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ACS Omega Jun 2024Ferroptosis and apoptosis are programmed cell death pathways with distinct characteristics. Sometimes, cancer cells are aided by the induction of a different pathway,...
Ferroptosis and apoptosis are programmed cell death pathways with distinct characteristics. Sometimes, cancer cells are aided by the induction of a different pathway, such as ferroptosis, when they develop chemoresistance and avoid apoptosis. Identifying the nanomedicine that targets dual pathways is considered as one of the best strategies for diverse cancer types. In our previous work, we synthesized gold nanoparticles (GNP) utilizing in conjunction with compound K (CK) and coprisin (CopA3), yielding GNP-CK-CopA3. Here, we assessed the inhibitory effect of GNP-CK-CopA3 on AGS cells and the induction of apoptosis using Hoechst and PI, Annexin V-FITC/PI, and qRT-PCR. Subsequently, we conducted downstream proteomic analysis and molecular dynamic stimulation to identify the underlying molecular mechanisms. Our investigation of cultured AGS cells treated with varying concentrations of GNP-CK-CopA3 demonstrated the anticancer properties of these nanoparticles. Penetration of GNP-CK-CopA3 into AGS cells was visualized using an enhanced dark field microscope. Apoptosis induction was initially confirmed by treating AGS cells with GNP-CK-CopA3, as evidenced by staining with dyes such as Hoechst and PI. Additionally, mitochondrial disruption and cellular localization induced by GNP-CK-CopA3 were validated through Mito-tracker staining and transmission electron microscopy images. Annexin V-FITC/PI staining was used to distinguish early and late-stage apoptosis or necrosis based on fluorescence patterns. The gene expression of apoptotic markers indicated the initiation of cellular apoptosis. Further, proteomic analysis suggested that the treatment of GNP-CK-CopA3 to AGS cells led to the suppression of 439 proteins and the stimulation of 832 proteins. Among these, ferroptosis emerged as a significant interconnected pathway where glutathione peroxidase 4 (GPX4) and glutathione synthetase (GSS) were significant interacting proteins. Molecular docking and dynamic simulation studies confirmed the binding affinity and stability between CopA3 and CK with GSS and GPX4 proteins, suggesting the role of GNP-CK-CopA3 in ferroptosis induction. Overall, our study showed GNP-CK-CopA3 could play a dual role by inducing apoptosis and ferroptosis to induce AGS cell death.
PubMed: 38911731
DOI: 10.1021/acsomega.4c00554 -
Frontiers in Aging 2024Older adults with chronic disease prioritize functional independence. We aimed to describe the feasibility of capturing functional disability and treatment toxicity...
INTRODUCTION
Older adults with chronic disease prioritize functional independence. We aimed to describe the feasibility of capturing functional disability and treatment toxicity among older adults with lung cancer using a longitudinal comprehensive geriatric assessment (CGA) and molecular biomarkers of aging.
METHODS
This prospective study included adults ≥60 years with any newly diagnosed non-small-cell lung cancer. Participants were recruited from central Ohio (2018-2020). Study assessments included the Cancer and Aging Research Group CGA (CARG-CGA), short physical performance battery (SPPB), and the blessed orientation-memory concentration (BOMC) test at baseline, 3, 6, and 12 months. Activities of daily living (ADLs) and instrumental ADLs (IADLs), quality of life (QoL, PROMIS 10), and treatment toxicity were captured monthly. Stool and blood were collected to characterize the gut microbiome and age-related blood biomarkers.
RESULTS
This study enrolled 50 participants with an average age of 71.7 years. Ninety-two percent of participants were Caucasian, 58% were male, and all were non-Hispanic. Most had advanced stage (stage III/IV: 90%; stage I/II: 10%), with adenocarcinoma the predominant histologic subtype (68% vs. 24% squamous). First-line treatments included chemotherapy (44%), immune checkpoint inhibitors (ICIs, 22%), chemotherapy and ICIs (30%), or tyrosine kinase inhibitors (4%). The median baseline CARG toxicity score was 8 (range 2-12). Among patients with treatment-related toxicity ( = 49), 39 (79.6%) cases were mild (grade 1-2), and 10 (20.4%) were moderate to severe (≥ grade 3). Treatment toxicity was greater among those with a CARG score ≥8 (28.0% vs. 13.6%). Higher IADL independence, QoL, and SPPB scores at baseline were positively associated with , , and , , and and T cell and were associated with worse IADLs, QoL, and SPPB scores at baseline.
DISCUSSION
A longitudinal CGA and biomarker collection is feasible among older adults undergoing lung cancer treatment. Gut microbe and T cell gene expression changes correlated with subjective and objective functional status assessments. Future research will test causality in these associations to improve outcomes through novel supportive care interventions to prevent functional disability.
PubMed: 38911592
DOI: 10.3389/fragi.2024.1268232 -
Journal of Cancer 2024The role of endothelial cells in tumor progression is considerable, yet the effect of endothelial cell immune-related genes (EIRGs) is still unclear. This research...
The role of endothelial cells in tumor progression is considerable, yet the effect of endothelial cell immune-related genes (EIRGs) is still unclear. This research aimed to scrutinize the prognostic value of EIRGs in lung adenocarcinoma (LUAD) and provide further insights into the abovementioned uncertainties. After single-cell RNA sequencing (scRNA-seq) samples were obtained from the Gene Expression Omnibus (GEO) database, they were integrated with bulk RNA sequencing data from The Cancer Genome Atlas (TCGA). Prognostic markers were determined and a prognostic model was developed. From this model, a nomogram was constructed. We analyzed the biological mechanism of the EIRGs in LUAD, including functional enrichment, tumor mutational burden (TMB), tumor microenvironment (TME) analyses and drug sensitivity. We validated the signature by validating the external cohort GSE31210 and RT-qPCR. After analyzing the model constructed from eight EIRGs, we observed that high-risk group (HG) LUAD patients (a risk score exceeding 4.65) exhibited unfavorable outcomes according to Kaplan‒Meier survival curves. This outcome was confirmed by GSE31210. The nomogram based on the model demonstrated significant predictive value. HG was influenced primarily by steroid hormone biosynthesis and ECM receptor interactions. The TMB in HGs was greater than that in the LG. Analysis of drug sensitivity revealed the direction for individualized treatment for both risk cohorts. Variations in the expression of EIRGs have been confirmed via RT-qPCR in several LUAD cell lines. The prognostic model and nomogram above are valuable for determining the survival rate and treatment options for LUAD patients.
PubMed: 38911372
DOI: 10.7150/jca.94501 -
Gynecology and Minimally Invasive... 2024Vulvar intestinal adenocarcinoma is a rare malignancy. The most significant predictor of advanced vulvar cancer is achieving complete resection, although determining the...
Vulvar intestinal adenocarcinoma is a rare malignancy. The most significant predictor of advanced vulvar cancer is achieving complete resection, although determining the optimal treatment for this rare histologic type remains uncertain. We report the case of a 63-year-old woman with a primary vulvar tumor suspected of having rectal invasion and inguinal lymph node metastases based on preoperative magnetic resonance imaging and computed tomography scans. To achieve complete resection of stage IIIC intestinal-type vulvar adenocarcinoma, we performed a laparoscopic posterior pelvic exenteration (PPE) and radical vulvectomy, along with bilateral inguinal lymph node dissection. This case report highlights the use of a novel hybrid procedure that combines laparoscopic PPE with radical vulvectomy and bilateral inguinal lymph node dissection for vulvar adenocarcinoma of the intestinal type. Laparoscopic PPE can be considered a minimally invasive approach for vulvar tumor when complete resection is achievable with an appropriate safety margin.
PubMed: 38911313
DOI: 10.4103/gmit.gmit_103_23 -
RSC Medicinal Chemistry Jun 2024Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer,...
Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2'-bipyridine (2,2'-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[]thiophen-3-yl]-[4-(2,2'-bipyridin-4'-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells.
PubMed: 38911151
DOI: 10.1039/d4md00051j -
Experimental and Therapeutic Medicine Aug 2024[This retracts the article DOI: 10.3892/etm.2021.10857.].
[This retracts the article DOI: 10.3892/etm.2021.10857.].
PubMed: 38911046
DOI: 10.3892/etm.2024.12603 -
APL Bioengineering Jun 2024Previous lung-on-chip devices have facilitated significant advances in our understanding of lung biology and pathology. Here, we describe a novel lung-on-a-chip model in...
Previous lung-on-chip devices have facilitated significant advances in our understanding of lung biology and pathology. Here, we describe a novel lung-on-a-chip model in which human induced pluripotent stem cell-derived alveolar epithelial type II cells (iAT2s) form polarized duct-like lumens alongside engineered perfused vessels lined with human umbilical vein endothelium, all within a 3D, physiologically relevant microenvironment. Using this model, we investigated the morphologic and signaling consequences of the KRAS mutation, a commonly identified oncogene in human lung adenocarcinoma (LUAD). We show that expression of the mutant KRAS isoform in iAT2s leads to a hyperproliferative response and morphologic dysregulation in the epithelial monolayer. Interestingly, the mutant epithelia also drive an angiogenic response in the adjacent vasculature that is mediated by enhanced secretion of the pro-angiogenic factor soluble uPAR. These results demonstrate the functionality of a multi-cellular platform capable of modeling mutation-specific behavioral and signaling changes associated with lung adenocarcinoma.
PubMed: 38911024
DOI: 10.1063/5.0207228 -
Oncology Letters Aug 2024Recently, the treatment plan of pembrolizumab plus chemotherapy was regarded as a promising treatment for patients with advanced gastric cancer or gastroesophageal...
Efficacy and side effects of pembrolizumab plus chemotherapy vs. chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A meta‑analysis.
Recently, the treatment plan of pembrolizumab plus chemotherapy was regarded as a promising treatment for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC). However, the efficacy and side effects of pembrolizumab plus chemotherapy still lack evidence-based medical evidence to support. Therefore, a meta-analysis was conducted to evaluate the hot issue. By searching PubMed, EMBASE, Cochrane Library, Web of Science, any randomized clinical studies of pembrolizumab plus chemotherapy versus chemotherapy in patients with advanced GC/GEJC met the inclusion criteria were included. The quality of the literature was evaluated and the data was extracted. A correlative software was also used to analyze the data and to draw a conclusion. After screening 14,015 studies, four studies were eligible for the meta-analysis. Compared with chemotherapy alone group, the overall survival (OS) rate was significantly longer. In programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 subgroup and PD-L1 CPS ≥10 subgroup analyses, the results showed that the response rate (RR) and complete response rate (CR) were both higher in pembrolizumab plus chemotherapy group compared with chemotherapy alone group. There were not significant differences in the CR, the treatment-related adverse events, succumbed to drug-related events and succumbed to immune-mediated events between the two groups. However, the effect events such as the treatment-related adverse events led to discontinuation, the 3-5 treatment-related adverse events and the immune-mediated adverse events and infusion reactions were more common in pembrolizumab plus chemotherapy group. In conclusion, the current meta-analysis revealed that, in treating advanced GC/GEJC, pembrolizumab plus chemotherapy had improved therapeutic efficacies than chemotherapy alone, as evidenced by the significantly longer OS. Furthermore, the patients in PD-L1 CPS ≥1 subgroup and PD-L1 CPS ≥10 subgroup appeared to benefit from pembrolizumab plus chemotherapy treatment because of higher RR and CR. However, side effects such as the treatment-related adverse events leading to discontinuation, the 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions deserved more attention.
PubMed: 38910906
DOI: 10.3892/ol.2024.14504 -
Oncology Letters Aug 2024Lung adenocarcinoma (LUAD) presents a significant global health challenge owing to its poor prognosis and high mortality rates. Despite its involvement in the initiation...
Lung adenocarcinoma (LUAD) presents a significant global health challenge owing to its poor prognosis and high mortality rates. Despite its involvement in the initiation and progression of a number of cancer types, the understanding of the precise impact of MIS18 kinetochore protein A (MIS18A) on LUAD remains incomplete. In the present study, the role of MIS18A in LUAD was investigated by analyzing the genomic and clinical data from multiple public datasets. The expression of MIS18A was validated using reverse transcription-quantitative polymerase chain reaction, and experiments involving small interfering RNA-induced downregulation of MIS18A in lung cancer cells were conducted to further explore its impact. These findings revealed that elevated MIS18A expression in LUAD was associated with advanced clinical features and poor prognosis. Functional analysis also revealed the role of MIS18A in regulating the cell cycle and immune-related pathways. Moreover, MIS18A altered the immune microenvironment in LUAD, influencing its response to immunotherapy and drug sensitivity. The results of the experiments indicated that suppression of MIS18A expression reduced the proliferative and migratory capacities of LUAD cells. In summary, MIS18A possesses potential as a biomarker and may serve as a possible therapeutic target for LUAD, with significant implications for tumor progression by influencing both cell cycle dynamics and immune infiltration.
PubMed: 38910901
DOI: 10.3892/ol.2024.14509 -
Frontiers in Pharmacology 2024Lung cancer is the most commonly diagnosed and the main cause of cancer death, usually related to cigarette smoking. Furthermore, the microbiota of people exposed to...
INTRODUCTION
Lung cancer is the most commonly diagnosed and the main cause of cancer death, usually related to cigarette smoking. Furthermore, the microbiota of people exposed to cigarette smoke can be modified, making it difficult to eliminate opportunistic microorganisms. The leaves of are a by-product of fruit production and, to date, there have been no studies addressing the antiproliferative, anti-inflammatory, and antimicrobial activities.
OBJECTIVE
Investigate the antimicrobial, Nitric Oxide (NO)-production inhibition, and antiproliferative activities of the essential oil from leaves and its possible effect on the treatment and prevention of damage caused by tobacco.
METHODS
The essential oil (EO) was obtained by hydrodistillation (3 h). Its chemical composition was investigated by GC-MS. It was proposed to investigate antiproliferative activity against human tumor cell lines, namely, breast adenocarcinoma (MCF-7), lung (NCI-H460), cervical (HeLa), and hepatocellular (HepG2) carcinomas. A non-tumor primary culture from pig liver (PLP2) was also tested. The EO capacity to inhibit nitric oxide (NO) production was evaluated by a lipopolysaccharide stimulated murine macrophage cell line. Antibacterial and antifungal activities against opportunistic pathogens were investigated against seven strains of bacteria and eight fungi.
RESULTS
The results indicated the presence of 23 compounds in the essential oil, the majority were spathulenol (45.63%) and β-caryophyllene oxide (12.72%). Leaf EO provided 50% inhibition of nitric oxide production at a concentration of 92.04 µg mL. The EO also demonstrated antiproliferative activity against all human tumor cell lines studied, with GI50 values comprised between 270.86 and 337.25 µg mL. The essential oil showed antimicrobial potential against the bacteria monocytogenes (Murray et al.) Pirie (NCTC 7973) and ATCC 13311 (MIC 1870 µg mL) and fungi ATCC 11730, ATCC 12066, ATCC 90288, var. cyclopium (Westling) Samson, Stolk & Hadlok (food isolate) (MIC 1870 µg mL) and Pers. IAM 5061 (1,400 µg mL).
CONCLUSION
The demonstrated anti-inflammatory, antiproliferative, and antimicrobial activities in the leaves of can add value to the production chain of this plant, being a possible option for preventing and combating cancer, including lung cancer.
PubMed: 38910894
DOI: 10.3389/fphar.2024.1415659