ability to kill glioma cells both in vivo and in vitro. This article begins by introducing conventional therapies for glioma, followed by an overview of the potential of NK cell‑based immunotherapy in glioma treatment and the regulatory mechanisms of NK cells within the glioma immune microenvironment. It then summarizes preclinical studies on CAR‑NK cells and clinical advancements in NK cell therapy for glioma. Finally, the paper discusses recent progress in immunotherapy for gliomas and explores novel therapeutic strategies combining NK cell immunotherapy with other treatment modalities.