Tumor Differentiation Research Articles

Texture analysis based on CT for predicting the differentiation of esophageal squamous cancer: An observational study.

To explore the feasibility and application value of texture analysis based on computed tomography (CT) for predicting the differentiation of esophageal squamous cell carcinoma (ESCC). Patients diagnosed with ESCC who underwent chest contrast-enhanced CT before treatment were selected. Based on the pathological results, the patients were stratified into poorly differentiated and moderately well-differentiated groups. FireVoxel software was used to analyze the region of interest based on venous phase CT images. Texture parameters including the mean, median, standard deviation (SD), inhomogeneity, skewness, kurtosis, and entropy were obtained automatically. Differences in the texture parameters and their relationship with the degree of differentiation between the 2 groups were analyzed. The value of CT texture parameters in identifying poor differentiation and moderate-well differentiation of esophageal cancer was analyzed using the ROC curve. A total of 48 patients with ESCC were included, including 24 patients in the poorly differentiated group and 24 patients in the moderate-well-differentiated group. There were negative correlations between SD, inhomogeneity, entropy, and the degree of differentiation of esophageal cancer (P < .05). The correlation of inhomogeneity was the highest (r = -0.505, P < .001). SD, inhomogeneity, and entropy could effectively distinguish between the poorly and moderately well-differentiated groups, with statistically significant differences between the 2 groups (P < .05). The best critical values for SD, inhomogeneity, and entropy were 17.538, 0.017, and 3.917, respectively. The areas under the ROC curve were 0.793, 0.792, and 0.729, respectively, with the SD and inhomogeneity being the best. The application of texture analysis on venous phase CT images holds promise as a method for forecasting the degree of differentiation in esophageal cancers, which could significantly contribute to the preoperative noninvasive evaluation of tumor differentiation.

Association between Higher Expression of Vav1 in Hepatocellular Carcinoma and Unfavourable Clinicopathological Features and Prognosis

Objective: The aim was to investigate the potential relationship between Vav1 protein and prognosis in patients with hepatocellular carcinoma (HCC). Methods: Samples were collected from 96 patients with HCC. For each patient, cancerous tissue and adjacent non-cancerous tissue were obtained. The Vav1 expression levels in these tissues were determined using immunohistochemistry. Chi-square and Fisher's exact tests were used to analyse the associations between Vav1 expression and clinicopathological characteristics. Kaplan– Meier analysis was used to assess the relationship between Vav1 expression and 5-year overall survival (OS). Results: The expression level of Vav1 protein in primary tumour samples (64.46%; 59/96) was higher (33.33%; 32/96; P&lt;0.001). Moreover, the high expression rate of Vav1 was correlated with tumour differentiation, TNM stage, and tumour recurrence (P&lt;0.05). Univariate and multivariate Cox analysis further demonstrated that tumour differentiation, TNM stage, vascular invasion, tumour recurrence and Vav1 expression were independent prognostic factors for 5-year OS. Notably, follow-up analysis determined that patients with HCC with higher Vav1 expression levels have lower survival rates (P&lt;0.05). Conclusion: Vav1 may serve as a promising molecular prognostic biomarker for patients diagnosed with HCC.

Prognostic value of ABO blood groups in upfront operated pancreatic ductal adenocarcinomas

PurposePancreatic ductal adenocarcinoma (PDAC) has been shown to have a lower incidence in patients with blood group O. It is currently uncertain if patients with group O have a better prognosis after pancreatectomy. This study assessed the overall survival (OS) and disease-free survival (DFS) of PDAC patients who underwent upfront pancreatoduodenectomy based on ABO blood groups.MethodsA cross-sectional study was performed including patients from two university centers. All consecutive head PDAC patients who underwent upfront pancreatoduodenectomy from 2000 to 2016 were included. OS and DFS were compared between blood groups A, B, AB, and O using Kaplan-Meier curves and log-rank tests.ResultsA total of 438 patients were included (215 women, median age 67). Pre- and intraoperative details were comparable between all subgroups. Median OS did not differ between the four blood groups (A: 23 months, 95% CI 18–28; B: 32, 95% CI 20–44; AB: 37, 95% CI 18–56 and O: 26, 95% CI 20–32, p = 0.192). Median DFS were also similar (A: 19 months, 95% CI 15–23; B: 26, 95% CI 19–33; AB: 35, 95% CI 15–55 and O: 22, 95% CI 15–29, p = 0.441). There was no OS difference between O and non-O groups (median: 26 months, 95% CI 20–33 vs. 25 months, 95% CI 20–30, p = 0.773). On multivariable analysis blood groups were not prognostic of OS. Only lymph node involvement, tumor differentiation, and adjuvant chemotherapy were independent prognostic factors.ConclusionOS and DFS were similar between all four blood groups after pancreatoduodenectomy. Independent predictors of OS were associated with tumor characteristics and adjuvant treatment.

Intratumoral calcification on CT assists in distinguishing benign and malignant upper abdomen neoplasm.

The significance of calcification and microcalcification in diagnosing malignant tumors is well established, but their role in the upper abdomen is less explored in routine radiology. To assess the effectiveness of computed tomography (CT) imaging in detecting intratumoral calcification within upper abdominal tumors. This study retrospectively enrolled patients with upper abdominal tumors featuring intratumoral calcifications who underwent plain and contrast-enhanced CT scans between January 2016 and December 2019. We examined the imaging characteristics of calcifications, including location, edges, shape, CT values, and association with necrosis. The diagnostic utility of calcification for distinguishing benign and malignant tumors was assessed using receiver operating characteristic curves. Univariate and multivariate logistic regression analyses were conducted to identify independent predictive factors for the diagnosis of malignancy characterized by intratumoral calcification. This study included 153 patients (median age 49 ± 21years; 83 men) with pathologically confirmed tumors of the upper abdomen (including liver, pancreas, and gastrointestinal tract) with intratumoral calcifications. Significant differences in CT values between benign and malignant tumors were observed (P < .001), with high diagnostic accuracy of calcification in CT imaging (receiver operating characteristic area = 0.884, sensitivity = 0.815, specificity = 0.976). The characteristics of calcification, including its edge and shape, were significantly correlated with tumor differentiation (P < .01). Multivariate logistic regression analysis revealed that the presence of adjacent necrosis around intracalcification is an independent predictor of malignancy (odds ratio = 5.48; 95% confidence interval: 1.55, 19.41; P = .008). Intratumoral calcification in CT imaging is a key marker for distinguishing between benign and malignant epigastric tumors, offering high specificity. Key message • What is already known on this topic - Intratumoral calcification, as a highly sensitive radiological marker, has shown potential in differentiating between benign and malignant tumors in thyroid and breast cancers. However, its discriminatory role in upper abdominal tumors is often overlooked. Therefore, assessing the diagnostic accuracy of intratumoral calcification on CT scans is crucial for improving diagnostic efficiency and avoiding unnecessary examinations. • What this study adds - Intratumoral calcification on CT exhibits high specificity in differentiating between benign and malignant upper abdominal tumors, providing a simple and reliable criterion for improving diagnostic accuracy. • How this study might affect research, practice or policy - This study highlights the significance of intratumoral calcification characteristics observed on CT in determining whether upper abdominal tumors are benign or malignant. The findings could pave the way for the development of a CT-based calcification scoring system, which would facilitate rapid and accurate diagnostics in clinical practice, thereby optimizing treatment strategies and enhancing patient prognosis.

SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has a devastating influence on recipients' survival; however, the risk of recurrence is not routinely stratified. Risk stratification is vital with a long LT waiting time, as that could influence the recurrence despite strict listing criteria. This study aims to identify predictors of recurrence and develop a novel risk prediction score to forecast HCC recurrence following LT. A retrospective review of LT for HCC recipients at University Hospitals Birmingham between July 2011 and February 2020. Univariate and multivariate analyses were performed to identify recurrence predictors, based on which the novel SIMAP500 (satellite nodules, increase in size, microvascular invasion, AFP > 500, poor differentiation) risk score was proposed. 234 LTs for HCC were performed with a median follow-up of 5.3 years. Recurrence developed in 25 patients (10.7%). On univariate analyses, RETREAT score > 3, α-fetoprotein (AFP) at listing 100-500 and > 500, bridging, increased tumour size between imaging at the listing time and explant histology, increase in the size of viable tumour between listing and explant, presence of satellite nodules, micro- and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence, based on which, the SIMAP500 risk score is proposed. The SIMAP500 demonstrated an excellent predictive ability (c-index = 0.803) and outperformed the RETREAT score (c-index = 0.73). SIMAP500 is indicative of the time to disease recurrence. SIMAP500 risk score identifies the LT recipients at risk of HCC recurrence. Risk stratification allows patient-centric post-transplant surveillance programs. Further validation of the score is recommended.

Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope?

Hepatocellular carcinoma (HCC) is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity. One of the favourable curative surgical therapeutic options for HCC is liver transplantation (LT) in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival. Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres, the recurrence rate still occurs which could negatively affect HCC patients' survival. Hence HCC recurrence post-LT could predict patients' survival and prognosis, depending on the exact timing of recurrence after LT (early or late), and whether intra/extrahepatic HCC recurrence. Several factors may aid in such a complication, particularly tumour-related criteria including larger sizes, higher grades or poor tumour differentiation, microvascular invasion, and elevated serum alpha-fetoprotein. Therefore, managing such cases is challenging, different therapeutic options have been proposed, including curative surgical and ablative treatments that have shown better outcomes, compared to the palliative locoregional and systemic therapies, which may be helpful in those with unresectable tumour burden. To handle all these issues in our review.

Strategically engineered Au(I) complexes for orchestrated tumor eradication via chemo-phototherapy and induced immunogenic cell death

Cancer is a significant cause of death around the world, and for many varieties, treatment is not successful. Therefore, there is a need for the development of innovative, efficacious, and precisely targeted treatments. Here, we develop a series of Au(I) complexes (1-4) through rational manipulation of ligand structures, thereby achieving tumor cell specific targeting and orchestrated tumor eradication via chemo-phototherapy and induced immunogenic cell death. A comprehensive exploration based on in vitro and in vivo female mice experimentation shows that complex 4 exhibits proficiency in specific tumor imaging, endoplasmic reticulum targeting, and has robust therapeutic capabilities. Mechanistic elucidation indicates that the anticancer effect derives from the synergistic actions of thioredoxin reductase inhibition, highly efficient reactive oxygen species production and immunogenic cell death. This work presents a report on a robust Au(I) complex integrating three therapeutic modalities within a singular system. The strategy presented in this work provides a valuable reference for the development of high-performance therapeutic agents.

Poor Prognostic Factors in Long-Term Survivors of Resected Pancreatic Ductal Adenocarcinoma: An International, Multicenter Cohort Study.

To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS. Long-term survival (>5y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear. An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression. 3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features. This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS.

Diagnostic mistakes in assessing MRI semiotics of primary extra-axial brain tumors tumors.

Primary extra-axial brain tumors (PExT) are represented by benign and malignant tumors of the meninges and cranial nerves. Their preoperative differential diagnosis based on an analysis of the semiotics of magnetic resonance imaging. The critically important points that make it possible to classify tumors of this group are the following characteristics: tumors structure, contrast enhancements, invasion and relationship tumors with the meninges or cranial nerves. Differential diagnostic typical PExT is not difficult, because most of they heave typical MRI visual signs. With atypical MRI manifestations, reliable differentiation of tumors can be difficult. The greatest difficulty in this case is the differentiation of benign and malignant meningiomas, the distinction between solitary fibrous tumors and meningiomas, and the tumors when they localized in the cerebellopontine angles. The case series presented containing the most typical situations leading to errors in the differential diagnosis of PexT, all tumors had untypical signs. All presented tumors were histological verified. Analysis of the given clinical examples shows that consideration of the entire set of semiotic signs can reduce the number of diagnostic errors.

Small bowel neuroendocrine tumors: Unique features and low lethality compared with small bowel adenocarcinoma.

Population-based studies comparing clinical characteristics and survival disparities between patients with small bowel adenocarcinoma (SBA) and small bowel neuroendocrine tumors (SBNETs) in the United States are limited. Data for patients with SBA or SBNETs, obtained from the Surveillance, Epidemiology, and End Results database for the years between 2000 and 2018 were analyzed. Between 2000 and 2018, the age-adjusted incidence of SBA experienced a marginal increase whereas SBNETs demonstrated a significant increase, emerging as the predominant subtype of small bowel cancer (SBC). Diagnoses peaked at ages 65-69years for SBA and 60-64years for SBNETs, with the latter exhibiting a heightened age-specific incidence and maintaining equilibrium in gender distribution. Clinicopathologic disparities revealed SBA's duodenal predilection, larger tumor size, and advanced stages, contrasting with SBNETs' ileal predilection, early-stage presentation, and superior outcomes. SBNETs patients underwent surgery more frequently but received less chemotherapy and radiation than SBA patients. Factors intricately correlated with a diagnosis of SBNETs included female gender, White race, advanced age, marital status, recent diagnoses, superior tumor differentiation, smaller size, distal location, and early-stage presentation. Survival analysis unveiled a remarkable 79% reduction in the mortality risk for SBNETs compared with SBA. Subgroup analysis further confirmed the consistently favorable survival advantages of SBNETs, highlighting the clinical relevance of histological classification in prognostication. Compared with SBA, SBNETs exhibited distinctive clinicopathological features characterized by a higher inclination toward low-grade and early-stage manifestations, thereby contributing to superior survival outcomes.

Abstract A055: Multiomics profiling reveals druggable tumor-stroma interactions in ATM-deficient pancreatic cancer

Abstract The complex biology of pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge and limits overcoming its dismal prognosis. The tumor microenvironment (TME), shaped by dynamic interactions between cancer-associated fibroblasts (CAFs), immune and tumor cells, plays a crucial role in PDAC pathogenesis. Uncharted field lies in the impact of specific gene mutations within the tumor epithelium on orchestrating distinct oncogenic TME patterns. Our investigation into homologous recombination deficiency (HRD), caused by mutations in genes like ATM, reveals its role in promoting PDAC aggressiveness and triggering a pronounced desmoplastic reaction, suggesting a unique TME programing. Through single-cell-resolved and multiomics analyses of murine ATM and/or P53-depleted PDACs, and validation in human cases, we unveil transcriptional, translational, and secretory regulatory events, shed light on the intricate interplay between tumor genetics and PDAC microenvironment and pave the way for the elaboration of novel personalized therapies. Murine tumor analysis using single-nucleus multiomics RNA and ATAC sequencing, alongside histological validation in human tissues, revealed specific enrichment of myCAFs in ATM-deficient tumors and reduced populations of T cells and macrophages. Molecular signatures and cell-cell communication inference uncovered ATM-specific interactions within the TME, highlighting TGF-β signaling as pivotal in mediating dialog between CAFs and an aggressive EMT-like tumor cell subset prevalent in ATM-depleted tumors. Additionally, distinct communication patterns were observed between CAFs and immune cells, associated with specific epigenetic and molecular profiles. Mechanistically, transcriptomics, secretomics and proteomics investigations confirmed increased TGFβ release by ATM-deficient PDAC cells and identified a reactive oxygen species (ROS)-mediated mechanism affecting tumor cell behavior and interactions with CAFs. Consistently, a combinatorial therapy targeting TGF-β-mediated tumor-stroma dialog reversed cancer-promoting TME remodeling and exacerbated FOLFIRINOX cytotoxic effects, in vivo, exclusively in ATM-deficient HRD PDACs. Dissecting the biology of ATM-deficient HRD malignant cells, our study unveils their pivotal role in orchestrating oncogenic communication networks with CAFs and immune cells, along with specific tumor promoting stromal reprogramming. Our findings paint a comprehensive picture of how distinct tumor-stroma interactions reshape the TME, steering it towards a cancer-promoting outcome and shed light on the potential to exploit genotype-specific vulnerabilities via tailored tumor-stroma interference strategies. Citation Format: Elodie Roger, Hannah M. Mummey, Eleni Zimmer, Julia Ragg, Yuna Lee, Kyle J. Gaulton, Alica K. Beutel, Christopher J. Halbrook, Lukas Perkhofer, Johann Gout, Alexander Kleger. Multiomics profiling reveals druggable tumor-stroma interactions in ATM-deficient pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A055.

Research on enzymatic co-assembly nanomedicine in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) represents the predominant form of malignancy within the head and neck region, accounting for more than 90 ​% of all oral cavity tumors. OSC cells commonly overexpress epidermal growth factor receptor (EGFR), which is closely associated with the development, progression, and differentiation of tumors. Despite surgery and chemotherapy being the primary therapeutic interventions for OSCC, their efficacy is suboptimal compared with that of other oral malignancies. We engineered a polypeptide molecule (HCPT-GDFDFDpYERGD, designated HP), which features the chemotherapeutic agent 10-hydroxycamptothecin (HCPT) at its N-terminus and the tumor-homing ligand Arginine-Glycine-Aspartic acid (RGD) at its C-terminus. The RGD moiety confers upon the polypeptide the ability to co-target cancer cells synergistically. The EGFR inhibitor cetuximab was co-assembled with HP via an enzymatic catalysis co-assembly technique to create a nanofibrillar structure, resulting in antibody‒polypeptide coassembly. In vitro assays have demonstrated that the co-assembled nanomedicine exhibits high affinity for OSCC cells, is efficiently internalized, and elicits potent inhibitory effects. Furthermore, bioinformatics analysis suggested that the co-assembled nanomedicine downregulated genes enriched in the PI3K-Akt signaling cascade. The co-assembled nanomedicine dramatically reduces cancer while sparing negative effects, as shown by in vivo animal models. This research endeavors to develop a new nanomedicine delivery platform that integrates molecular targeting with efficient intracellular drug delivery. This system not only markedly augments the therapeutic efficacy of the chemotherapeutic agent HCPT but also substantially mitigates patient adverse effects, thus offering a more secure and efficacious therapeutic strategy for the management of OSCC.

Development of microsurgical forceps equipped with haptic technology for in situ differentiation of brain tumors during microsurgery

The stiffness of human cancers may be correlated with their pathology, and can be used as a biomarker for diagnosis, malignancy prediction, molecular expression, and postoperative complications. Neurosurgeons perform tumor resection based on tactile sensations. However, it takes years of surgical experience to appropriately distinguish brain tumors from surrounding parenchymal tissue. Haptics is a technology related to the touch sensation. Haptic technology can amplify, transmit, record, and reproduce real sensations, and the physical properties (e.g., stiffness) of an object can be quantified. In the present study, glioblastoma (SF126-firefly luciferase-mCherry [FmC], U87-FmC, U251-FmC) and malignant meningioma (IOMM-Lee-FmC, HKBMM-FmC) cell lines were transplanted into nude mice, and the stiffness of tumors and normal brain tissues were measured using our newly developed surgical forceps equipped with haptic technology. We found that all five brain tumor tissues were stiffer than normal brain tissue (p < 0.001), and that brain tumor pathology (three types of glioblastomas, two types of malignant meningioma) was significantly stiffer than normal brain tissue (p < 0.001 for all). Our findings suggest that tissue stiffness may be a useful marker to distinguish brain tumors from surrounding parenchymal tissue during microsurgery, and that haptic forceps may help neurosurgeons to sense minute changes in tissue stiffness.

Tumour immune characterisation of primary triple-negative breast cancer using automated image quantification of immunohistochemistry-stained immune cells

The tumour immune microenvironment (TIME) in breast cancer is acknowledged with an increasing role in treatment response and prognosis. With a growing number of immune markers analysed, digital image analysis may facilitate broader TIME understanding, even in single-plex IHC data. To facilitate analyses of the latter an open-source image analysis pipeline, Tissue microarray MArker Quantification (TMArQ), was developed and applied to single-plex stainings for p53, CD3, CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 antibody) in a 218-patient triple negative breast cancer (TNBC) cohort with complementary pathology scorings, clinicopathological, whole genome sequencing, and RNA-sequencing data. TMArQ’s cell counts for analysed immune markers were on par with results from alternative methods and consistent with both estimates from human pathology review, different quantifications and classifications derived from RNA-sequencing as well as known prognostic patterns of immune response in TNBC. The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC.

Surface protein analysis of breast cancer exosomes using visualized strategy on centrifugal disk chip

Breast cancer, the most common cancer among women worldwide, lacks specific tumor markers for accurate diagnosis. Recent advances have highlighted tumor-derived exosomes as a promising non-invasive biomarker for cancer detection. Continuous monitoring of surface protein markers on exosomes in the blood could offer valuable insights for breast cancer diagnosis. However, integrating the isolation and detection of exosomes from whole blood is bulky, time-consuming, and requires professional operations. To address this difficulty, we developed a method of integrated centrifugal disk chip (CD chip) exosome enrichment directly from whole blood followed by a colorimetric visualization strategy for multiplex analysis. The disc consists of multi-chambers and multi-microchannels with immediate smartphone-enabled processing of colorimetric results. The combination of CEA + CA125 + EGFR on-chip detection could significantly differentiate the different stages of cancer in tumor-bearing mice and successfully distinguish between breast cancer patients and healthy individuals. Crucially, small volumes (100 μL) of blood samples were adequate. In addition, the chip was simple and fast, with results within 10 min, which provides immediate exosomal information through consecutive blood sampling, which could potentially result in a more timely and well-informed clinical breast cancer diagnosis.

ACYP2 functions as an innovative nano-therapeutic target to impede the progression of hepatocellular carcinoma by inhibiting the activity of TERT and the KCNN4/ERK pathway

An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.Graphical

Association of Titin Polymorphisms with the Progression of Oral Squamous Cell Carcinoma and Its Clinicopathological Characteristics.

This study examined the correlation of titin (TTN) polymorphisms with the sensitivity of oral squamous cell cancer (OSCC) and clinical characteristics. Six TTN SNPs, including rs10497520, rs12463674, rs12465459, rs2042996, rs2244492, and rs2303838, were evaluated in 322 control groups and 606 patients with oral cancer. We then investigated whether the SNP genotypes rs10497520 had associations with clinical pathological categories. Our data showed that the TC + CC genotype of rs10497520 was associated with moderate/poor tumor cell differentiation. The carriers of TTN rs10497520 polymorphic variant "TC + CC" in OSCC patients with cigarette smoking were linked with poor tumor differentiation (p = 0.008). Our results suggest that the TTN SNP rs10497520 is a possible genetic marker for oral cancer patients in the cigarette-smoking population. The TTN rs10497520 polymorphisms may be essential biomarkers to predict the onset and prognosis of oral cancer disease.

Molecular Profiling Defines Three Subtypes of Synovial Sarcoma.

Synovial Sarcomas (SS) are characterized by the presence of the SS18::SSX fusion gene, which protein product induce chromatin changes through remodeling of the BAF complex. To elucidate the genomic events that drive phenotypic diversity in SS, we performed RNA and targeted DNA sequencing on 91 tumors from 55 patients. Our results were verified by proteomic analysis, public gene expression cohorts and single-cell RNA sequencing. Transcriptome profiling identified three distinct SS subtypes resembling the known histological subtypes: SS subtype I and was characterized by hyperproliferation, evasion of immune detection and a poor prognosis. SS subtype II and was dominated by a vascular-stromal component and had a significantly better outcome. SS Subtype III was characterized by biphasic differentiation, increased genomic complexity and immune suppression mediated by checkpoint inhibition, and poor prognosis despite good responses to neoadjuvant therapy. Chromosomal abnormalities were an independent significant risk factor for metastasis. KRT8 was identified as a key component for epithelial differentiation in biphasic tumors, potentially controlled by OVOL1 regulation. Our findings explain the histological grounds for SS classification and indicate that a significantly larger proportion of patients have high risk tumors (corresponding to SS subtype I) than previously believed.

The content of soluble forms of galectins -1, -3, -4, -7, -9 in patients with renal cell cancer of various morphological types

Background: Galectins are a family of β-galactoside binding proteins that regulate the vast majority of cellular functions, including proliferation, migration, adhesion, and phagocytosis in both health and disease. More and more experimental and clinical evidence indicates that galectins are involved in many stages of carcinogenesis, including patients with renal cell carcinoma (RCC). Aim: To analyze the clinical significance of soluble forms of galectins -1, -3, -4, -7, -9 in patients with various histological RCC types. Materials and methods: We performed a retrospective analysis of the clinical significance of galectins -1, -3, -4, -7, -9 in the serum of 140 RCC patients (84 with clear cell RCC (ccRCC), 38 with papillary (papRCC), 18 with chromophobe (chrRCC)) and in 73 healthy donors (control group), who were examined and treated from 2019 to 2023 in the N. N. Blokhin National Medical Research Center of Oncology. Galectin levels were measured in serum (obtained according to standard methods before the initiation of specific treatment) with an enzyme-linked immunosorbent assay. Results: There was a significant increase in serum galectin -1, -3, -9 levels in the whole RCC patient group, compared to the healthy donor control group; no increase was found for galectins -4 and -7. Serum galectin-1 levels in the ccRCC and papRCC patients were significantly higher than those in the controls (p = 0.0003 and p = 0.0135, respectively). No association between the serum galectins -1 and -7 and the clinical and morphological characteristics of RCC was found; however, serum galectin-7 levels in the papRCC patients correlated with the grade of tumor differentiation (r = -0.592; p = 0.001). The area under the ROC curve (AUC) for galectin-1 in ccRCC was 0.721 (p 0.0001), in papRCC 0.673 (p = 0.0086), and in chrRCC 0.576 (p = 0.355). For galectin-7, the ROC AUC values were 0.527 (p = 0.634) in ccRCC, 0.513 (p = 0.845) in papRCC, and 0.566 (p = 0.425) in chrRCC. In all histological types of RCC, there was a significant increase in serum galectin-3 compared to the controls (ccRCC, p = 0.0208; papRCC, p = 0.0014; chrRCC, p = 0.0041). The ROC analysis for galectin-3 in patients with RCC of various histological types showed AUC = 0.721 (p 0.0001) for ccRCC, 0.673 (p = 0.0086) for papRCC, and 0.576 (p = 0.355) for chrRCC. Galectin-9 levels was directly and significantly associated with the tumor size, as well as with regional metastases (r = 0.251, p = 0.021; r = 0.239, p = 0.028, respectively). The AUC values for galectin-4 were 0.619 (p = 0.021) in ccRCC, 0.577 (p = 0.214) in papRCC, and 0.534 (p = 0.666) for chrRCC. For galectin-9, they were 0.649 (p = 0.0075), 0.613 (p = 0.087), and 0.539 (p = 0.637), respectively. Conclusion: The study has demonstrated a certain association between serum galectin -1, -3, -4, -7, and -9 in the patients with RCC of various histological types. Although the results of the ROC analysis indicated average quality of the model, which does not allow for the use of the obtained data for diagnostic purposes, it is necessary to continue the research for better understanding of the mechanisms of galectin functioning, before galectin-based therapeutic agents would be introduced into clinical practice for the treatment of RCC.

The &lt;i&gt;LGALS1&lt;/i&gt; gene polymorphism is not associated with galectin-1 levels in tumor tissue and blood of colon cancer patients

Background: Galectin-1 plays an important role in the pathogenesis of colorectal cancer (CRC). The blood and tumoral levels of galectin-1 could be dependent on the polymorphism of the promotor region of LGALS1 gene. Aim: To analyze an association between galectin-1 levels in tumor tissue and plasma and the genotype of the rs4820293 and rs4820294 polymorphisms of the LGALS1 gene in CRC patients. Materials and methods: The study included a total of 70 inpatients with pathologically verified CRC (International Classification of Diseases 10th Revision codes C18-C20, 39 men and 31 women, mean age 65.4 ± 5.7 years), who were receiving treatment in the Tomsk Regional Oncology Center and Cancer Research Institute of the Tomsk National Research Medical Center from 2020 to 2022. The control group consisted of 70 healthy volunteers (34 men and 36 women, mean age 62.3 ± 7.2 years). Venous blood samples were taken from all study participants and tumor tissue samples were obtained from the CRC patients. Galectin-1 expression in the tumor tissue was assessed by immunohistochemistry and plasma galectin-1 levels by enzyme-linked immunosorbent assay. The LGALS1 gene polymorphisms rs4820293 and rs4820294 were identified by restriction fragment length polymorphism analysis. Results: The distributions of genotype and allele frequencies of polymorphic variants rs4820293 and rs4820294 of the LGALS1 gene in the CRC patients and in the healthy donors were comparable (p 0.05). Calculation of odds ratios did not confirm any association between LGALS1 gene polymorphisms and CRC. However, the rs4820294 polymorphism had a strong association with regional metastasis and tumor differentiation grade (Cramer's V above 0.4, p 0.001). The plasma galectin-1 levels in the CRC patients with the AA genotype of the rs4820294 polymorphism were higher than in the healthy carriers (17.42 versus 12.92 ng/ml, p = 0.040). However, there were no significant differences in the content of galectin-1+ cells in the tumor and galectin-1 in plasma of the CRC patients depending on the genotype of the LGALS1 gene polymorphisms (p 0.05). Conclusion: The LGALS1 gene polymorphism is not associated with CRC, but in the carriers of the rs4820294 variant is related to clinical and morphological parameters of the tumor process. The intratumoral expression and blood levels of galectin-1 in CRC patients are not dependent on the genotype of rs4820293 and rs4820294 polymorphisms of the LGALS1 gene.