Epithelial-mesenchymal transition (EMT) is an essential process for the metastasis of multiple malignancies, including hepatocellular carcinoma (HCC). Farrerol is a plant-derived flavonoid and has significant pharmacological effects. However, the anticancer activities of farrerol have not been fully elucidated. Here, we investigated the effects of farrerol on HCC progression.

We describe 3 patients with clear cell stromal tumor (CCST) of the lung, all of whom presented with multifocal disease. The patients were 2 men and 1 woman aged 47-58 years (mean, 54 years). Two patients had evidence of autoimmune disease and their pulmonary disease was an incidental finding; one patient presented with non-specific respiratory symptoms. Radiologic imaging revealed multiple pulmonary nodules in all patients. Histologically, the tumors were solid-cystic and composed of cytologically bland, medium-sized ovoid to spindle cells with eosinophilic to clear cytoplasm arranged in a subtle nested pattern. These tumor cells were set in a highly vascularized stroma. Occasional cytologic atypia with multinucleated tumor cells was noted but mitotic activity was low. An infiltrate of mixed inflammatory cells was apparent in all tumors. Immunohistochemical analysis demonstrated diffuse expression of vimentin and TFE3 in all cases. Next generation sequencing revealed the presence of YAP1::TFE3 fusion in 1/1 case. All patients have remained alive albeit with stable or progressive disease, 24-66 months after diagnosis. These cases highlight the existence of multifocal pulmonary CCST and seem to support the notion that multifocality in CCST may be associated with more protracted clinical course. Awareness of the existence of multifocal pattern is important for patient management and prognosis.

Diabetic foot ulcers (DFUs) are a microvascular complication that affects almost 21 % of the diabetic population. DFUs are characterized by lower limb abnormalities, chronic inflammation, and a heightened hypoxic environment. The challenge of healing these chronic wounds arises from impaired blood flow, neuropathy, and dysregulated cell death processes. The pathogenesis of DFUs involves intricate mechanisms of programmed cell death (PCD) in different cell types, which include keratinocytes, fibroblasts, and endothelial cells. The modes of cell death comprise apoptosis, autophagy, ferroptosis, pyroptosis, and NETosis, each defined by distinct biochemical hallmarks. These diverse mechanisms contribute to tissue injury by inducing neutrophil extracellular traps and generating cellular stressors like endoplasmic reticulum stress, oxidative stress, and inflammation. Through a comprehensive review of experimental studies identified from literature databases, this review synthesizes current knowledge on the critical signaling cascades implicated in programmed cell death within the context of diabetic foot ulcer pathology.

Intracerebral hemorrhage (ICH) is one deadly subtype of stroke with high morbidity and mortality. Oxidative stress and inflammation are major factors contributing to blood-brain barrier (BBB) dysfunction, which induces perihematoma edema and exacerbates ICH-induced secondary brain injury. SYN1 is a crucial neuronal phosphoprotein that plays a pivotal role in neuronal development. Our study was devised to clarify the function of SYN1 in hemin-induced cell injury in PC12 cells and brain injury in ICH rat models.

Glioblastoma (GBM) poses formidable challenges due to its high malignancy and therapeutic resistance and still exhibits dismal 5-year survival rates, high recurrence propensity, and limited treatment modalities. There is an acute need for innovative treatments for recurrent glioblastoma due to the lack of established protocols. This necessity is driving research into the cellular underpinnings that initiate and drive the disease forward, aiming to discover groundbreaking targets for therapy that could enhance the efficacy of medical interventions.

Trophoblast cell-surface antigen 2 (TROP2), a transmembrane receptor expressed in many carcinomas, is a target for novel antibody-drug conjugates such as sacituzumab govitecan. TROP2-targeted therapy is used for unresectable locally advanced or metastatic triple-negative and hormone receptor-positive, HER2-negative breast cancers. The role of TROP2 as a predictive marker is yet unclear. Standardized interpretation criteria for TROP2 immunohistochemistry (IHC) are lacking. Here, we compared three antibody clones and two methods for semi-quantitative assessment, aiming to establish reproducible evaluation criteria. First, TROP2 IHC was performed on normal tissues and nine breast cancers, using the BSB-148, EPR20043 and SP293 clones. EPR20043 was selected for subsequent evaluation in 69 breast cancers without pathological complete response to neoadjuvant chemotherapy (NAC). Four pathologists applied the ASCO/CAP guidelines for HER2 IHC testing (designated as the 'membrane score') and the H-score. All H-scores were categorized as low (0-100), intermediate (101-200) and high (201-300). Although the membrane scores strongly correlated with the categorized H-scores, the latter showed higher interobserver variability. Next, TROP2 IHC was performed on 94 breast cancer metastases and evaluated by six pathologists, confirming the strong correlation between the membrane scores and H-scores. In metastases, the interobserver variability was similar for both methods. Our observations support the application of the HER2 ASCO/CAP guidelines for semi-quantitative evaluation of membranous TROP2 protein expression, as this method strongly correlates with the H-score and is less prone to interobserver variability in post-NAC breast resections. Future studies should investigate the association between the TROP2 membrane score and response to TROP2-targeted therapy.

Malignant biphasic tumors of the lungs are rare, more so in the pediatric population. Here, we present the whole-genome characterization of a pleuropulmonary blastoma Type III and an unclassified biphasic thoracic embryonal neoplasm. The pleuropulmonary blastoma harbored pathogenic DICER1 germline and somatic mutations, and additional somatic variants in TP53 and BCOR. The other malignant tumor demonstrated a t(11;19) balanced translocation with a YAP1::LEUTX fusion that was confirmed by fluorescence in situ hybridization. No DICER1 germline or somatic mutation was present. YAP1 and LEUTX have been implicated in tumorigenesis of various neoplasms, and YAP1 fusion genes are an emerging oncogenic entity in a variety of malignancies. In this study we highlight the importance of whole-genome characterization of rare and unclassified tumors to identify biologic mechanisms and potential therapeutic targets.

Non-Hodgkin's lymphoma (NHL) is a significant global malignancy, with diffuse large B cell lymphoma (DLBCL) being the most prevalent subtype, accounting for 25-50 % of newly diagnosed cases in China. Despite a 60 % survival rate achieved with R-CHOP regiment for DLBCL, approximately 40 % of patients experience relapse or develop resistance to treatment. While the oncogenic transcription factor B-cell chronic lymphocytic leukaemia/lymphoma 11 A (BCL11A) has been implicated in various tumors, its specific role in DLBCL remains unclear. In this study, we conducted retrospective histomorphological and immunophenotypic analyses on paraffin sample tissues and collected fresh tissue samples for protein and mRNA analyses to investigate the relationship between BCL11A and DLBCL. Additionally, we classified DLBCL into subtypes based on cells of origin (COO) and examined the expressions of BCL11A, C-MYC, P53 and other protein expressions to better understand the factors contributing to poor clinical outcomes in DLBCL. Our findings revealed elevated BCL11A expression in DLBCL, with increased expression associated with worse prognosis and higher C-MYC expression. Patients exhibiting co-expression of C-MYC and BCL11A had significantly lower survival rates compared to those with singular expression. Furthermore, BCL11A protein expression levels demonstrated significant associations with P53 and C-MYC protein expression levels in the Germinal Center B-cell-like (GCB) subtype. These findings suggest that BCL11A may serve as a potential prognostic marker and therapeutic target for DLBCL.

Acute myocardial infarction (AMI) represents a critical cardiovascular condition necessitating rapid and precise diagnostic strategies. This study investigates the diagnostic implications of genes involved in copper metabolism homeostasis in AMI. We identified genes related to copper metabolism and AMI from Genecards and GEO databases, conducting differential gene analysis via R software. Gene function was annotated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, while the STRING database facilitated key gene identification via topological analysis. The diagnostic value of these genes, particularly cytokine signaling 3 (SOCS3), was assessed using ROC curve analysis. SOCS3 expression was validated using in-vitro and in-vivo models, including cardiomyocyte hypoxia/reoxygenation (H/R) and rat myocardial infarction (MI) model. Further, we examined the effects of SOCS3 knockout on cell proliferation, apoptosis, and myocardial infarction severity. 77 genes were identified, with 73 showing upregulation and 4 downregulation. These genes mainly participated in pathways related to cytokine activation, inflammation regulation, and lipid metabolism. Network analysis highlighted 10 key genes, with SOCS3 exhibiting significant diagnostic potential (AUC > 0.9). Validation experiments confirmed SOCS3 overexpression in disease models, with its knockout leading to decreased apoptosis, reduced infarct size, and improved cardiac function. This study highlights the diagnostic relevance of genes associated with copper metabolism, particularly SOCS3, in AMI. These findings offer novel insights into the molecular mechanisms of AMI, supporting the development of targeted diagnostic and therapeutic strategies.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that poses a significant threat to human health. Patients are often diagnosed at advanced stages of the disease, resulting in poor clinical outcomes and a short survival period. Recent advances have revealed that ESCC tumors exhibit distinct molecular biological characteristics. Our study investigated the expression and biological function of Stanniocalcin-1 (STC1) in ESCC.

Histological grade is a validated prognostic factor of breast cancer but may show alterations following neoadjuvant chemotherapy (NACT). Its reporting after NACT is recommended by several guidelines, but evidence of its retained prognostic impact is scarce. Patients treated with NACT followed by surgery and having sufficient residual tumour for the determination of grade were analysed for the survival effects of posttreatment grade (yG). Kaplan-Meier analyses and the log-rank test were applied, followed by the univariable and multivariable Cox proportional hazards models. The cohort comprised 355 patients with known yG, and 320 of them had also a pretreatment grade available. Pretreatment grade changed in 99/320 (31 %) cases following NACT, and downgrading was more common (n=78/320, 24 %) than upgrading (21/320, 7 %). Among 355 breast cancer patients, those with yG3 (poorly differentiated) tumours (n=155) had worse 5-year relapse-free and overall survival estimates than those with yG2 (n=169) or yG1 (n=31) tumours. This was also substantiated by univariable analysis; however, yG lost its significance in the multivariable model. Post-NACT histological grade has a prognostic impact, but does not seem to be an independent prognosticator in the post-NACT setting; however, these results lend support for its reporting by pathologists after primary systemic treatment.

Recently, our research group reported an upregulated expression profile of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), key enzymes involved in hydrogen sulfide (HS) production, in triple-negative breast cancer (TNBC) patients. However, the regulatory mechanisms underlying such altered expression patterns are not yet fully understood. In this study, we focused on the role of the STAT3/CSE/HS axis and the potential involvement of non-coding RNAs (ncRNAs), including long and short ncRNAs, in modulating this pivotal pathway. The results revealed that STAT3 was upregulated and positively correlated with CSE expression in BC patients. Additionally, the lncRNA MALAT-1 was found to regulate STAT3 expression, indirectly influencing CSE levels. Furthermore, we explored the interplay between the IGF-1R as a gatekeeper for JAK/STAT pathway and accordingly its impact on the STAT3/CSE/HS axis in TNBC cell lines. Our results demonstrated that miR-486-5p, a tumor suppressor miRNA, directly targets IGF-1R, leading to the downstream suppression of STAT3 and CSE in MDA-MB-231 cells. To identify a direct upstream repressor of CSE and CBS, we conducted an in silico analysis and identified miR-30a-5p as a promising candidate. When ectopically expressed, miR-30a-5p was downregulated in BC tissues and effectively suppressed CSE and CBS expression. In conclusion, this study revealed novel regulatory mechanisms involved in CSE and CBS expression in TNBC patients and cell lines. Abolishing HS-synthesizing machinery, particularly via miR-30a-5p, may represent a promising therapeutic strategy for TNBC patients.

SPRED2 (Sprouty-related, EVH1 domain-containing protein 2), a negative regulator of the ERK1/2 pathway, is downregulated in several cancers; however, the significance of SPRED2 expression in lung adenocarcinoma (LUAD) remains unclear. Here, we investigated the pathological expression of SPRED2 and its relationship with ERK1/2 activation (ERK1/2 phosphorylation), Ki67 index and clinicopathological features in 77 LUAD tissues from clinical patients. Immunohistochemically, SPRED2 expression was decreased in invasive adenocarcinoma (IA) compared to adenocarcinoma in situ (AIS). There was a negative correlation between SPRED2 expression and pERK1/2 levels and a positive correlation between SPRED2 expression and Ki67 index. In the database analysis, the survival probability was higher in patients with higher SPRED2 expression than in those with lower expression. In vitro, SPRED2 deletion increased cell proliferation, migration and invasion of three LUAD cell lines (A549:KRAS mutation, H1993:METamplification, and HCC4006:EGFR mutation), whereas SPRED2 overexpression decreased these responses. Thus, SPRED2 appears to be a regulator of LUAD progression and a potential target for the treatment of LUAD.

Gastric cancer is the fifth most common malignancy and the fifth primary cause of death from cancer all over the world. Because of diagnosis of gastric cancer at advanced, incurable stages and limited response to treatment, the disease has an adverse prognosis and a low survival rate. Chemotherapy consisting of medications such as platinum and 5-Fluorouracil can be effective for patients with advanced stomach cancer. Nevertheless, drug resistance eventually leads to unsuccessful therapy and adverse outcomes for gastric cancer patients. Most therapy failures in gastric cancer patients undergoing chemotherapy are caused by the development of drug resistance. Several studies have shown that noncoding RNAs (ncRNAs) play important roles in the resistance of gastric cancer to chemotherapy drugs. The development of stomach cancer is greatly impacted by a number of ncRNAs, including microRNAs (e.g., miR-21, miR-27a), circular RNAs (e.g., CircPVT1), and long noncoding RNAs (e.g., HOTAIR). Because of their regulatory characteristics in certain genes implicated in the chemoresistant phenotype of gastric cancer, much evidence has demonstrated their function in the emergence and persistence of drug resistance. In the future, ncRNA-based treatment could represent a novel approach to treating drug resistance. Despite numerous studies on anticancer drug resistance mechanisms, it is still unclear how these mechanisms are regulated. In this review, we investigated the evolving function and molecular mechanisms of ncRNAs related to drug resistance, their function in controlling drug resistance in gastric cancer, and their potential to create targeted therapeutics for reducing drug resistance in gastric cancer.

3-Dimensional (3D) cultures of cancer cell lines exhibit unique morphologies, a feature that can be utilized for understanding several aspects of solid tumors. This study aims to investigate the morphology and morphometrics of agarose hydrogel-induced 3D aggregates of SiHa cell line. Floating 3D aggregates of SiHa cells were obtained using liquid overlay technique on 1 % agarose hydrogel. The aggregates were monitored daily for its progressive growth and morphology, and documented. The morphometric analysis of the multicellular 3D spheroids were performed on cultures in the late exponential/log phase (the 93rd hour in culture). The morphology exhibited by the 3D aggregates at this stage was "grape-like". Three morphometric parameters viz. average area, average number, and average roundness of aggregates, were determined and was found that the compactness of the aggregates was the maximum on Day 5 post-seeding. Additionally, the aggregates exhibited multi-acinar structures and extracellular matrix, characteristic of tumour progression. Establishing the morphological parameters of SiHa is an approach to better understand the characteristics of 3D aggregates. Such analysis has a direct bearing on translational benefits towards solid tumour research.

Tumor-associated macrophages (TAMs) crucially contribute to lung cancer's advancement and escape from the immune system. TAMs, particularly the M2 phenotype, promote an immunosuppressive microenvironment, facilitating tumor growth and metastasis. The MEK-STAT3 signalling pathway is a critical mediator in this process, driving TAM reprogramming and contributing to lung cancer's resistance to treatment. Inhibiting the MEK and STAT3 pathways disrupts key cancer-promoting mechanisms, including immune evasion, angiogenesis, and metastasis. Preclinical studies have demonstrated the effectiveness of MEK inhibitors, such as trametinib and selumetinib, in synergistic therapies for NSCLC, particularly in modulating the tumor microenvironment. We analyse the present understanding of approaches that can transform TAMs via the inhibition of MEK-STAT3 with either solo or combined treatments in lung cancer therapy.

The performance of cell blocks (CBs) can vary significantly depending on the specimen collection and processing techniques used. This study compared the efficiency of three distinct specimen collection methods for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples.

By the ubiquitin-proteasomes, cellular proteins are structurally degraded and turnover. Many essential functions and regulations of cells are regulated and controlled by these proteins. Recent studies indicated that many cancer types have been associated with aberrations in the ubiquitination pathway, which involves three enzymatic steps. Dietary phytochemicals have been identified as having the potential to inhibit carcinogenesis recently. As part of this group of phytochemicals, curcumin can play a crucial role in suppressing carcinogenesis by changing many reactions affected by the ubiquitin-proteasome pathway. Due to its ability to change some biological processes such as NF-κB, inhibit some cyclins, and induce apoptosis, it can be used as a drug in cancer treatment.

Necrotizing enterocolitis (NEC) is a major cause of mortality in preterm infants. Its pathophysiology remains poorly understood but intestinal epithelial barrier dysfunction contributes to the disease. We characterized junctional proteins in intestinal specimens from preterm infants. Samples from 27 patients with NEC and 20 patients with focal intestinal perforation (FIP) from the center of the specimens (affected) or the macroscopically healthy resection margins whenever available (non-affected) were collected. NEC patients displayed higher mortality and more commonly occurrence of impaired glucose homeostasis, patent ductus arteriosus, anemia and antibiotic treatment compared to FIP patients. Discrimination between NEC and FIP was not possible in affected areas based on H.E. staining using a newly developed scoring system. Immunofluorescence revealed reduced Claudin-3 in affected NEC samples and decreased Claudin-4 in affected FIP and all NEC samples. E-cadherin and Desmoglein-2 were reduced in a subgroup of the affected NEC samples. Plakophilin-2 was decreased in intestine affected by FIP and unaffected intestine in patients with NEC. In affected areas of NEC, Plakophilin-2 was completely lost. Plakoglobin reduction in affected NEC samples correlated with poor survival. This study provides novel insights into changes of junctional proteins in NEC, suggesting Claudin-3 and Plakophilin-2 as diagnostic markers to differentiate FIP from NEC and reduced Plakoglobin as a prognostic marker.

Gastric cancer is a malignant disease with a poor prognosis and few therapeutic options once it has advanced. Immunotherapy using ICIs has emerged as a viable therapeutic method; nevertheless, reliable immunological biomarkers are required to identify who may benefit from these therapies. It focuses on key immune biomarkers and predictive signatures in gastric cancer, such as PD-L1 expression, microsatellite instability (MSI), tumor mutational burden (TMB), and Epstein-Barr virus (EBV) status, to optimize gastric cancer patients' immunotherapy responses. PD-L1 expression is a popular biomarker for ICI effectiveness. Tumors with high MSI-H and TMB are the most susceptible to ICIs because they are highly immunogenic. EBV-positive stomach tumors are highly immunogenic, and immunotherapy has a high response rate. Combining composite biomarker panels with multi-omics-based techniques improved patient selection accuracy. In recent years, machine learning models have been integrated into next-generation sequencing. Dynamic, real-time-monitorable biomarkers for real-time immune response monitoring are also being considered. Thus, enhancing biomarker-driven immunotherapy is critical for improving clinical outcomes with gastric cancer. There is still more work to be done in this field, and verifying developing biomarkers will be an important component in the future of customized cancer therapy.