• DLGAP5
• MYC
• bladder cancer
• chemoresistance
• glycolysis

• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/genetics
• Humans
• Animals
• Drug Resistance, Neoplasm
• Glycolysis/drug effects
• Proto-Oncogene Proteins c-myc/metabolism
• Proto-Oncogene Proteins c-myc/genetics
• Mice
• Cell Line, Tumor
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Gemcitabine
• Protein Stability
• Xenograft Model Antitumor Assays
• Ubiquitination
• Gene Expression Regulation, Neoplastic

• bladder cancer
• chemotherapy
• drug delivery
• nanoparticle
• phototherapy
• toxicity

• Humans
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/therapy
• Nanoparticles/chemistry
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/administration & dosage
• Drug Delivery Systems/methods
• Animals
• Immunotherapy/methods
• Genetic Therapy/methods
• Nanoparticle Drug Delivery System/chemistry

• acute kidney injury
• cisplatin
• hypoalbuminemia
• meta-analysis
• retrospective study

• bladder cancer
• cell invasiveness
• chemoresistance
• hyperthermia
• immunosuppression

• Humans
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/immunology
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/therapy
• Drug Resistance, Neoplasm/drug effects
• Neoplasm Invasiveness
• Hyperthermia, Induced/methods
• Cell Movement/drug effects
• Cell Line, Tumor
• Killer Cells, Natural/immunology
• Killer Cells, Natural/drug effects
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• Immune Evasion
• Cell Survival/drug effects

• M2 macrophage
• SPARCL1
• bladder cancer
• immune infiltration
• prognosis

• Humans
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/immunology
• Calcium-Binding Proteins/metabolism
• Calcium-Binding Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Extracellular Matrix Proteins/metabolism
• Extracellular Matrix Proteins/genetics
• Cell Proliferation/genetics
• Prognosis
• Cell Line, Tumor
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Cell Movement/genetics
• Female
• Male
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Receptors, Cell Surface
• Antigens, Differentiation, Myelomonocytic
• Antigens, CD

• 2022507093 Zhejiang Medical Science and Technology Project
• 2024KY230 Zhejiang Medical Science and Technology Project
• A20210162 Hangzhou Health and Technology Project
• ZD20210043 Hangzhou Health and Technology Project

• Bladder cancer
• Immunogenic cell death
• Nomogram
• TCGA
• Tumor Immune Microenvironment
• lncRNAs

• 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
• Gene Expression Regulation, Neoplastic
• Immunogenic Cell Death
• Female
• Male
• Biomarkers, Tumor/genetics
• Gene Expression Profiling
• Middle Aged
• ROC Curve
• Aged
• Kaplan-Meier Estimate

• SKJP＿220202675 Science and Technology Plan of Jiangxi Health Commission

• Bioinformatics
• Bladder cancer
• Disulfidptosis
• Immune microenvironment
• Prognosis signature
• Tumor subgroups

• 18FDG-PET/CT
• Metastatic bladder cancer
• Positron emission tomography computed tomography
• Response to chemotheraphy

• DNA fragmentation
• Leonotis ocymifolia
• antioxidant
• nephroprotective
• oxidative stress

• Cancer
• Canine model
• Disease
• Precision medicine
• Tumor

• Animals
• Carcinogenesis
• Dog Diseases/drug therapy
• Dogs
• High-Throughput Nucleotide Sequencing
• Humans
• Neoplasms/therapy
• Precision Medicine

Cisplatin (CP) is a conventional chemotherapeutic agent with serious adverse effects. Its toxicity was linked to the stimulation of oxidative stress and inflammation. As a result, this study explored the protective effect of baicalein and alpha-tocopherol in nephrotoxicity induced by cisplatin. Until receiving an intraperitoneal injection of CP (3 mg/kg BW), rats were given baicalein orally 100 mg/kg for seven days or/and a single intraperitoneal injection of α-tocopherol 250 mg/kg. Renal function was tested to explore whether baicalein and α-tocopherol have any beneficial effects; blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) content, antioxidant activity biomarkers and histopathology of renal tissue, oxidative stress biomarkers, inflammatory response markers, and histopathological features of kidney architecture were measured. Cisplatin treatment resulted in extreme renal failure, as measured by high serum creatinine and BUN levels and severe renal changes. Cisplatin therapy resulted in increased lipid peroxidation and decreased glutathione and superoxide dismutase levels, reflecting oxidative stress. Upon treatment with α-tocopherol, baicalein, and combined therapy, there was augmentation in the antioxidant status as well as a reduction in IL-6, NF-κB, TNF, TLR2, and TLR4 and a significant increase in Keap-1 and NRF-2. The combined treatment was the most effective and the nearest to the normal status. These findings suggest that baicalein and α-tocopherol may be useful in preventing cisplatin-induced nephrotoxicity.

Bladder cancer remains one of the most common forms of cancer and yet there are limited small molecule targeted therapies. Here, we present a computational platform to identify new potential targets for bladder cancer therapy. Our method initially exploited a set of known driver genes for bladder cancer combined with predicted bladder cancer genes from mutationally enriched protein domain families. We enriched this initial set of genes using protein network data to identify a comprehensive set of 323 putative bladder cancer targets. Pathway and cancer hallmarks analyses highlighted putative mechanisms in agreement with those previously reported for this cancer and revealed protein network modules highly enriched in potential drivers likely to be good targets for targeted therapies. 21 of our potential drug targets are targeted by FDA approved drugs for other diseases — some of them are known drivers or are already being targeted for bladder cancer (FGFR3, ERBB3, HDAC3, EGFR). A further 4 potential drug targets were identified by inheriting drug mappings across our in-house CATH domain functional families (FunFams). Our FunFam data also allowed us to identify drug targets in families that are less prone to side effects i.e., where structurally similar protein domain relatives are less dispersed across the human protein network. We provide information on our novel potential cancer driver genes, together with information on pathways, network modules and hallmarks associated with the predicted and known bladder cancer drivers and we highlight those drivers we predict to be likely drug targets.

• CATH-FunFams
• bladder cancer
• drug side effects
• drug targets
• protein interaction network

Cisplatin (cis-diaminedichloroplatinum, CDDP) is a broad-spectrum antineoplastic agent. However, CDDP has been blamed for its nephrotoxicity, which is the main dose-limiting adverse effect. Ganoderma lucidum (GL), a medicinal mushroom, has antioxidant and inflammatory activities. Therefore, this study is aimed at finding out the potential nephroprotection of GL against CDDP-induced nephrotoxicity in rats and the possible molecular mechanisms including the EGFR downstream signaling, apoptosis, and autophagy.

Rats were given GL (500 mg/kg) for 10 days and a single injection of CDDP (12 mg/kg, i.p).

Nephrotoxicity was evidenced by a significant increase in renal indices and oxidative stress markers. Additionally, CDDP showed a plethora of inflammatory and apoptotic responses as evidenced by a profound increase of HMGB-1, NF-κB, and caspase-3 expressions, whereas administration of GL significantly improved all these indices as well as the histopathological insults. Renal expression of EGFR showed a similar trend after GL administration. Furthermore, activation of autophagy protein, LC3 II, was found to be involved in GL-mediated nephroprotection correlated with the downregulation of apoptotic signaling, caspase-3 and terminal deoxynucleotidyl transferase (TDT) renal expressions.

These results suggest that GL might have improved CDDP-induced nephrotoxicity through antioxidant, anti-inflammatory, and autophagy-mediated apoptosis mechanisms and that inhibition of EGFR signaling might be involved in nephroprotection.

Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.

• Alzheimer’s disease
• anticancer drug
• disease modifying anti-rheumatic drug
• immunosuppressive drug
• methotrexate
• myasthenia gravis

• Autoimmune Diseases/drug therapy
• Folic Acid/metabolism
• Humans
• Methotrexate/chemistry
• Methotrexate/therapeutic use
• Neoplasms/drug therapy
• Nervous System Diseases/drug therapy
• Pharmaceutical Preparations/chemistry

• Cisplatin
• Growth hormone
• HMGB-1
• HO-1
• IGF-1
• Keap1
• Nephrotoxicity
• Nrf2

Background: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) have been the first-line treatments for advanced or metastatic urothelial carcinoma (AMUC). However, their effects are unsatisfactory, and more drugs and regimens still need to be explored.

Objective: We aimed to comprehensively compare all possible regimens with GC or MVAC in randomized controlled trials (RCTs) by network meta-analysis.

Methods: We searched the PubMed, Embase, and Cochrane databases for RCTs that evaluated regimens compared to GC or MVAC on AMUC patients. The major outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). A network meta-analysis was used to assess the effectiveness and safety of the included treatment regimens, and the regimens were then clustered by the average linkage method.

Results: A total of 19 trials that assessed 3,363 AMUC patients were included. For PFS, paclitaxel plus GC (PGC) was significantly superior to GC (log hazard ratio (HR): −0.16; 95% confidence interval (CI): −0.32, 0.00) with a moderate level of reliability. However, there was no significant difference between PGC and MVAC (log HR: −0.03; 95% CI: −0.27, 0.20). For OS, PGC was significantly superior to GC (log HR:−0.17; 95% CI: −0.33, −0.00) with a moderate reliability level but not significantly different from MVAC (log HR: −0.10; 95% CI: −0.35, 0.15). Analysis of ORR showed that PGC was superior to MVAC (log odds ratio (OR): 0.59; 95% CI: 0.02, 1.16) with a low reliability level and GC (log OR: 0.41; 95% CI: 0.12, 0.71) with a moderate reliability level. In the cluster results, PGC and sorafenib plus GC (GCS) exhibited relative advantages in efficiency, followed by MVAC and apatorsen plus GC (GCA); however, PGC, gemcitabine plus carboplatin (GP), and MVAC had more serious side effects.

Conclusions: In our analysis, PGC was superior to MVAC and GC in only the ORR results and superior to GC in the OS and PFS results but was not significantly different from MVAC. More individualized therapies with targeted drugs need to be studied.

• advanced
• bladder cancer
• meta-analysis
• metastatic
• treatment
• urothelial carcinoma

There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breed-associated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.

• animal models
• bladder cancer
• cancer prevention
• dog
• immunotherapy
• targeted therapy
• transitional cell carcinoma
• urothelial carcinoma

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

• acute kidney injury
• cisplatin nephrotoxicity
• kidney injury molecule-1

The current chemotherapy regimens may extend survival for patients with metastatic bladder cancer (BCa) for a few months, but eventually most patients succumb to disease because they develop resistance to their chemotherapy.

TCGA human clinical sample survey and urothelial tumor tissue microarrays (TMAs) were applied to investigate the expression of androgen receptor (AR) and NF-κB. Multiple BCa cell lines were used to test chemotherapy’s efficacy via multiple assays including XTT, flow cytometry, TUNEL, and BrdU incorporation. The effects of the AR degradation enhancer, ASC-J9®, combined with various chemotherapy reagents were examined both in vivo and in vitro.

We unexpectedly found that in muscle-invasive BCa (miBCa) the signals of both the AR and NF-κB were increased via a TCGA sample survey. Results from multiple approaches revealed that targeting these two increased signals by combining various chemotherapeutic agents, including Cisplatin, Doxorubicin or Mitomycin C, with ASC-J9® led to increase the therapeutic efficacy. The combined therapy increases the expression of the pro-apoptosis BAX gene and cell cycle inhibitor p21 gene, yet suppresses the expression of the pro-survival BCL2 gene in miBCa cells. Preclinical studies using an in vivo mouse model with xenografted miBCa cells confirmed in vitro cell line data showing that treatment with ASC-J9® combined with Cisplatin can result in suppressing miBCa progression better than Cisplatin alone.

Together, these results support a novel therapeutic approach via combining Cisplatin with ASC-J9® to better suppress the progression of miBCa.

The online version of this article (10.1186/s13046-019-1258-0) contains supplementary material, which is available to authorized users.

• ASC-J9®
• Androgen receptor
• Bladder cancer
• Cisplatin
• NF-κB

Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury (AKI) which develop due to renal accumulation and biotransformation of CDDP. The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients. However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients.

In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity. Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects.

Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity.

• Acute kidney injury
• Apoptosis
• Cisplatin
• Inflammation
• Nephrotoxicity

• BTCC
• LNR
• bladder transitional cell carcinoma
• cancer-specific survival
• lymph node ratio
• nomogram

• hla-f adjacent transcript 10
• epithelial to mesenchymal transition
• cancer initiating cells
• cisplatin resistance
• bladder cancer

• Adult
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• Cisplatin/administration & dosage
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Oncogene Proteins/biosynthesis
• Survival Rate
• Ubiquitins/biosynthesis
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/mortality

• Adenocarcinoma
• Drug therapy
• Urinary bladder

• Adenocarcinoma/diagnostic imaging
• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Palliative Care
• Retrospective Studies
• Treatment Outcome
• Urinary Bladder Neoplasms/drug therapy
• Young Adult

Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.

• Bladder cancer
• Chemotherapy
• Cisplatin eligibility
• Cisplatin toxicity
• Renal function

• P30 CA014089 NCI NIH HHS

• Bladder cancer
• gemcitabine
• maintenance therapy
• metastasis

We previously identified 1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone (IPP51), a new chalcone derivative that is capable of inducing prometaphase arrest and subsequent apoptosis of bladder cancer cells. Here, we demonstrate that IPP51 selectively inhibits proliferation of tumor-derived cells versus normal non-tumor cells. IPP51 interfered with spindle formation and mitotic chromosome alignment. Accumulation of cyclin B1 and mitotic checkpoint proteins Bub1 and BubR1 on chromosomes in IPP51 treated cells indicated the activation of spindle-assembly checkpoint, which is consistent with the mitotic arrest. The antimitotic actions of other chalcones are often associated with microtubule disruption. Indeed, IPP51 inhibited tubulin polymerization in an in vitro assay with purified tubulin. In cells, IPP51 induced an increase in soluble tubulin. Furthermore, IPP51 inhibited in vitro capillary-like tube formation by endothelial cells, indicating that it has anti-angiogenic activity. Molecular docking showed that the indol group of IPP51 can be accommodated in the colchicine binding site of tubulin. This characteristic was confirmed by an in vitro competition assay demonstrating that IPP51 can compete for colchicine binding to soluble tubulin. Finally, in a human bladder xenograft mouse model, IPP51 inhibited tumor growth without signs of toxicity. Altogether, these findings suggest that IPP51 is an attractive new microtubule-targeting agent with potential chemotherapeutic value.

• antitumor agent
• bladder cancer
• flavonoid
• microtubule inhibitor
• mitosis

• Radiation therapy
• Sciurus carolinensis
• squirrel
• transitional cell carcinoma
• urethra

• MLK3
• NF-κB
• bladder urothelial carcinoma
• miR-199a-5p

• Antimetabolites, Antineoplastic/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Drug Screening Assays, Antitumor
• Gene Expression/drug effects
• Humans
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/metabolism
• Gemcitabine

• adjuvant chemotherapy
• lymph node positive
• radical nephroureterectomy
• survival
• upper tract urothelial carcinoma

• Adhesion
• Anabolic
• Androgen
• Migration
• Urothelial carcinoma cell
• Urothelial cell

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Comparative Genomic Hybridization
• Disease Progression
• Drug Resistance, Multiple
• Female
• Genes, Retinoblastoma
• Genes, p53
• Humans
• In Situ Hybridization, Fluorescence
• Karyotyping
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/pathology