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 (p < 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.

A real-world analysis of FDA Adverse Event Reporting System (FAERS) events for liposomal and conventional doxorubicins.

The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.

Pyrrole-Doped Polydopamine-Pyrrole (PDA-nPY) Nanoparticles with Tunable Size and Improved NIR Absorption for Photothermal Therapy.

Polydopamine (PDA) as a melanin-like biomimetic material with excellent biocompatibility, full spectrum light absorption capacity and antioxidation property has been extensively applied in the biomedical field. Based on the high reactivity of dopamine (DA), exploiting new strategies to fabricate novel PDA-based nano-biomaterials with controllable size and improved performance is valuable and desirable. Herein, we reported a facile way to synthesize pyrrole-doped polydopamine-pyrrole nanoparticles (PDA-nPY NPs) with tunable size and enhanced near-infrared (NIR) absorption capacity through self-oxidative polymerization of DA with PY in an alkaline ethanol/H2O/NH4OH solution. The PDA-nPY NPs maintain excellent biocompatibility and surface reactivity as PDA. By regulating the volume of added PY, PDA-150PY NPs with a smaller size (<100 nm) and four-fold higher absorption intensity at 808 nm than that of PDA can be successfully fabricated. In vitro and in vivo experiments effectively further demonstrate that PDA-150PY NPs can effectively inhibit tumor growth and completely thermally ablate a tumor. It is believed that these PY doped PDA-nPY NPs can be a potential photothermal (PT) agent in biomedical application.

Poly(norepinephrine)-coated FeOOH nanoparticles as carriers of artemisinin for cancer photothermal-chemical combination therapy.

The photothermal-chemical combination therapy is a promising approach for cancer treatment, however, chemotherapy often causes severe toxic and side effects on normal tissues. Herein, tumor-specific FeOOH@PNE-Art nanoparticles were fabricated via coating poly(norepinephrine) (PNE) on FeOOH nanoparticles, followed by loading of artemisinin (Art). The as-prepared nanoparticles exhibited excellent biocompatibility, strong near-infrared (NIR) absorbance and pH-responsive synchronous release of Art and iron ions. The released iron ions could not only supply iron ions in cancer cells which mediate endoperoxide bridge cleavage of Art and generate reactive oxygen species (ROS), but also react with H2O2 at tumour sites via the Fenton reaction and produce hydroxyl radicals, inducing a tumour-specific killing. Moreover, owing to the synchronous release of Art and iron ions as well as the low leakage of iron ions, FeOOH@PNE-Art nanoparticles showed extremely low toxicity to normal tissue. Under NIR light irradiation, the tumours in FeOOH@PNE-Art injected mice were thoroughly eliminated after 7 days of treatment and no tumour recurrence was found 30 days after treatment, manifesting very high efficacy of combination therapy.

Fe3O4-Based Multifunctional Nanospheres for Amplified Magnetic Targeting Photothermal Therapy and Fenton Reaction.

Multifunctional nanoplatforms have attracted the interests of many scientists because they can achieve better therapeutic effect in the combined treatment of cancer. A novel cancer therapeutic strategy which combines an Fe3O4-based in vivo Fenton reaction with polypyrrole (PPy)-based photothermal therapy (PTT) was proposed. The multifunctional nanocomposite was comprised of Fe3O4 as the core, PPy as the shell, and polyethylene glycol. PPy could absorb near-infrared (NIR) light strongly and convert it into heat for tumor photothermal ablation, and Fe3O4 NPs were used as a target component to guide the nanoparticles to the tumor site under an external magnetic field. It was found that the PPy coating could be used not only for inducing PTT to ablate tumor cells but also for promoting Fe2+/3+ release from Fe3O4 nanoparticles. In vitro cell experiments confirmed that the increased Fe2+/3+ release could effectively enhance the Fe3O4-based Fenton reaction, which catalyzed the conversion of H2O2 into a highly toxic hydroxyl radical (•OH), thus inducing tumor cell apoptosis. Furthermore, our experiments also showed that the PPy coating could generate a photothermal effect to kill 4T1 tumor cells under NIR light exposure but did no harm to normal cells in the dark. Under the guidance of the magnet, we found Fe3O4@PPy-PEG (Fe3O4@P-P) nanoparticles could effectively enrich in the tumor site, and the therapeutic effect from PTT and the photothermal strengthened Fenton reaction was also verified in vivo. It is confirmed for the first time that the photothermal effect could promote the release of iron ions from Fe3O4 under acid conditions and enhance the Fenton reaction. Therefore, the Fe3O4@P-P nanoparticles, combined with the Fenton reaction and photothermal effect, and obviously the magnetic targeting and magnetic resonance imaging ability, are able to be a candidate for novel tumor theranostic agents.

Functionalized poly(pyrrole-3-carboxylic acid) nanoneedles for dual-imaging guided PDT/PTT combination therapy.

Herein, poly(pyrrole-3-carboxylic acid) (PPyCOOH) nanoneedles with abundant carboxyl groups were synthesized by aqueous dispersion polymerization method using pyrrole-3-carboxylic acid as conductive polymer monomer. The PPyCOOH nanoneedles not only owned good photothermal performance, but also more importantly showed enhanced tumor cell uptake efficiency (1.64 fold) compared with size and zeta-potential matched nanospheres. After loading photosensitizer aluminum phthalocyanine tetrasulfonate (AlPCS4) and modifying with poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA) onto the PPyCOOH nanoneedles, novel nanoneedle complexes (AlPCS4@PPyCONH-PAH-PAA) integrating photodynamic therapy (PDT) and photothermal therapy (PTT) were successfully fabricated. The as-prepared nanoneedle complexes improved uptake efficiency of AlPCS4 both in vitro and in vivo. Moreover, the nanoneedle complexes have infrared thermal and fluorescent properties. By combined PDT/PTT under the guiding of dual modal imaging, the tumors in mice were completely eliminated and no recurrence was observed in 30 days after treatment, indicating that PPyCOOH nanoneedles have great potential as a novel drug carrier for constructing multifunctional nanoplatform used for cancer treatment.

BSA-modified poly(pyrrole-3-carboxylic acid) nanoparticles as carriers for combined chemo-photothermal therapy.

A facile reverse microemulsion method was developed for the synthesis of homogenous poly(pyrrole-3-carboxylic acid) (PPyCOOH) nanoparticles, which used n-heptane as the oil phase, sodium dodecyl sulfate as the surfactant, 1-butanol as the co-surfactant and pyrrole-3-carboxylic solution as the aqueous phase. The obtained PPyCOOH nanoparticles had uniform sizes, high near-infrared absorption and abundant functional groups. To improve their stability and enhance the tumor inhibition rate, the PPyCOOH nanoparticles were modified with bovine serum albumin (BSA) and doxorubicin (DOX). The as-fabricated drug delivery system (DOX@BSA-PPyCOOH) combining photothermal therapy and chemotherapy exhibited pH-sensitive and near infrared laser controlled drug release, which was beneficial for drug enrichment in the tumor and for reducing the toxicity and side effects in normal tissue. Combined chemo-photothermal therapy in vivo revealed that the tumors were completely eliminated and no obvious toxicity was found in the major organs, suggesting that DOX@BSA-PPyCOOH nanoparticles are an efficient nanoagent for cancer treatment.

Polydopamine-functionalized nanographene oxide: a versatile nanocarrier for chemotherapy and photothermal therapy.

For releasing both drug and heat to selected sites, a combination of chemotherapy and photothermal therapy in one system is a more effective way to destroy cancer cells than monotherapy. Graphene oxide (GO) with high drug-loading efficiency and near-infrared (NIR) absorbance has great potential in drug delivery and photothermal therapy, but it is difficult to load drugs with high solubility. Herein, we develop a versatile drug delivery nanoplatform based on GO for integrated chemotherapy and photothermal therapy by a facile method of simultaneous reduction and surface functionalization of GO with poly(dopamine) (PDA). Due to the excellent adhesion of PDA, both low and high solubility drugs can be encapsulated in the PDA-functionalized GO nanocomposite (rGO-PDA). The fabricated nanocomposite exhibits good biocompatibility, excellent photothermal performance, high drug loading capacity, an outstanding sustained release property, and efficient endocytosis. Moreover, NIR laser irradiation facilitates the release of loaded drugs from rGO-PDA. These features make the rGO-PDA nanocomposite achieve excellent in vivo synergistic antitumor therapeutic efficacy.

A phase I clinical trial of dose escalation of lobaplatin in combination with fixed-dose docetaxel for the treatment of human solid tumours that had progressed following chemotherapy.

In this study, the maximum tolerated dose (MTD) of lobaplatin (LBP) when it was combined with docetaxel (TXT) for the treatment of solid tumours that had progressed following chemotherapy was determined, and toxicities to this regimen were evaluated. A modified Fibonacci method was used for the dose escalation of LBP. The patients received TXT (at a fixed dose of 60 mg/m2) on day one (d1) and LBP (at an initial tested dose of 30 mg/m2) on day two (d2) of a treatment cycle that was repeated every 21 days. Each dose group consisted of at least three cases. In the absence of dose-limiting toxicity (DLT), we proceeded to the next dose group, with a dose increment of 5 mg/m2 between groups, until DLT occurred. The dose immediately below the dose that produced DLT was regarded as the MTD. The 17 patients examined in this study completed a total of 58 cycles of chemotherapy, and a total of three dose-escalation groups (30 mg/m2 LBP, 35 mg/m2 LBP, and 40 mg/m2 LBP) were established. The main adverse event that was observed was myelosuppression. DLT occurred in four patients, including three patients in the 40 mg/m2 LBP group and one patient in the 35 mg/m2 LBP group. In total, three out of the four patients in the 40 mg/m2 LBP group exhibited DLT. We determined that the treatment administered to the 35 mg/m2 LBP group represented the MTD. Thus, our phase I trial revealed that the MTD for the tested LBP combination regimen was 35 mg/m2 LBP and 60 mg/m2 TXT. This regimen resulted in mild adverse reactions and favourable patient tolerance. Therefore, we recommend the use of these dosages in phase II clinical trials.

Sequence polymorphisms in the D-loop region of mitochondrial DNA and outcome of non-Hodgkin lymphoma.

Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) might be associated with cancer risk and disease outcome. We have identified 140 SNPs including 26 SNPs with frequency distribution of minor allele greater than 5% in a case-control study for non-Hodgkin lymphoma patients previously. In this study, we assessed the predictive power of D-loop SNPs in NHL patients. Five SNP sites were identified by log-rank test for statistically significant prediction of NHL survival in a univariate analysis. In an overall multivariate analysis, allele 16304 was identified as an independent predictor of NHL outcome. The survival time of NHL patients with 16304C was significantly shorter than that of patients with 16304T (relative risk, 0.513; 95% CI, 0.266-0.989; p = 0.046). The analysis of genetic polymorphisms in the mitochondrial D-loop can help identify subgroups of patients who are at a high risk of a poor disease outcome.

Prognostic value of microRNA 502 binding site SNP in the 3'-untranslated region of the SET8 gene in patients with non-Hodgkin's lymphoma.

AIMS AND BACKGROUND: A number of important cancer-associated covalent modifications of histone genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3'-untranslated regions. We evaluated the effect of single-nucleotide polymorphisms (SNPs) at the miR-502 binding site in the 3'-untranslated region of the SET8 gene on the clinical outcome of non-Hodgkin's lymphomas (NHL). METHODS AND STUDY DESIGN: The miR-502 binding site SNP of rs16917496 in the 3'-untranslated region of SET8 was genotyped with the ligation detection reaction method. The association of rs16917496 with NHL survival was calculated with the log-rank test using the Kaplan-Meier method. Multivariate survival analysis was performed using a Cox proportional hazards model. RESULTS: Patients carrying the rs16917496 CC genotype had a significantly longer survival time than patients carrying the CT genotype (P = 0.043) or TT genotype (P = 0.086). In addition, rs16917496 was associated independently with the survival of NHL patients in multivariate analysis (CC vs TT, 95% CI: 1.021-3.279, RR: 1.829, P = 0.043; CC vs CT, 95% CI: 1.026-3.339, RR: 1.851, P = 0.041). The association of rs16917496 with NHL survival was further identified in the peripheral T cell lymphoma (pTCL) subtype of NHL at borderline statistically significant levels (P = 0.069). CONCLUSION: Our study provides evidence that the SNP in the miRNA binding site of the SET8 3'-untranslated region seems to influence survival of NHL. It may have possible prognostic and survival value in the clinic.

High-dose 3-dimensional conformal radiotherapy with concomitant vinorelbine plus carboplatin in patients with non-small cell lung cancer: A feasibility study.

The aim of this study was to evaluate the feasibility of high-dose 3-dimensional conformal radiotherapy (3DCRT) (70 Gy) with concomitant vinorelbine (NVB) plus carboplatin (CBP) chemotherapy in patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with 3-dimensional conformal radiotherapy in conventional fractionation: 2 Gy/fraction, 1 fraction/day, 5 fractions/week; total dose 70 Gy. The radiotherapy planning of every case had met the following conditions: the percentage of total lung volume receiving 20 Gy (V20) ≤30% and the percentage of total lung volume receiving 30 Gy (V30) ≤20%. Chemotherapy was commenced on the first day of radiotherapy: NVB 25 mg/m(2), day 1 and day 8, CBP at AUC of 5 mg/ml(-1).min(-1), day 8, repeated for 28 days, two concomitant cycles during radiotherapy, and not more than 4 cycles following radiotherapy. A total of 37 patients were recruited and each of them completed the entire radiation procedure. No Grade V toxicity was observed within the group. The hematological toxicity rates were: Grade III/IV neutropenia was observed in 18.9% (7/37) of cases, Grade III/IV thrombocytopenia in 8.1% (3/37) of cases, but no cases of Grade III/IV anemia were noted. For non-hematological toxicities the rates were: Grade III radiation pneumonitis, 8.1% (3/37) of cases; Grade III radiation esophagitis, 13.5% (5/37); but no cases of Grade IV/V non-hematological toxicities. High-dose 3DCRT also achieved a favorable efficacy: the complete response (CR) rate was 13.5% (5/37) and the partial response (PR) rate was 64.9% (24/37). The total response (CR+PR) rate was 78.4% (29/37). The median survival time was 12 months and the 1-year overall survival rate was 45.1%. Given that 35% of patients in the study had stage IV disease, the survival results were comparable with other similar studies. In conclusion, in our small-sample exploratory study, the high-dose regimen of 70 Gy using 3DCRT with concomitant NVB plus CBP was feasible for patients with NSCLC. Further evaluation of this regimen is ongoing in a prospective controlled phase II trial.