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Heliyon May 2024This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC).
The upregulation and transcriptional regulatory mechanisms of Extra spindle pole bodies like 1 in bladder cancer: An immunohistochemistry and high-throughput screening Evaluation.
BACKGROUND
This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC).
METHODS
A multicentre database of samples (n = 1391) was assayed for ESPL1 mRNA expression in BC and validated at the protein level by immunohistochemical (IHC) staining of in-house samples (n = 202). Single-cell sequencing (scRNA-seq) analysis and enrichment analysis explored ESPL1 distribution and their accompanying molecular mechanisms. ATAC-seq, ChIP-seq and Hi-C data from multiple platforms were used to investigate ESPL1 upstream transcription factors (TFs) and potential epigenetic regulatory mechanisms. Immune-related analysis, drug sensitivity and molecular docking of ESPL1 were also calculated. Furthermore, upstream microRNAs and the binding sites of ESPL1 were predicted. The expression level and early screening efficacy of miR-299-5p in blood (n = 6625) and tissues (n = 537) were examined.
RESULTS
ESPL1 was significantly overexpressed at the mRNA level (p < 0.05, SMD = 0.75; 95 % CI = 0.09, 1.40), and IHC staining of in-house samples verified this finding ( < 0.0001). ESPL1 was predominantly distributed in BC epithelial cells. Coexpressed genes of ESPL1 were enriched in cell cycle-related signalling pathways, and ESPL1 might be involved in the communication between epithelial and residual cells in the Hippo, ErbB, PI3K-Akt and Ras signalling pathways. Three TFs (H2AZ, IRF5 and HIF1A) were detected upstream of ESPL1 and presence of promoter-super enhancer and promoter-typical enhancer loops. ESPL1 expression was correlated with various immune cell infiltration levels. ESPL1 expression might promote BC growth and affect the sensitivity and therapeutic efficacy of paclitaxel and gemcitabine in BC patients. As an upstream regulator of ESPL1, miR-299-5p expression was downregulated in both the blood and tissues, possessing great potential for early screening.
CONCLUSIONS
ESPL1 expression was upregulated in BC and was mainly distributed in epithelial cells. Elevated ESPL1 expression was associated with TFs at the upstream transcription start site (TSS) and distant chromatin loops of regulatory elements. ESPL1 might be an immune-related predictive and diagnostic marker for BC, and the overexpression of ESPL1 played a cancer-promoting role and affected BC patients' sensitivity to drug therapy. miR-299-5p was downregulated in BC blood and tissues and was also expected to be a novel marker for early screening.
PubMed: 38813236
DOI: 10.1016/j.heliyon.2024.e31192 -
Frontiers in Oncology 2024Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients...
INTRODUCTION
Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use.
METHODS
The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS).
RESULTS
2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone.
CONCLUSION
Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.
PubMed: 38812783
DOI: 10.3389/fonc.2024.1341655 -
Cell Death Discovery May 2024The mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in...
The mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in PDAC, particularly its impact on cancer stemness and gemcitabine resistance under hypoxic conditions. We found substantial downregulation of miR-485-3p in PDAC tissues, with lower expression correlating to poor patient outcomes. Mechanistically, miR-485-3p influenced stemness characteristics, as evidenced by reduced tumor-sphere formation and increased sensitivity to gemcitabine upon overexpression. Moreover, we identified SOX9 and SLC7A11 as two targets of miR-485-3p, which play a vital role in stemness and ferroptosis. Under the hypoxic condition, DNMT3B expression was upregulated, leading to hypermethylation of the miR-485-3p promoter region. The reduced miR-485-3p expression promoted stemness and chemoresistance of PDAC. In conclusion, our findings elucidate the intricate interplay of hypoxia, epigenetic modifications, and ferroptosis in PDAC and shed light on potential avenues for targeted interventions that modulate cancer stemness and chemosensitivity, offering prospects for improved therapeutic strategies for PDAC.
PubMed: 38811540
DOI: 10.1038/s41420-024-02035-x -
Non-coding RNA May 2024Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasia, characterized by early metastasis, low diagnostic rates at early stages, resistance to...
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasia, characterized by early metastasis, low diagnostic rates at early stages, resistance to drugs, and poor prognosis. There is an urgent need to better characterize this disease in order to identify efficient diagnostic/prognostic biomarkers. Since microRNAs (miRNAs) contribute to oncogenesis and metastasis formation in PDAC, they are considered potential candidates for fulfilling this task. In this work, the levels of two miRNA subsets (involved in chemoresistance or with oncogenic/tumor suppressing functions) were investigated in a panel of PDAC cell lines and liquid biopsies of a small cohort of patients. We used RT-qPCR and droplet digital PCR (ddPCR) to measure the amounts of cellular- and vesicle-associated, and circulating miRNAs. We found that both PDAC cell lines, also after gemcitabine treatment, and patients showed low amounts of cellular-and vesicle-associated miR-155-5p, compared to controls. Interestingly, we did not find any differences when we analyzed circulating miR-155-5p. Furthermore, vesicle-related miR-27a-3p increased in cancer patients compared to the controls, while circulating let-7a-5p, miR-221-3p, miR-23b-3p and miR-193a-3p presented as dysregulated in patients compared to healthy individuals. Our results highlight the potential clinical significance of these analyzed miRNAs as non-invasive diagnostic molecular tools to characterize PDAC.
PubMed: 38804361
DOI: 10.3390/ncrna10030029 -
Autopsy & Case Reports 2024Primary cardiac tumors are rare. The cardiac sarcomas are the most common malignant cardiac tumors. These tumors have a dismal prognosis with an overall median survival...
Primary cardiac tumors are rare. The cardiac sarcomas are the most common malignant cardiac tumors. These tumors have a dismal prognosis with an overall median survival of 25 months. Clinical features include dyspnea, arrhythmias, pericardial effusions, heart failure, and sudden cardiac death. The diagnosis is often challenging. Therefore, the cardiac imaging workup plays a central role in addition to a high clinical suspicion in the setting of atypical presentations that do not respond to standard therapies. The echocardiography, computed tomography, and cardiac MRI are crucial in clinching the diagnosis. Multimodal treatment with surgery, chemotherapy, and radiotherapy has been shown to improve outcomes, as opposed to using either of these modalities alone. We describe the case of a 30-year-old gentleman with COVID-19 infection who developed recurrent hemorrhagic pericardial effusions refractory to standard treatment and was eventually diagnosed as a case of pericardial angiosarcoma after his biopsy revealed the diagnosis and staging was performed using PET-CT-FDG scan. Our case re-emphasizes the importance of considering a malignant etiology early in the course of the disease presentation, especially in recurrent hemorrhagic effusions despite an inflammatory cytologic diagnosis of fluid. It also highlights the place for cardiac CT and MRI to ascertain the location and spread and to plan the further course of treatment. If diagnosed early, the estimated survival time can be prolonged by instituting a multimodal approach.
PubMed: 38803483
DOI: 10.4322/acr.2024.488 -
Molecular and Clinical Oncology Jun 2024The increasing incidence of urothelial carcinoma, coupled with advancements in its therapeutic landscape, has resulted in improved survival rates for patients. This, in...
The increasing incidence of urothelial carcinoma, coupled with advancements in its therapeutic landscape, has resulted in improved survival rates for patients. This, in turn, has led to a growing population of patients requiring specialized oncological care, with Enfortumab vedotin (EV) emerging as a pivotal treatment for metastatic urothelial carcinoma. While EV is associated with hyperglycemia, ketoacidosis is exceedingly rare. To the best of our knowledge, the link between EV and hemophagocytic lymphohistiocytosis (HLH) has not yet been explored. A 56-year-old patient diagnosed with metastatic urothelial carcinoma underwent EV treatment as a third-line treatment after progression following treatment with cisplatin/gemcitabine and pembrolizumab. Notably, after receiving two doses of EV, the patient exhibited refractory insulin resistance, leading to ketoacidosis. Subsequently, HLH emerged, necessitating a treatment regimen involving dexamethasone and etoposide. Despite intensive efforts, the patient experienced septic shock, resulting in death. The present case report highlights refractory insulin resistance and ketoacidosis, followed by reactive HLH, in the context of EV therapy. The limited literature on these complications demonstrates the need for further research to improve the understanding of the underlying mechanisms. With growing evidence of the efficacy of EV and evolving survival rates in urothelial carcinoma, healthcare professionals must remain vigilant for potential adverse effects, ensuring early recognition and optimal patient care.
PubMed: 38799283
DOI: 10.3892/mco.2024.2742 -
Aging May 2024As a newly defined regulated cell death, ferroptosis is a potential biomarker in ovarian cancer (OV). However, its underlying mechanism in tumor microenvironment (TME)...
BACKGROUND
As a newly defined regulated cell death, ferroptosis is a potential biomarker in ovarian cancer (OV). However, its underlying mechanism in tumor microenvironment (TME) and clinical prediction significance in OV remained to be elucidated.
METHODS
The transcriptome data of high-grade serous OV from The Cancer Genome Atlas (TCGA) database were downloaded. Molecular subtypes were classified based on ferroptosis-correlated genes from the FerrDb database by performing consensus clustering analysis. The associations between the subtypes and clinicopathologic characteristics, mutation, regulatory pathways and immune landscape were assessed. A ferroptosis-related prognostic model was constructed and verified using International Cancer Genome Consortium (ICGC) cohort and GSE70769.
RESULTS
Three molecular subtypes of OV were defined. Patients in subtype C3 tended to have the most favorable prognosis, while subtype C1 showing more mesenchymal cells, increased immune infiltration of Macrophages_M2, lower tumor purity, and epithelial-to-mesenchymal transition (EMT) features had the poorest prognosis. A ferroptosis-related risk model was constructed using 8 genes (PDP1, FCGBP, EPHA4, GAS1, SLC7A11, BLOC1S1, SPOCK2, and CXCL9) and manifested a strong prediction performance. High-risk patients had enriched EMT pathways, more Macrophages_M2, less plasma cells and CD8 cell infiltration, greater tendency of immune escape and worse prognosis. The risk score has negatively correlated relation with LAG3, TIGIT, CTLA4, IDO1, CD27, ICOS, and IL2RB but positively correlated with PVR, CD276, and CD28. Moreover, low-risk patients were more sensitive to Cisplatin and Gefitinib, Gemcitabine.
CONCLUSIONS
Our results could improve the understanding of ferroptosis in OV, providing promising insights for the clinical targeted therapy for the cancer.
PubMed: 38795391
DOI: 10.18632/aging.205857 -
Cancers May 2024Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free...
Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, = 110; D-RVd, = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 10/L, = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 10/kg BW, = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, = 0.0164; and 16 vs. 14 days, = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT.
PubMed: 38791933
DOI: 10.3390/cancers16101854 -
Biomedicines May 2024To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and...
To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.
PubMed: 38790973
DOI: 10.3390/biomedicines12051011 -
Nature Communications May 2024Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination...
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (
gemcitabine and cisplatin plus pembrolizumab; NAC-ICI) for MIBC, 22/39 patients responded (pathologic downstaging as primary outcome), as previously described. Here, we report post-hoc correlative analyses. Treatment was associated with changes in tumor mutational profile, immune gene signatures, and RNA subtype switching. Clinical response was associated with an increase in plasma IL-9 from pre-treatment to initiation of cycle 2 of therapy. Tumors harbored diverse predicted antigen landscapes that change across treatment and are associated with APOBEC, tobacco, and other etiologies. Higher pre-treatment tumor PD-L1 and TIGIT RNA expression were associated with complete response. IL-8 signature and Stroma-rich subtype were associated with improved response to NAC-ICI versus neoadjuvant ICI (ABACUS trial, NCT02662309). Plasma IL-9 represents a potential predictive biomarker of NAC-ICI response, while tumor IL-8 signature and stroma-rich subtype represent potential predictive biomarkers of response benefit of NAC-ICI over neoadjuvant ICI. Future efforts must include additional independent biomarker discovery and validation, ultimately to improve the selection of patients for ICI-related treatments. Topics: Humans; Urinary Bladder Neoplasms; Neoadjuvant Therapy; Deoxycytidine; Gemcitabine; Immunotherapy; Male; Cisplatin; Female; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Immune Checkpoint Inhibitors; Aged; Middle Aged; Neoplasm Invasiveness; Interleukin-9; B7-H1 Antigen; Biomarkers, Tumor; Treatment Outcome
PubMed: 38789460
DOI: 10.1038/s41467-024-48480-1