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1.
Sci Rep ; 14(1): 13106, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849410

ABSTRACT

Immunogenic cell death (ICD) is a newly discovered form of cellular demise that triggers adaptive immune responses mediated by T cells. However, the immunogenic cell death-related lncRNAs (ICDRLs) involved in bladder cancer (BC) development and progression remain to be further elucidated. Molecular profiling data and clinicopathological information for BC patients were obtained from TCGA, and the ICDRGs list was obtained from published literature. For the identification of ICDRLs, Pearson co-expression analysis was performed, and a prognostic signature based on 13 ICDRLs was constructed by univariate assays and LASSO assays. Herein, an ICDRLSig consisting of 13 ICDRLs was constructed. KM curves and ROC curves demonstrated that the constructed signature in the TCGA training, testing, entire and external sets have good predictive performance. Multivariate assays illuminated that the signature is an independent predictor for BC patients' OS, exhibiting greater predictive power for the survival than traditional clinicopathological features. Additionally, patients in the high-ICDRLSig risk subgroup had more abundant immune infiltration, higher immune checkpoint gene expression, lower TMB and poorer response to immunotherapy. We have developed a novel ICDRLSig that can be exploited for survival prediction and provide a reference for further individualized treatment.


Subject(s)
Gene Expression Regulation, Neoplastic , Immunogenic Cell Death , RNA, Long Noncoding , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/mortality , RNA, Long Noncoding/genetics , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Prognosis , Female , Male , Biomarkers, Tumor/genetics , Gene Expression Profiling , Middle Aged , ROC Curve , Aged , Kaplan-Meier Estimate
2.
BMC Ophthalmol ; 24(1): 240, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849786

ABSTRACT

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.


Subject(s)
Immune Checkpoint Inhibitors , Uveomeningoencephalitic Syndrome , Humans , Uveomeningoencephalitic Syndrome/chemically induced , Uveomeningoencephalitic Syndrome/diagnosis , Immune Checkpoint Inhibitors/adverse effects , Male , Uveitis/chemically induced , Uveitis/diagnosis , Urinary Bladder Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Female , Middle Aged , Aged , Antineoplastic Agents, Immunological/adverse effects
4.
Nat Commun ; 15(1): 4690, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824132

ABSTRACT

Accurate identification of genetic alterations in tumors, such as Fibroblast Growth Factor Receptor, is crucial for treating with targeted therapies; however, molecular testing can delay patient care due to the time and tissue required. Successful development, validation, and deployment of an AI-based, biomarker-detection algorithm could reduce screening cost and accelerate patient recruitment. Here, we develop a deep-learning algorithm using >3000 H&E-stained whole slide images from patients with advanced urothelial cancers, optimized for high sensitivity to avoid ruling out trial-eligible patients. The algorithm is validated on a dataset of 350 patients, achieving an area under the curve of 0.75, specificity of 31.8% at 88.7% sensitivity, and projected 28.7% reduction in molecular testing. We successfully deploy the system in a non-interventional study comprising 89 global study clinical sites and demonstrate its potential to prioritize/deprioritize molecular testing resources and provide substantial cost savings in the drug development and clinical settings.


Subject(s)
Algorithms , Deep Learning , Humans , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Clinical Trials as Topic , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/diagnosis , Male , Female , Patient Selection , Urologic Neoplasms/pathology , Urologic Neoplasms/diagnosis , Urologic Neoplasms/genetics
5.
Oncol Res ; 32(6): 1021-1030, 2024.
Article in English | MEDLINE | ID: mdl-38827321

ABSTRACT

Background: Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC), an endogenous mutator, induces DNA damage and activates the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) pathway. Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer (MIBC), it has a poor survival rate. Therefore, this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B (APOBEC3B) expressing MIBC. Methods: Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC. The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis. Western blot analysis was performed to confirm differences in phosphorylated Chk1 (pChk1) expression according to the APOBEC3B expression. Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin. Conclusion: There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC. Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels. Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression. Compared to cisplatin single treatment, combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression. Conclusion: Our study shows that APOBEC3B's higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition. This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.


Subject(s)
Ataxia Telangiectasia Mutated Proteins , Cisplatin , Cytidine Deaminase , Minor Histocompatibility Antigens , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Ataxia Telangiectasia Mutated Proteins/metabolism , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Cell Line, Tumor , Male , Minor Histocompatibility Antigens/metabolism , Minor Histocompatibility Antigens/genetics , Middle Aged , Female , Checkpoint Kinase 1/metabolism , Checkpoint Kinase 1/antagonists & inhibitors , Checkpoint Kinase 1/genetics , Apoptosis , Aged , Neoplasm Invasiveness , Cell Proliferation , Cell Survival/drug effects
6.
BMJ Case Rep ; 17(6)2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834309

ABSTRACT

Rhabdomyosarcomas are the most common soft-tissue sarcomas, found usually in the younger age group. Histologically, they are subdivided into embryonal, alveolar, pleomorphic and not otherwise specified. They have a heterogenous appearance on imaging with few additional characteristic features based on the subtype. Botryoid variant of embryonal rhabdomyosarcoma commonly involves the genitourinary and the biliary system. They can be multifocal. Most of these lesions have a heterogenous appearance on imaging with areas of necrosis and haemorrhage. On ultrasound, they are polypoidal with cystic areas and are vascular. The lesions are hyperintense on T2 sequences, isointense to the skeletal muscle on T1 sequences and show heterogenous enhancement. Surgery is the mainstay of treatment along with radiotherapy or chemotherapy depending on the site and the stage of the tumour. We report a case of botryoid variant of rhabdomyosarcoma involving the vagina and the urinary bladder.


Subject(s)
Rhabdomyosarcoma, Embryonal , Urinary Bladder Neoplasms , Vaginal Neoplasms , Humans , Rhabdomyosarcoma, Embryonal/pathology , Rhabdomyosarcoma, Embryonal/diagnosis , Rhabdomyosarcoma, Embryonal/diagnostic imaging , Rhabdomyosarcoma, Embryonal/surgery , Female , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/pathology , Vaginal Neoplasms/pathology , Vaginal Neoplasms/diagnostic imaging , Vaginal Neoplasms/surgery , Vaginal Neoplasms/diagnosis , Magnetic Resonance Imaging , Child , Ultrasonography
7.
Sci Rep ; 14(1): 12659, 2024 06 03.
Article in English | MEDLINE | ID: mdl-38830942

ABSTRACT

Bladder carcinoma (BC) accounts for > 90% of all urothelial cancers. Pathological diagnosis through cytoscopic biopsy is the gold standard, whereas non-invasive diagnostic tools remain lacking. The "Atyp.C" parameter of the Sysmex UF-5000 urine particle analyzer represents the ratio of nucleus to cytoplasm and can be employed to detect urinary atypical cells. The present study examined the association between urinary Atyp.C values and BC risk. This two-center, retrospective case-control study identified clinical primary or newly recurrent BC (study period, 2022-2023; n = 473) cases together with controls with urinary tract infection randomly matched by age and sex (1:1). Urinary sediment differences were compared using non-parametric tests. The correlations between urinary Atyp.C levels and BC grade or infiltration were analyzed using Spearman's rank correlation. The BC risk factor odds ratio of Atyp.C was calculated using conditional logistic regression, and potential confounder effects were adjusted using stepwise logistic regression (LR). Primary risk factors were identified by stratified analysis according to pathological histological diagnosis. The mean value of urinary Atyp.C in BC cases (1.30 ± 3.12) was 8.7 times higher than that in the controls (0.15 ± 0.68; P < 0.001). Urinary Atyp.C values were positively correlated with BC pathological grade and invasion (r = 0.360, P < 0.001; r = 0.367, P < 0.001). Urinary Atyp.C was an independent risk factor for BC and closely related with BC pathological grade and invasion. Elevated urinary Atyp.C values was an independent risk factor for BC. Our findings support the use of Atyp.C as a marker that will potentially aid in the early diagnosis and long-term surveillance of new and recurrent BC cases.


Subject(s)
Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/urine , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/pathology , Male , Female , Risk Factors , Aged , Middle Aged , Retrospective Studies , Case-Control Studies , Cell Nucleus
8.
Iran Biomed J ; 28(2&3): 120-31, 2024 03 01.
Article in English | MEDLINE | ID: mdl-38850011

ABSTRACT

Background: The HSD17B family has been implicated in the prognosis and treatment prediction of various malignancies; however, its association with BLCA remains unclear. This study aimed to evaluate the potential of HSD17B1, as a prognostic biomarker, for the survival of patients with BLCA and to determine its effectiveness as a supplemental biomarker for BLCA. Methods: A series of bioinformatics techniques were applied to investigate the expression of HSD17B1 in different types of cancer and its potential association with the prognosis of BLCA patients using diverse databases. The UALCAN, Human Protein Atlas, cBioPortal, Metascape, GEPIA, MethSurv, and TIMER were employed to analyze expression differences, mutation status, enrichment analysis, overall survival, methylation, and immune-infiltrating cells. The qRT-PCR was implemented to detect the mRNA expression levels of HSD17B1 in vitro. Results: Elevated mRNA and protein levels of HSD17B1, surpassing normal levels, were observed in BLCA samples. In addition, the BLCA patients with higher mRNA expression level of HSD17B1 significantly reduced the OS. Also, several immune infiltrating cells, including mast cell resting CIBERSORT-ABS, have been identified as tumor-associated biomarker genes, with the potential to significantly influence the immunological environment. Finally, qRT-PCR analysis revealed a significant upregulation of HSD17B1 mRNA expression level in the cancer cells compared to the human 293T cells, which was consistent with the bioinformatic data. Conclusion: There is a strong correlation between the elevated HSD17B1 expression and positive prognosis in patients with BLCA. Therefore, HSD17B1 can be used as a prognostic biomarker in these patients.


Subject(s)
Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Urinary Bladder Neoplasms , Humans , Biomarkers, Tumor/genetics , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Prognosis , Cell Line, Tumor , Estradiol Dehydrogenases/genetics , Estradiol Dehydrogenases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Computational Biology/methods
9.
Int J Oncol ; 65(1)2024 Jul.
Article in English | MEDLINE | ID: mdl-38847230

ABSTRACT

CD46, a transmembrane protein known for protecting cells from complement­mediated damage, is frequently dysregulated in various types of cancer. Its overexpression in bladder cancers safeguards the cancer cells against both complement and antibody­mediated cytotoxicity. The present study explored a new role of CD46 in facilitating cancer cell invasion and metastasis, examining its regulatory effect on matrix metalloproteases (MMPs) and their effect on the metastatic capability of bladder cancer cells. Specifically, CD46 alteration positively influenced MMP9 expression, but not MMP2, in several bladder cancer cell lines. Furthermore, CD46 overexpression triggered phosphorylation of p38 MAPK and protein kinase B (AKT), leading to enhanced activator protein 1 (AP­1) activity via c­Jun upregulation. The inhibition of p38 or AKT pathways attenuated the CD46­induced MMP9 and AP­1 upregulation, indicating that the promotion of MMP9 by CD46 involved activating both p38 MAPK and AKT. Functionally, the upregulation of MMP9 by CD46 translated to increased migratory and invasive capabilities of bladder cancer cells, as well as enhanced in vivo metastasis. Overall, the present study revealed a novel role for CD46 as a metastasis promoter through MMP9 activation in bladder cancers and highlighted the regulatory mechanism of CD46­mediated MMP9 promotion via p38 MAPK and AKT activation.


Subject(s)
Cell Movement , Matrix Metalloproteinase 9 , Membrane Cofactor Protein , Proto-Oncogene Proteins c-akt , Urinary Bladder Neoplasms , p38 Mitogen-Activated Protein Kinases , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/genetics , Humans , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/genetics , Cell Line, Tumor , p38 Mitogen-Activated Protein Kinases/metabolism , Mice , Animals , Proto-Oncogene Proteins c-akt/metabolism , Membrane Cofactor Protein/metabolism , Membrane Cofactor Protein/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Metastasis , Neoplasm Invasiveness , Transcription Factor AP-1/metabolism , Up-Regulation , Signal Transduction
10.
Eur J Med Res ; 29(1): 316, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38849949

ABSTRACT

BACKGROUND: Previous observational studies have indicated a potential link between insomnia and bladder cancer, yet the underlying causal relationship remains uncertain. The current study employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate this association. METHODS: A two-sample MR analysis was conducted utilizing publicly available summary data from genome-wide association studies (GWAS) on insomnia and bladder cancer. Various regression methods including the inverse variance weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode methods were employed for the MR analysis. The presence of pleiotropy and heterogeneity in the MR results was also assessed. Furthermore, additional sensitivity tests were performed to mitigate potential biases. RESULTS: No significant causal relationship was detected between insomnia and bladder cancer using IVW method (OR = 0.761, 95% CI 0.996-1.005; P = 0.76). Similarly, the IVW model did not reveal any causal effect of bladder cancer on the risk of insomnia (OR = 1.47, 95% CI 0.772-2.799; P = 0.24). Consistent results were obtained from the other four methods employed. There was no evidence of horizontal pleiotropy or heterogeneity in our MR analysis (P > 0.05). The sensitivity analyses further supported the reliability of the estimated causal effects. CONCLUSIONS: This study presents no evidence for a causal relationship between insomnia and bladder cancer.


Subject(s)
Genome-Wide Association Study , Mendelian Randomization Analysis , Sleep Initiation and Maintenance Disorders , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Mendelian Randomization Analysis/methods , Sleep Initiation and Maintenance Disorders/genetics , Sleep Initiation and Maintenance Disorders/complications , Polymorphism, Single Nucleotide , Risk Factors
11.
J Cell Mol Med ; 28(11): e18473, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38847477

ABSTRACT

Bladder cancer is one of the most prevalent cancers worldwide, and its morbidity and mortality rates have been increasing over the years. However, how RAC family small GTPase 3 (RAC3) affects the proliferation, migration and invasion of cisplatin-resistant bladder cancer cells remains unclear. Bioinformatics techniques were used to investigate the expression of RAC3 in bladder cancer tissues. Influences of RAC3 in the grade, stage, distant metastasis, and survival rate of bladder cancer were also examined. Analysis of the relationship between RAC3 expression and the immune microenvironment (TIME), genomic mutations, and stemness index. In normal bladder cancer cells (T24, 5637, and BIU-87) and cisplatin-resistant bladder cancer cells (BIU-87-DDP), the expression of RAC3 was detected separately with Western blotting. Plasmid transfection was used to overexpress or silence the expression of RAC3 in bladder cancer cells resistant to cisplatin (BIU-87-DDP). By adding activators and inhibitors, the activities of the JNK/MAPK signalling pathway were altered. Cell viability, invasion, and its level of apoptosis were measured in vitro using CCK-8, transwell, and flow cytometry. The bioinformatics analyses found RAC3 levels were elevated in bladder cancer tissues and were associated with a poor prognosis in bladder cancer. RAC3 in BIU-87-DDP cells expressed a higher level than normal bladder cancer cells. RAC3 overexpression promoted BIU-87-DDP proliferation. The growth of BIU-87-DDP cells slowed after the knockdown of RAC3, and RAC3 may have had an impact on the activation of the JNK/MAPK pathway.


Subject(s)
Apoptosis , Cell Movement , Cell Proliferation , Cisplatin , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Neoplasm Invasiveness , Urinary Bladder Neoplasms , rac GTP-Binding Proteins , Humans , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/drug therapy , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , rac GTP-Binding Proteins/metabolism , rac GTP-Binding Proteins/genetics , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Female , Male , Middle Aged , Tumor Microenvironment , MAP Kinase Signaling System/drug effects
12.
J Exp Med ; 221(8)2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38847806

ABSTRACT

Due to bladder tumors' contact with urine, urine-derived cells (UDCs) may serve as a surrogate for monitoring the tumor microenvironment (TME) in bladder cancer (BC). However, the composition of UDCs and the extent to which they mirror the tumor remain poorly characterized. We generated the first single-cell RNA-sequencing of BC patient UDCs with matched tumor and peripheral blood mononuclear cells (PBMC). BC urine was more cellular than healthy donor (HD) urine, containing multiple immune populations including myeloid cells, CD4+ and CD8+ T cells, natural killer (NK) cells, B cells, and dendritic cells (DCs) in addition to tumor and stromal cells. Immune UDCs were transcriptionally more similar to tumor than blood. UDCs encompassed cytotoxic and activated CD4+ T cells, exhausted and tissue-resident memory CD8+ T cells, macrophages, germinal-center-like B cells, tissue-resident and adaptive NK cells, and regulatory DCs found in tumor but lacking or absent in blood. Our findings suggest BC UDCs may be surrogates for the TME and serve as therapeutic biomarkers.


Subject(s)
Tumor Microenvironment , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Humans , Tumor Microenvironment/immunology , Male , Killer Cells, Natural/immunology , Female , CD8-Positive T-Lymphocytes/immunology , Aged , CD4-Positive T-Lymphocytes/immunology , Single-Cell Analysis/methods , Dendritic Cells/immunology , Middle Aged , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , RNA-Seq , Single-Cell Gene Expression Analysis
13.
Front Public Health ; 12: 1385443, 2024.
Article in English | MEDLINE | ID: mdl-38846611

ABSTRACT

Introduction: Bladder cancer is one of the most important diseases that threatens oral and dental health due to its nature and side effects of chemotherapy. Therefore, the present study was conducted to investigate the relationship between oral health literacy and oral health-related quality of life in patients with bladder cancer. Methods: This cross-sectional study was conducted on patients with bladder cancer in Ahvaz, 2023. Subjects were selected randomly from the patients those were registered in Cancer Registry Center in Ahvaz Jundishapur University of Medical sciences and invited to Golestan Hospital for data collection through clinical evaluation, the Oral Health Literacy Adult Questionnaire (OHL-AQ), and the Oral Health Impact Profile-14 (OHIP-14PER) questionnaire. The data were analyzed using Pearson correlation coefficient, independent t-test, and analysis of variance. Results: The number of participants was 194. The mean oral health literacy in patients with bladder cancer was 9.74 ± 2.39, indicating insufficient oral health literacy. A significant association was observed between OHL-AQ and DMFT index, but no significant association was found between OHIP-14PER and DMFT index. Furthermore, a significant correlation was found between OHL-AQ and OHIP-14PER (r = -0.68) in patients with bladder cancer. Conclusion: Based on the findings of the present study, all dimensions of oral health literacy have correlation with the oral health-related quality of life in patients with bladder cancer. Therefore, adopting oral health behaviors and increasing oral health literacy can be the best way to improve the oral health-related quality of life to among patients with bladder cancer.


Subject(s)
Health Literacy , Oral Health , Quality of Life , Urinary Bladder Neoplasms , Humans , Quality of Life/psychology , Urinary Bladder Neoplasms/psychology , Oral Health/statistics & numerical data , Male , Female , Health Literacy/statistics & numerical data , Cross-Sectional Studies , Middle Aged , Surveys and Questionnaires , Aged , Adult , Iran
14.
Diagn Pathol ; 19(1): 75, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38851736

ABSTRACT

BACKGROUND & OBJECTIVES: Tumor grade determines prognosis in urothelial carcinoma. The classification of low and high grade is based on nuclear morphological features that include nuclear size, hyperchromasia and pleomorphism. These features are subjectively assessed by the pathologists and are not numerically measured, which leads to high rates of interobserver variability. The purpose of this study is to assess the value of a computer-based image analysis tool for identifying predictors of tumor grade in bladder cancer. METHODS: Four hundred images of urothelial tumors were graded by five pathologists and two expert genitourinary pathologists using a scale of 1 (lowest grade) to 5 (highest grade). A computer algorithm was used to automatically segment the nuclei and to provide morphometric parameters for each nucleus, which were used to establish the grading algorithm. Grading algorithm was compared to pathologists' agreement. RESULTS: Comparison of the grading scores of the five pathologists with the expert genitourinary pathologists score showed agreement rates between 88.5% and 97.5%.The agreement rate between the two expert genitourinary pathologists was 99.5%. The quantified algorithm based conventional parameters that determine the grade (nuclear size, pleomorphism and hyperchromasia) showed > 85% agreement with the expert genitourinary pathologists. Surprisingly, the parameter that was most associated with tumor grade was the 10th percentile of the nuclear area, and high grade was associated with lower 10th percentile nuclei, caused by the presence of more inflammatory cells in the high-grade tumors. CONCLUSION: Quantitative nuclear features could be applied to determine urothelial carcinoma grade and explore new biologically explainable parameters with better correlation to grade than those currently used.


Subject(s)
Algorithms , Cell Nucleus , Neoplasm Grading , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/pathology , Neoplasm Grading/methods , Cell Nucleus/pathology , Observer Variation , Image Interpretation, Computer-Assisted/methods , Image Processing, Computer-Assisted/methods , Carcinoma, Transitional Cell/pathology
15.
Microbiome ; 12(1): 89, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745230

ABSTRACT

BACKGROUND: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. RESULT: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. CONCLUSION: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. Video Abstract.


Subject(s)
Dietary Fiber , Dietary Supplements , Gastrointestinal Microbiome , Inulin , Mice, Inbred C57BL , Psyllium , Urinary Bladder Neoplasms , Animals , Mice , Gastrointestinal Microbiome/drug effects , Inulin/administration & dosage , Urinary Bladder Neoplasms/radiotherapy , Urinary Bladder Neoplasms/pathology , Humans , Female , Radiation Injuries/prevention & control , Intestines/microbiology , Intestines/radiation effects , CD8-Positive T-Lymphocytes
16.
Int J Mol Sci ; 25(9)2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38731992

ABSTRACT

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.


Subject(s)
BCG Vaccine , Immunotherapy , Macrophages , Neoplasm Recurrence, Local , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Tumor Microenvironment/immunology , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Male , BCG Vaccine/therapeutic use , Neoplasm Recurrence, Local/immunology , Female , Immunotherapy/methods , Aged , Middle Aged , Macrophages/immunology , Macrophages/metabolism , Carcinoma, Papillary/pathology , Carcinoma, Papillary/immunology , Carcinoma, Papillary/therapy , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Prognosis , Aged, 80 and over
17.
Int J Mol Sci ; 25(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38732087

ABSTRACT

Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.


Subject(s)
Deoxycytidine , Gemcitabine , Light , Riboflavin , Urinary Bladder Neoplasms , Humans , Riboflavin/pharmacology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Oxidative Stress/drug effects , Cell Survival/drug effects , Cell Survival/radiation effects , Lipid Peroxidation/drug effects , Adenosine Triphosphate/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/radiation effects , Blue Light
18.
Cell Mol Biol Lett ; 29(1): 66, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38724931

ABSTRACT

The development of compact CRISPR systems has facilitated delivery but has concurrently reduced gene editing efficiency, thereby limiting the further utilization of CRISPR systems. Enhancing the efficiency of CRISPR systems poses a challenging task and holds significant implications for the advancement of biotechnology. In our work, we report a synthetic dual-antibody system that can stably exist in the intracellular environment, specifically inhibiting the functions of NF-κB and ß-catenin. This not only elevates the transgenic expression of the CRISPR system by suppressing the innate immune response within cells to enhance the gene editing efficiency but also demonstrates a notable tumor inhibitory effect. Based on the specific output expression regulation of CRISPR-CasΦ, we constructed a CRISPR-based gene expression platform, which includes sensor modules for detecting intracellular ß-catenin and NF-κB, as well as an SDA module to enhance overall efficiency. In vitro experiments revealed that the CRISPR-based gene expression platform exhibited superior CDK5 expression inhibition efficiency and specific cytotoxicity towards tumor cells. In vitro experiments, we found that CRISPR-based gene expression platforms can selectively kill bladder cancer cells through T cell-mediated cytotoxicity. Our design holds significant assistant potential of transgene therapy and may offer the capability to treat other diseases requiring transgene therapy.


Subject(s)
CRISPR-Cas Systems , Gene Editing , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/metabolism , Humans , CRISPR-Cas Systems/genetics , Cell Line, Tumor , Gene Editing/methods , beta Catenin/metabolism , beta Catenin/genetics , NF-kappa B/metabolism , NF-kappa B/genetics , Gene Expression/genetics , Gene Expression Regulation, Neoplastic , Clustered Regularly Interspaced Short Palindromic Repeats/genetics
20.
Investig Clin Urol ; 65(3): 202-216, 2024 May.
Article in English | MEDLINE | ID: mdl-38714511

ABSTRACT

PURPOSE: With the recent rising interest in artificial intelligence (AI) in medicine, many studies have explored the potential and usefulness of AI in urological diseases. This study aimed to comprehensively review recent applications of AI in urologic oncology. MATERIALS AND METHODS: We searched the PubMed-MEDLINE databases for articles in English on machine learning (ML) and deep learning (DL) models related to general surgery and prostate, bladder, and kidney cancer. The search terms were a combination of keywords, including both "urology" and "artificial intelligence" with one of the following: "machine learning," "deep learning," "neural network," "renal cell carcinoma," "kidney cancer," "urothelial carcinoma," "bladder cancer," "prostate cancer," and "robotic surgery." RESULTS: A total of 58 articles were included. The studies on prostate cancer were related to grade prediction, improved diagnosis, and predicting outcomes and recurrence. The studies on bladder cancer mainly used radiomics to identify aggressive tumors and predict treatment outcomes, recurrence, and survival rates. Most studies on the application of ML and DL in kidney cancer were focused on the differentiation of benign and malignant tumors as well as prediction of their grade and subtype. Most studies suggested that methods using AI may be better than or similar to existing traditional methods. CONCLUSIONS: AI technology is actively being investigated in the field of urological cancers as a tool for diagnosis, prediction of prognosis, and decision-making and is expected to be applied in additional clinical areas soon. Despite technological, legal, and ethical concerns, AI will change the landscape of urological cancer management.


Subject(s)
Artificial Intelligence , Urologic Neoplasms , Humans , Urologic Neoplasms/therapy , Prostatic Neoplasms/therapy , Kidney Neoplasms , Urinary Bladder Neoplasms/therapy , Male , Medical Oncology/methods , Deep Learning , Machine Learning
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