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The treatment of patients with CLL has undergone significant changes in recent years. Standard chemoimmunotherapy is changing to targeted inhibition with modern drugs. The listed drugs have better efficacy and significantly improve the overall survival of patients according to registry clinical studies. In a retrospective analysis, we evaluated 43 patients with CLL who underwent venetoclax treatment at the Hematology Department, University Hospital and Polyclinic F. D. Roosevelt Banská Bystrica, Slovakia (FNsP FDR BB) in 2019-2024. The aim of this work was to evaluate retrospectively the efficacy and safety of venetoclax in the treatment of patients with CLL. The median age of patients at the time of initiation of venetoclax treatment was 58 years, range 41-79 years. The majority of patients, 27 (63%) were men and 16 (37%) were women. Patients were treated with venetoclax in the first and higher line, in combination with obinutuzumab, with rituximab, and in monotherapy. Of these, 16 (37%) patients were after previous treatment with ibrutinib. Treatment indications and response assessment were based on the 2018 international workshop on the Chronic Lymphocytic Leukemia (iwCLL) Criteria. Patients were evaluated after at least 2 months of treatment until disease progression. The effect of treatment was assessed by objective examination of the patient, possibly by imaging examination (USG, CT scan) and evaluation of blood parameters. Adverse effects were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In case of disease progression, treatment was interrupted. The results of our work confirmed the efficacy and safety of venetoclax in combination with obinutuzumab, and rituximab, even as monotherapy in patients with CLL. The efficacy of the above regimens in our group of patients is comparable to that in clinical studies, even in patients with high-risk genetic features, such as 17p deletion and unmutated IgVH status. Treatment with venetoclax was also effective and well tolerated in patients after previous treatment with ibrutinib. The limitations of our evaluation are the small patient population and the short median follow-up of patients. In line with the conclusions of clinical trials and retrospective analysis from real-life practice, we can say that venetoclax-based treatment regimens are highly effective in patients with CLL in the first and higher line of treatment, with acceptable and well-manageable toxicity. This treatment is also effective in patients after previous treatment with ibrutinib.

Refractory diffuse gastric cancer (DGC) is rising in incidence and has a bad prognosis. Individuals who are administered second-line or subsequent therapies frequently exhibit diminished physical fitness, rendering them inappropriate for intensive treatment. Despite this, PD-1 inhibitors and anti-angiogenesis drug apatinib have demonstrated efficacy in advanced gastric cancer. This study aimed to evaluate the effectiveness, prognostic factors, and safety of PD-1 inhibitors in combination with apatinib in advanced DGC. The present study is a retrospective analysis of 34 patients with advanced DGC treated with apatinib combined with PD-1 inhibitors in the Affiliated Cancer Hospital of Zhengzhou University from 2019 to 2022. Apatinib 250 mg was administered to patients once a day. The median progression-free survival (mPFS) and the median overall survival (mOS) were estimated using Kaplan-Meier curves, whereas objective response rate (ORR), disease control rate (DCR), prognostic variables, and adverse events were among the other outcomes. Data from 34 patients were collected, and the ORR was 5.9% (2 out of 34), while the DCR was 55.9% (19 out of 34). The mPFS was 2.5 months (95% CI: 1.9-3.0), while the mOS was 6.8 months (95% CI: 3.7-9.9). Log-rank univariate analysis indicated that the mOS of patients with carcinoembryonic antigen (CEA) levels <4.7 ng/ml (11.3 months, 95% CI: 7.1-15.5) was significantly different from those with levels ≥4.7 ng/ml (2.7 months, 95% CI: 0.0-6.1) (p=0.008). A notable disparity in mOS and mPFS was observed between patients with CA125 <35 U/ml (7.7 months, 95% CI: 3.6-11.9) and those with CA125 ≥35 U/ml (2.5 months, 95% CI: 1.9-3.0) (p=0.003), as well as between patients with lactate dehydrogenase (LDH) <245 U/l (11.3 months, 95% CI: 7.2-15.5) and those with LDH ≥245 U/l (2.2 months, 95% CI: 1.5-2.9) (p=0.007), and between patients with PLTs <350×109/l (7.5 months, 95% CI: 6.4-8.7) compared to those with PLTs ≥350×109/l (1.7 months, 95% CI: 0.0-3.9) (p=0.001). Multivariate Cox regression analysis indicated that CA125, LDH, and PLT levels were independent prognostic variables. The occurrence of grade 3 or 4 treatment-related adverse events was 17.6% (6/34). The study suggests that the integration of PD-1 inhibitors and apatinib in second-line and subsequent therapies demonstrated promising efficacy and acceptable safety in advanced DGC patients. The concentrations of CA125, LDH, and PLTs may serve as prognostic indicators for DGC.

The objective of this study was to investigate the prognostic significance of the frequency of primary cilia (PC) and β-catenin expression in 218 patients (pts) with non-small cell lung cancer (NSCLC), including 125 pts with adenocarcinoma and 93 pts with squamous cell carcinoma. In the whole group of 218 pts with NSCLC, overall survival (OS) was significantly inferior among pts with present PC than without PC (p=0.024) and with higher cytoplasmic β-catenin expression (25-75%) than with lower cytoplasmic β-catenin expression (<25%) (p=0.008). In the univariate Cox proportional hazard model, the hazard ratio was 1.653 in pts with present PC (p=0.026) and 1.851 in pts with higher cytoplasmic β-catenin (25-75%) (p=0.009). Multivariate testing of the whole group of 218 pts with NSCLC showed that the presence of PC was associated with a worse prognosis (p=0.018). In the subgroup of 125 pts with adenocarcinoma, OS was significantly improved in pts with higher membranous β-catenin expression (≥50%) than in pts with lower expression (<50%) (p=0.0300) and OS was significantly inferior in pts with higher cytoplasmic β-catenin expression (25-75%) than in pts with lower expression (<25%) (p=0.0004). Multivariate testing of the subgroup of pts with adenocarcinoma showed that cytoplasmic β-catenin (p<0.001) and pleural invasion (p=0.017) were associated with worse prognosis. The present results indicate a negative prognostic significance of PC and cytoplasmic β-catenin expression in NSCLC and a negative prognostic significance of cytoplasmic β-catenin expression in adenocarcinoma.

Many lines of evidence suggest that circular RNAs (circRNAs) are closely associated with the occurrence and progression of colon cancer. The objective of this study was to investigate the regulatory effects and mechanisms of circ_0075829 on ferroptosis and immune escape in colon cancer. We utilized colon cancer cell lines and a xenograft mouse model to analyze the function of circ_0075829 in vitro and in vivo. The gene expression level was assessed by qRT-PCR and western blotting. Cell proliferation was evaluated using the CCK-8 assay. The targeting relationships between circ_0075829, miR-330-5p, and TCF4 were analyzed through a dual-luciferase reporter experiment and RNA pull-down experiment. Cytokine levels were measured using the ELISA assay. Fe2+, MDA, and SOD levels were tested using appropriate kits, and the ROS level was detected by immunofluorescence. Knockdown of circ_0075829 resulted in increased levels of Fe2+, ROS, and MDA and decreased levels of GPX4 and xCT proteins in cells. Furthermore, silencing of circ_0075829 increased the cell proliferation rates of CD8+T cells co-cultured with colon cells. Moreover, it also enhanced IFN-γ, IL-2, and TNF-α concentration in the supernatants of the co-culturing system and reduced PD-L1 protein expression levels. Subsequently, silencing of circ_0075829 induced ferroptosis and inhibited immune escape in vivo. Meaningfully, we certified that circ_0075829 functions as a sponge for miR-330-5p, leading to the upregulation of TCF4 expression. TCF4 was identified as a downstream target of miR-330-5p. Additionally, co-transfection with anti-miR-330-5p or TCF4 overexpression plasmid reversed the effects observed following the knockout of circ_0075829. Collectively, our research indicates that the circ_0075829 plays a significant role in regulating ferroptosis and immune escape in colon cancer by sponging miR-330-5p to modulate TCF4 expression.

DNA methylation is recognized as an early event in cancer initiation and progression. This review aimed to compare the methylation status of promoter regions in selected genes across different histological subtypes of non-small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and the rare but highly aggressive large-cell neuroendocrine carcinoma (LCNEC). A comprehensive literature search was conducted in the PubMed database until August 17, 2024, using standardized keywords to identify reports on promoter methylation in NSCLC. Seventy-five studies were reviewed, focusing on the promoter methylation of key genes, such as APC, BRCA1, CDH1, CDH13, DAPK1, DLEC1, FHIT, GSTP1, hMLH1, MGMT, CDKN2A, RARβ, RASSF1, RUNX3, and TIMP3. These studies explored diagnostic, prognostic, epidemiological, and therapeutic aspects across NSCLC subtypes. Additionally, mutational profiles of TP53, RB1, KEAP1, and STK11 and expression patterns of ASCL1, DLL3, and NOTCH were analyzed. The findings suggest that LCNEC may serve as a biological bridge between non-small cell and small-cell lung carcinoma. Our analysis highlights that the methylation status of selected genes could enhance diagnosis, prognosis, and personalized treatment strategies in patients with NSCLC, particularly those with LCNEC.

Pediatric central nervous system (CNS) tumors represent 20-25% of childhood malignancies, with 35-40 new cases annually in Slovakia. Despite treatment advances, high mortality and poor quality of life in a lot of cases persist. This study assesses the clinical features, treatment modalities, and survival rates of pediatric CNS tumor patients in the single largest center in Slovakia. A retrospective analysis was conducted on pediatric CNS tumors from January 1, 2000, to December 31, 2020, at the Department of Pediatric Oncology and Hematology at the National Institute of Children's Diseases in Bratislava, Slovakia. Among 397 patients (242 males, 155 females), the most common histological types were astrocytomas (42.8%), followed by embryonal tumors (18.4%), brain stem tumors (10.3%), and ependymal tumors (8.1%). Tumor locations were supratentorial (48.1%), infratentorial (46.9%), and spinal (4.3%). Surgical interventions included radical excision (30.2%), subtotal/partial excision (41.8%), and biopsy (9.3%). Treatment modalities varied, with 31.2% receiving combined surgery, chemotherapy, and radiotherapy; 27.5% surgery alone; 9.6% surgery with radiotherapy; 7.8% chemotherapy only; and 6.3% having no treatment. By 2020, 74.3% of patients were alive, with a 25.7% mortality rate. This study outlines the characteristics of pediatric CNS tumors in Bratislava, highlighting the need for multidisciplinary national and international collaboration to advance diagnosis and treatment. Our data align with global findings from other centers.

Esophageal squamous cell carcinoma (ESCC) has high mortality. The role and regulatory mechanism of hsa_circ_0021727 (circ_0021727) in ESCC remain largely unknown. This study focused on the undiscovered impact of circ_0021727 on cell cycle progression, apoptosis, and angiogenesis of ESCC. We found that circ_0021727 levels were significantly upregulated in ESCC cells. TUNEL, flow cytometry, and tubule formation assay indicated that knockdown of circ_0021727 in ESCC induced cell arrest at the G0/G1 phase, promoted apoptosis, and inhibited angiogenesis, whereas overexpression of circ_0021727 produced the opposite effect. Gastrulation brain homeobox 2 (GBX2) GBX2 was a downstream target gene of circ_0021727, and overexpression of GBX2 reversed the effect of circ_0021727 knockdown in ESCC progression. The results of the RIP and RNA pull-down showed that circ_0021727 and GBX2 mRNA bound with eukaryotic translation initiation factor 4A3 (EIF4A3). Overexpression of circ_0021727 promoted GBX2 mRNA stability by binding with EIF4A3. In a tumor xenograft model, the knockdown of circ_0021727 inhibited tumor growth, which was reversed by further overexpression of GBX2. In conclusion, circ_0021727 increased GBX2 mRNA stability by recruiting EIF4A3, which promoted cell cycle progression and angiogenesis in ESCC.

MTHFD2 is highly overexpressed in breast cancer tissues, indicating that it might be used as a target in breast cancer treatment. This study aims to determine the role of MTHFD2 in breast cancer cell proliferation and the molecular pathways involved. In order to investigate MTHFD2 gene expression and its downstream pathways in breast cancer, we started our inquiry with a bioinformatics analysis. We then engineered breast cancer cell lines with either silenced or overexpressed MTHFD2 to study its effects on the cell cycle, proliferation, and the m6A methylation status of the gene IFRD1, predicted as a downstream target. Overexpression of MTHFD2 enhanced cellular proliferation, increased the proportion of EdU-positive cells, and accelerated progression into the S+G2/M phase. In contrast, MTHFD2 knockdown led to opposite effects. MTHFD2 and IFRD1 expression levels showed a strong positive association. Increased MTHFD2 activity boosted HDAC3 and mTOR phosphorylation, activating p70 S6K and 4EBP1-key regulators of cell proliferation. Moreover, overexpression of MTHFD2 was associated with reduced p53 acetylation and total protein levels. Silencing MTHFD2 decreased m6A methylation of IFRD1 RNA, whereas its overexpression increased methylation. Notably, IFRD1 siRNA transfection reversed the proliferative effects induced by MTHFD2 overexpression. Furthermore, MTHFD2 knockdown enhanced the sensitivity of breast cancer cells to several chemotherapeutic agents. In conclusion, MTHFD2 influences breast cancer cell proliferation by modulating the m6A methylation of IFRD1 RNA, which regulates the HDAC3/p53/mTOR pathway. These findings suggest that MTHFD2 inhibitors may synergistically enhance the efficacy of existing chemotherapies.

Regarding flotillin knockdown, drug resistance is reversed in colorectal cancer (CRC) cell lines; this is associated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, as our previous experimental results indicated. However, the exact mechanism underlying this pathway remains unclear. PI3K inhibitor and activator were added separately to clarify the role of the PI3K pathway in reversing drug resistance. The results showed decreased resistance after inhibiting PI3K activity. Furthermore, the reduced resistance due to flotillin knockdown was restored after adding the PI3K activator. Additional results showed no changes in PI3K molecules. However, p-AKT expression was downregulated. Further results suggested that the phosphatidylinositol (3,4,5)-trisphosphate/phosphatidylinositol 4,5-bisphosphate (PIP3/PIP2) ratio was downregulated, whereas the phosphatase and tensin homolog (PTEN) expression was upregulated. In addition, we also found that P-gp activity inhibition resulted in increased adriamycin accumulation and reversal of resistance, and flotillin knockdown was accompanied by a downregulation of P-gp expression in CRC cells. In conclusion, our study demonstrated that flotillin knockdown could reverse drug resistance in CRC cells by downregulating the PTEN/PI3K/AKT pathway and P-gp.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast malignancy. Although some patients benefit from immune checkpoint therapy, current treatment methods rely mainly on chemotherapy. It is imperative to develop predictors of efficacy and identify individuals who will be sensitive to particular treatment regimens. This study analyzed peripheral interferons and immune cell subsets in TNBC patients receiving pre-operative neoadjuvant therapy. The effects of interferon-induced helicase 1 (IFIH1) on the biological characteristics of apoptosis and PD-L1 expression of cancer cells and its potential mechanism were investigated using bioinformatics analysis, clinical specimens, and in vitro study. We found that serum interferon-γ and interferon-α2 levels were significantly higher in TNBC patients with pathologic complete response (pCR). The expression of IFIH1 is markedly upregulated in various tumors, including breast cancer. Immunohistochemical results revealed that IFIH1 was specifically located in the cytoplasm of cancer cells. Gene set enrichment analysis showed that genes co-expressed with IFIH1 were involved in tumor immune-related pathways and apoptosis. Knockdown of IFIH1 in MDA-MB-231 and BT-549 cells resulted in significantly increased cell proliferation and colony formation. Regarding apoptosis-related pathway proteins, there was a significant decrease in levels of phosphorylated TANK-binding kinase 1 (TBK1) and phosphorylated interferon regulatory factor 3 (IRF3). In addition, the expression of PD-L1 was significantly downregulated. Furthermore, we demonstrated the existence of binding sites between IRF3 and PD-L1 promotors. Our data indicate that cancer cell IFIH1 promotes apoptosis and PD-L1 expression, suggesting its potential as a predictive marker of efficacy and therapeutic target in TNBC.