Search Results (44)

The aim of this work was to investigate the relationship between the growth rate of tumor cells and their fractionation gain. Two head and neck squamous cell carcinoma (HNSCC) cell lines, one human papillomavirus (HPV) negative (HPV−) and one HPV+, and a primary fibroblast cell line were supplemented with four different concentrations of fetal bovine serum (FBS) to achieve different division rates. The effect of five different fractionation regimens was studied, namely 1 × 10 Gy, 2 × 5 Gy, 3 × 3.3 Gy, 4 × 2.5 Gy, and 5 × 2 Gy. Survival was studied using the colony-forming assay. Different concentrations of FBS were used to achieve different doubling rates for all cell lines. The HPV+ cell line was significantly more sensitive to radiation than the HPV− cell line in all fractionation schemes. The fibroblast cell line was less sensitive at low fractionation compared to the tumor cell lines. Low fractionation had a significantly higher effect, except for 5 × 2 Gy fractionation, which had a higher effect than 4 × 2.5 Gy. The number of radiosensitive mitoses during irradiation in the fractionation scheme could not explain the higher effect of 5 × 2 Gy. There was no difference in survival with the four different concentrations of FBS in all three cell lines and different fractionations. The doubling time (DT) rates of cell lines resulting from FBS deprivation do not reflect the expected increased radiation sensitivity of rapidly dividing cells. Full article

Clear-cell renal cell carcinoma (ccRCC) is associated with the mutated von Hippel–Lindau (VHL) gene leading to the activation of hypoxia-inducible factor 1A (HIF1A) and subsequent overexpression of erythropoietin (EPO). We analyzed tumor and healthy tissues from 43 ccRCC patients after radical nephrectomy and cultured 786-O (biallelic VHL inactivation) and Caki-1 (wild-type VHL) cells in normal (21% O₂) and low oxygen (3% O₂) with 10% and 2% fetal bovine serum (FBS). DNA sequencing, including Sanger sequencing, MLPA and LOH, revealed 27 somatic mutations of VHL in ccRCC. HIF1A protein showed decreased or no expression in tumors compared to healthy tissue, independent of VHL alteration. The 786-O cells showed increased HIF1A protein expression after 48 h under low oxygen and 10% FBS. EPO and erythropoietin receptor (EPOR) were significantly decreased in ccRCC without HIF1A expression. EPO mRNA increased in the 786-O cells at 3% O₂ after 48 h, while the Caki-1 cells had low or no EPO expression. Hypoxia increased EPOR mRNA in the Caki-1 cells at 10% FBS, but decreased in the 786-O cells at 2% FBS after 48 h. JAK2/STAT5A activity was increased only in HIF1A-positive tumors. These results suggest that EPO/EPOR activation in ccRCC is mainly driven by low oxygen, not VHL regulation of hypoxia-related responses. Full article

Liver cancer is one of the most prevalent cancers worldwide. The first-line therapeutic drug sorafenib offers only a moderate improvement in patients’ conditions. Therefore, an approach to enhancing its therapeutic efficacy is urgently needed. It has been revealed that hepatocellular carcinoma (HCC) cells with heightened intracellular quiescin sulfhydryl oxidase 1 (QSOX1) exhibit increased sensitivity to sorafenib. QSOX1 is a secreted disulfide catalyst, and it is widely recognized that extracellular QSOX1 promotes the growth, invasion, and metastasis of cancer cells through its participation in the establishment of extracellular matrix. Inhibiting QSOX1 secretion can increase intracellular QSOX1 and decrease extracellular QSOX1. Such an approach would sensitize HCC cells to sorafenib but remains to be established. Since (−)-epigallocatechin-3-gallate (EGCG) has been demonstrated to be an effective inhibitor of α-fetal protein secretion from HCC cells, we screened QSOX1 secretion inhibition using polyphenolic compounds. We examined eight dietary polyphenols (EGCG, quercetin, fisetin, myricetin, caffeic acid, chlorogenic acid, resveratrol, and theaflavin) and found that EGCG and quercetin effectively inhibited QSOX1 secretion from human HCC cells (HepG2 or Huh7), resulting in high intracellular QSOX1 and low extracellular QSOX1. The combination of EGCG or quercetin, both of which change the cellular distribution of QSOX1, with sorafenib, which has no influence on the cellular distribution of QSOX1, exhibited multiple synergistic effects against the HCC cells, including the induction of apoptosis and inhibition of invasion and metastasis. In conclusion, our current results suggest that dietary EGCG and quercetin have the potential to be developed as adjuvants to sorafenib in the treatment of HCC by modulating the cellular distribution of QSOX1. Full article

Using non-classical polyfluorophenyl ligands in Pt(II) complexes and other transition metals such as silver is a promising approach in the search for more effective and safer antitumoral drugs. In this work, a series of chelating N-donor ligands with 1,10-phenanthroline and 4,5-diazafluorene backbones and ketone groups were synthesized (1,10-phenanthroline-5,6-dione, 1; (R/S)-6-hydroxy-6-(2-oxypropyl)-1,10-phenanthroline-5(6H)-one, 2; 4,5-diazafluoren-9-one, 3; 9-hydroxy-9-(2-oxypropyl)-4,5-diazafluorene, 4). The corresponding [Ag(N,N)₂]NO₃ (1Ag–4Ag) and [Pt(C₆F₅)₂(N,N)] (1Pt–4Pt) complexes were prepared. The stability of these complexes in DMSO solution was studied, showing no dissociation over 48 h for almost all complexes, except 3Pt. The compounds were characterized by NMR (¹H, ¹³C, and ¹⁹F), MS, and X-ray diffraction (2, 4, 1Ag, 3Ag, 1Pt, and 3Pt). A study of the cytotoxicity of the compounds in lung carcinoma (A-549) and fetal lung fibroblast (MRC-5) cell lines was performed. Compounds 1, 2, 1Ag, 2Ag, 3Ag, 1Pt, 3Pt, and 4Pt were more active against A-549 cells than cisplatin. Complexes 3Ag and 1Pt showed an acceptable SI and better selectivity than cisplatin, proving that silver(I) complexes and Pt(polyfluorophenyl) complexes are valuable options in searching for new antitumoral drugs. Full article

Newly synthesized 7-chloro-4-aminoquinoline–benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC₅₀ value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC₅₀ ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure–activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R² = 0.886; R_ext² = 0.937; F = 41.589) and Dd2 strain (R² = 0.859; R_ext² = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities. Full article

Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary tumor microenvironment, there is a cell subpopulation called cancer stem cells (CSCs), which are capable of forming spheres in vitro and resisting anti-tumor treatments, partly explaining the recurrence of some tumors. Previously, it has been described that spheres derived from canine mammary carcinoma cells CF41.Mg and REM 134 exhibit stemness characteristics. Melatonin has shown anti-tumor effects on mammary tumor cells; however, its effects have been poorly evaluated in canine mammary CSCs. This study aimed to analyze the effect of melatonin on the chemoresistance exhibited by stem-like neoplastic cells derived from canine mammary carcinoma to cytotoxic drugs such as doxorubicin and mitoxantrone. CF41.Mg and REM 134 cells were cultured in high-glucose DMEM supplemented with fetal bovine serum and L-glutamine. The spheres were cultured in ultra-low attachment plates in DMEM/F12 medium without fetal bovine serum and with different growth factors. The CD44⁺/CD24^−/low phenotype was analyzed by flow cytometry. The viability of sphere-derived cells (MTS reduction) was studied in the presence of melatonin (0.1 or 1 mM), doxorubicin, mitoxantrone, and luzindole. In addition, the gene (RT-qPCR) of the multidrug resistance bombs MDR1 and ABCG2 were analyzed in the presence of melatonin. Both cell types expressed the MT1 gene, which encodes the melatonin receptor MT1. Melatonin 1 mM does not modify the CD44⁺/CD24^−/low phenotype; however, the hormone reduced viability (p < 0.0001) only in CF41.Mg spheres, without inducing an additive effect when co-incubated with cytotoxic drugs. These effects were independent of the binding of the hormone to its receptor MT1, since, by pharmacologically inhibiting them, the effect of melatonin was not blocked. In CF41.Mg spheres, the relative gene expression of ABCG2 and MDR1 was decreased in response to the hormone (p < 0.001). These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of MDR1 and ABCG2. Full article

Currently, there is still a lack of effective carriers with minimal side effects to deliver therapeutic miRNA. Thus, it is crucial to optimize novel drug delivery systems. MiR-375 has proven superior therapeutic potency in Hepatocellular carcinoma (HCC). The purpose of this study was to fabricate 2 novel and smart nano-carriers for the transportation efficiency of miR-375 in HCC cells and enhance its anti-tumor effects. We established the miR-375 construct through the pEGP- miR expression vector. Two nano-carriers of solid/liquid lipids and chitosan (CS) were strategically selected, prepared by high-speed homogenization, and optimized by varying nano-formulation factors. Thus, the two best nano-formulations were designated as F1 (0.5% CS) and F2 (1.5% CS) and were evaluated for miR-375 conjugation efficiency by gel electrophoresis and nanodrop assessment. Then, physio-chemical characteristics and stability tests for the miR-375 nano-plexes were all studied. Next, its efficiencies as replacement therapy in HepG2 cells have been assessed by fluorescence microscopy, flow cytometry, and cytotoxicity assay. The obtained data showed that two cationic nanostructured solid/liquid lipid carriers (NSLCs); F1 and F2 typically had the best physio-chemical parameters and long-term stability. Moreover, both F1 and F2 could form nano-plexes with the anionic miR-375 construct at weight ratios 250/1 and 50/1 via electrostatic interactions. In addition, these nano-plexes exhibited physical stability after three months and protected miR-375 from degradation in the presence of 50% fetal bovine serum (FBS). Furthermore, both nano-plexes could simultaneously deliver miR-375 into HepG2 cells and they ensure miR re-expression even in the presence of 50% FBS compared to free miR-375 (p-value < 0.001). Moreover, both F1 and F2 alone significantly exhibited minimal cytotoxicity in treated cells. In contrast, the nano-plexes significantly inhibited cell growth compared to free miR-375 or doxorubicin (DOX), respectively. More importantly, F2/miR-375 nano-plex exhibited more anti-proliferative activity in treated cells although its IC50 value was 55 times lower than DOX (p-value < 0.001). Collectively, our findings clearly emphasized the multifunctionality of the two CS-coated NSLCs in terms of their enhanced biocompatibility, biostability, conjugation, and transfection efficiency of therapeutic miR-375. Therefore, the NSLCs/miR-375 nano-plexes could serve as a novel and promising therapeutic strategy for HCC. Full article

This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children’s health—from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children’s IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare. Full article

The toxicity and carcinogenicity of hexavalent chromium via the inhalation route is well established. However, a scientific debate has arisen about the potential effects of oral exposure to chromium on human health. Epidemiological studies evaluating the connection between ingested chromium and adverse health effects on the general population are limited. In recent years, a wealth of biomonitoring studies has emerged evaluating the associations between chromium levels in body fluids and tissues and health outcomes. This systematic review brings together epidemiological and biomonitoring evidence published over the past decade on the health effects of the general population related to oral exposure to chromium. In total, 65 studies were reviewed. There appears to be an inverse association between prenatal chromium exposure and normal fetal development. In adults, parameters of oxidative stress and biochemical alterations increase in response to chromium exposure, while effects on normal renal function are conflicting. Risks of urothelial carcinomas cannot be overlooked. However, findings regarding internal chromium concentrations and abnormalities in various tissues and systems are, in most cases, controversial. Environmental monitoring together with large cohort studies and biomonitoring with multiple biomarkers could fill the scientific gap. Full article

Congenital tumors are rare and, owing to this rarity, there is limited information on many of them. A total of 839 fetal and postnatal MRI studies performed in the first 3 months of life were retrospectively reviewed. They were performed with the use of 1.5 T scanners. Seventy-six tumors were diagnosed based on fetal MRI between 20 and 37 gestational weeks, and 27 were found after birth, from 1 day of age to 3 months of life. Teratomas were the most common tumors in our dataset, mainly in the sacrococcygeal region (SCT), followed by cardiac rhabdomyomas and subependymal giant cell astrocytomas (SEGA) associated with TSC, and neuroblastomas. The group of less common tumors consisted of infantile fibrosarcomas, malignant rhabdoid tumors, mesoblastic nephromas and Wilms tumor, craniopharyngiomas, brain stem gliomas, desmoplastic infantile astrocytoma, choroid plexus carcinoma, glioblastoma, hemangiopericytoma, rhabdomyosarcoma, melanoma, mesenchymal hamartomas of the chest wall and the liver, and juvenile xanthogranuloma, with special consideration of blue rubber bleb nevus syndrome. MRI plays a significant role in further and better characterization of congenital tumors, leading to a correct diagnosis in many cases, which is crucial for pregnancy and neonatal management and psychological preparation of the parents. No diagnosis is impossible and can be absolutely excluded. Full article

Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs. Full article

The newly synthesized quinoline–benzimidazole hybrids containing two types of triazole-methyl-phenoxy linkers were characterized via NMR and elemental analysis. Additional derivatization was achieved by introducing bromine at the C-2 position of the phenoxy core. These novel hybrids were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts), leukemia and lymphoma cell lines: Hut78, THP-1 and HL-60, and carcinoma cell lines: HeLa and CaCo-2. The results obtained, presented as the concentration that achieves 50% inhibition of cell growth (IC₅₀ value), show that the compounds tested affect tumor cell growth differently depending on the cell line and the dose applied (IC₅₀ ranged from 0.2 to >100 µM). The quinoline–benzimidazole hybrids tested, including 7-chloro-4-(4-{[4-(5-methoxy-1H-1,3-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline 9c, 2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 10e, 2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 14e and 2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 15e, arrested the cell cycle of lymphoma (HuT78) cells. The calculated ADMET properties showed that the synthesized compounds violated at most two of Lipinski’s rules, making them potential drug candidates, but mainly for parenteral use due to low gastrointestinal absorption. The quinoline–benzimidazole hybrid 14e, which was shown to be a potent and selective inhibitor of lymphoma cell line growth, obtained the highest binding energy (−140.44 kcal/mol), by docking to the TAO2 kinase domain (PDB: 2GCD). Full article

Epithelial cells in periodontitis patients increasingly express chemokines, suggesting their active involvement in the inflammatory process. Enamel matrix derivative (EMD) is an extract of porcine fetal tooth germs clinically applied to support the regrowth of periodontal tissues. Periodontal regeneration might benefit from the potential anti-inflammatory activity of EMD for epithelial cells. Our aim was, therefore, to set up a bioassay where chemokine expression is initiated in the HSC2 oral squamous carcinoma cell line and then test EMD for its capacity to lower the inflammatory response. To establish the bioassay, HSC2 cells being exposed to TNFα and LPS from E. coli (Escherichia coli) or P. gingivalis (Porphyromonas gingivalis) were subjected to RNAseq. Here, TNFα but not LPS caused a robust increase of chemokines, including CXCL1, CXCL2, CXCL8, CCL5, and CCL20 in HSC2 cells. Polymerase chain reaction confirmed the increased expression of the respective chemokines in cells exposed to TNFα and IL-1β. Under these conditions, EMD reduced the expression of all chemokines at the transcriptional level and CXCL8 by immunoassay. The TGF-β receptor type I kinase-inhibitor SB431542 reversed the anti-inflammatory activity. Moreover, EMD-activated TGF-β-canonical signaling was visualized by phosphorylation of smad3 and nuclear translocation of smad2/3 in HSC2 cells and blocked by SB431542. This observation was confirmed with primary oral epithelial cells where EMD significantly lowered the SB431542-dependent expression of CXCL8. In summary, our findings suggest that TGF-β signaling mediates the effects of EMD to lower the forced expression of chemokines in oral epithelial cells. Full article

Right-sided ligamentum teres (RSLT) is a rare anatomic variant in which the fetal umbilical vein connects to the right portal vein. Patients with RSLT frequently have hepatic vasculature and bile duct anomalies, which increase the risk of complications with hepatectomy. Most patients with RSLT undergo open hepatectomy. Herein, we describe a patient with RSLT and hepatocellular carcinoma who underwent laparoscopic hepatectomy. The patient was a 69-year-old man with hepatocellular carcinoma located in the left liver based on computed tomography (CT) and magnetic resonance imaging. Imaging also demonstrated RSLT. Three-dimensional CT analysis revealed independent right lateral type anomalies of the portal vein and bile duct. A laparoscopic extended left lateral sectionectomy was performed after careful surgical planning. Ultrasonography was used frequently during surgery to avoid damaging the right hepatic vasculature. The left lateral and partial left median sections were removed as planned. The patient’s postoperative recovery was uneventful. Avoiding injury to the right hepatic vasculature is essential when performing left lobectomy, including left lateral sectionectomy, in patients with RSLT. Laparoscopic hepatectomy can be performed safely in patients with RSLT, provided that careful surgical planning is conducted using preoperative three-dimensional CT analysis and intraoperative ultrasonography. Full article

Lung cancer is one of the most frequently diagnosed cancers worldwide and the leading cause of cancer-related death. The 2021 World Health Organization (WHO) classification provided a detailed and updated categorization of lung adenocarcinomas with a special focus on rare histological types, including enteric, fetal and colloid types, as well as not otherwise specified adenocarcinoma, overall accounting for about 5–10% of all cases. However, rare entities are nowadays difficult to diagnose in most centers, and evidence of optimal therapeutic management for these patients is still lacking. In recent years, increasing knowledge about the mutational profile of lung cancer, in addition to the spreading diffusion of next-generation sequencing (NGS) in different centers, have been helpful in the identification of rare variants of lung cancer. Hence, the hope is that several new drugs will be available in the near future to treat these rare lung tumors, such as in targeted therapy and immunotherapy, which are often used in clinical practice for several malignancies. The aim of this review is to summarize the current knowledge about the molecular pathology and clinical management of the most common rare adenocarcinoma subtypes in order to provide a concise and updated report that can drive clinicians’ choices in their routine practice. Full article