Albumin-to-D-dimer ratios: A novel prognostic factor for evaluating first-line chemotherapy efficacy in advanced lung adenocarcinoma patients.

The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.

Mutations of key driver genes in gastric cancer metastasis risk: a systematic review and meta-analysis.

Objective: Associations between gene mutations and metastasis in gastric cancer (GC) remain contradictory, resulting in the inaccurate estimation of the magnitude of the risk associated with specific genotypes.Methods: In this study, we first screened out four key driver genes (TP53, PIK3CA, APC and ARID1A) by jointly analyzing the mutation levels and searching the literature for genes associated with GC metastasis. We then performed a meta-analysis to demonstrate the relationship between these key driver gene mutations and GC metastasis, including lymphatic and distance metastasis.Results: We found out four key driver genes (TP53, PIK3CA, APC and ARID1A), associated with risk of GC metastasis. The results showed that TP53 (OR 1.39, 95% CI 1.12-1.72) and APC mutations (OR 0.58, 95% CI 0.38-0.89) were associated with lymph node metastasis and distant metastasis in GC. And TP53 mutations (OR 1.65, 95% CI 1.25-2.18) were significantly related to GC metastasis in the Asian population. APC mutations (OR 0.54, 95% CI 0.29-1.00) were also related to GC metastasis in the European and American populations. There was no significant association with GC metastasis in PIK3CA or ARID1A mutations.Expert opinion:Mutations of TP53 and APC play important roles in lymph node metastasis and distant metastasis of GC and may be potential important biomarkers of progression and therapeutic targets. These observations should be further prospectively verified.

Prognostic Value of Albumin to D-Dimer Ratio in Advanced Gastric Cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. Notably, patients with advanced GC have a poor prognosis and quality of life, prompting the need for further studies on its prognostic markers. Among these, albumin and D-dimer are often used as prognostic factors in the prediction of a variety of tumors. Moreover, the albumin to D-dimer ratio (ADR) may be an improved predictor of chemotherapy effect and survival compared to albumin and D-dimer alone, but few studies have investigated this issue. Thus, we explored the relationship between pretreatment ADR and prognosis in advanced GC treated with first-line chemotherapy. A total of 247 advanced unresectable GC patients treated with first-line chemotherapy were retrospectively included. The cut-off value for ADR was determined using the receiver operating characteristic (ROC) curve. The ADR had a cut-off value of 41.64. Compared to albumin and D-dimer alone, ADR had the highest area under curve (AUC) value (AUC = 0.730), followed by albumin (AUC = 0.659) and D-dimer (AUC = 0.719). Additionally, we found that patients with a low ADR (<41.64) had a lower disease control rate (77.9% vs. 92.5%, P < 0.01), shorter overall survival (OS) (271 vs. 389 days), and shorter progression-free survival (PFS) (118 vs. 192 days) than patients with a high ADR (≥41.64). Similar results were also found on subgroup analysis, and ADR was found to be an independent advanced GC prognostic factor on multivariate analysis (all P < 0.001). Low ADR was found to be correlated with poor therapeutic effects of chemotherapy and shortened OS and PFS. Therefore, pretreatment ADR may be a useful tool for predicting the effect of chemotherapy and prognosis in advanced GC patients treated with first-line chemotherapy.

N6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1.

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin ß1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

Comparative Analysis and in vitro Experiments of Signatures and Prognostic Value of Immune Checkpoint Genes in Colorectal Cancer.

PURPOSE: Immune checkpoints, as pivotal regulators of immune escape in cancer, can motivate the emergence of immune checkpoint inhibitors (ICIs). The aim of this study is to identify the expression of the immune checkpoint genes (ICGs) in colorectal cancer (CRC) and to relate their individual as well as combined expression to prognosis and therapeutic effectiveness in CRC. METHODS: RNA expression of 47 ICGs and clinical information of CRC patients were collected from two public databases to elucidate the expression levels and prognostic values of these ICGs in CRC. Then, the Shapiro-Wilk normality test was used to determine the normality of variables. Overall survival (OS) rates of each subset were found by Kaplan-Meier method, and the statistical significance was determined by the Log rank test (p < 0.05). RESULTS: The expression of 13 and 9 ICGs was significantly associated with CRC prognosis in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. A series of ICGs was found to be significantly associated with TMB, neoantigens and MMR in CRC indicating that the combination of immunotherapy treatment biomarkers and ICGs may achieve accurate prognostic stratification of CRC, and potentially identify CRC cases that might respond to checkpoint inhibitors (CPIs). The subsets of high or low PD1/PD-L1/IDO1 expression stratified by CD48 were accurately associated with prognosis in CRC. In addition, in vitro experiments confirmed that VTCN1(B7-H4)-KD increases anti-PD-L1-mediated NK cell cytotoxicity on CRC tumor cells. CONCLUSION: Although the expression of a single immune-checkpoint molecule does not predict the efficacy of immunotherapy in CRC, our findings infer that subsets defined by ICGs are associated with prognosis and imply the possibility that VTCN1 and CD48 serve as new immunotherapeutic targets.

Succinylation Regulators Promote Clear Cell Renal Cell Carcinoma by Immune Regulation and RNA N6-Methyladenosine Methylation.

Succinylation is a newly discovered and multienzyme-regulated post-translational modification (PTM) that is associated with the initiation and progression of cancer. Currently, no systematic analyses on the role of succinylation regulators in tumors have been reported. In this study, we performed a comprehensive pan-cancer analysis on four well-known succinylation regulators (CPT1A, KAT2A, SIRT5, and SIRT7). We found that these regulators played specific and critical roles in the prognosis of clear cell renal cell carcinoma (ccRCC). We constructed a risk score (RS) based on two independent prognostic prediction factors, CPT1A and KAT2A, and subsequently developed a nomogram model containing the RS, which showed good accuracy in the prediction of overall survival (OS) in ccRCC patients. Furthermore, we used the similar expression pattern of four succinylation regulators according to consensus clustering analysis to divide the patients into three clusters that exhibited prominently different OS as well as clinicopathological characteristics. Differently expressed genes (DEGs) and pathway enrichment analyses of three clusters indicated that succinylation regulators might promote malignant progression of ccRCC by regulating the infiltration of immune cells and RNA N6-methyladenosine (m6A) methylation. Importantly, our data suggest that CPT1A and SIRT5 might up-regulate and down-regulate the expression of LRPPRC and EIF3B, respectively. Our study systematically analyzed the prognostic predictive values of four succinylation regulators and revealed their potential mechanisms in ccRCC aggressiveness. These data provide new insight into the understanding of succinylation modification and present clinical evidence for its role in ccRCC treatments.

Sodium to globulin ratio as a prognostic factor for patients with advanced gastric cancer.

Background: Electrolyte disturbance and systemic inflammation contributes to poor prognosis of cancer patients. Levels of serum sodium and globulin can reflect electrolyte homeostasis and inflammatory state, respectively, therefore have potential as prognostic factors for cancer patients. In this study, we hypothesized that sodium to globulin ratio (SGR) could have superior accuracy in predicting cancer patient survival, than sodium and globulin alone. We therefore sought to investigate its efficacy in prognosis of patients with advanced gastric cancer (GC) receiving first-line chemotherapy. Methods: A total of 265 patients, with advanced GC, were recruited in this retrospective study from January 2014 to January 2019. We first determined SGR cut-off values using the receiver operating characteristic (ROC) analysis, then analyzed the relationship between pretreatment SGR and clinicopathological features and the effect of chemotherapy. Finally, we evaluated progression-free survival (PFS) and overall survival (OS) rates of the entire and subgroup populations using univariate and multivariate logistic regressions. Results: SGR recorded a cut-off value of 5.54, and had a significantly higher area under the curve (AUC) value (0.619, p = 0.001) than fibrinogen (0.575, p = 0.034) and albumin (0.610, p = 0.002) alone. Organ metastasis, and peritoneal invasion ratios, as well as neutrophil and CA72-4 levels varied significantly between the low-SGR (SGR≤ 5.54) and high SGR (SGR> 5.54) groups (all p < 0.05). Specifically, patients in the low-SGR group exhibited significantly lower disease control rates (83.4%) than those in the high-SGR group (97.2%) (p < 0.001). Results from multivariate analysis indicated that high-SGR was an independent risk factor for PFS (Hazard ratio [HR]: 0.539, p < 0.001) and OS (HR: 0.574, p < 0.001). Moreover, patients in the low-SGR group exhibited significantly worse PFS (134 vs. 221 days, p < 0.001) and OS (311 vs. 420 days, p < 0.001) than those in the high-SGR group. Furthermore, subgroup analysis revealed that SGR was still a powerful prognostic indicator in GC patients with good prognosis or normal biochemical indexes, including no peritoneal infiltration, normal neutrophil counts, and normal serum sodium and globulin levels (all p < 0.001). Conclusions: Overall, our findings indicate that SGR is a novel and promising prognostic factor for GC patients. It has superior accuracy, to sodium and globulin alone, hence it is a powerful tool for evaluating effects of treatment, PFS, and OS in patients with advanced GC, who receive first-line chemotherapy.

Could microtubule inhibitors be the best choice of therapy in gastric cancer with high immune activity: mutant DYNC1H1 as a biomarker.

Immune checkpoint blockade (ICB) has achieved unprecedented breakthroughs in various cancers, including gastric cancer (GC) with high immune activity (MSI-H or TMB-H), yet clinical benefits from ICB were moderate. Here we aimed to identify the most appropriate drugs which can improve outcomes in GC. We firstly compared MSI-H and TMB-H GC samples with normal samples in TCGA-STAD cohort, respectively. After that, Connectivity Map database repurposed nine candidate drugs (CMap score < -90). Then, microtubule inhibitors (MTIs) were screened as the significant candidate drugs with their representative gene sets strongly enriched (p < 0.05) via GSEA. GDSC database validated higher activities of some MTIs in GC cells with MSI-H and TMB-H (p < 0.05). Furthermore, some MTIs activities were positively associated with mutant Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) (p < 0.05) based on NCI-60 cancer cell line panel. DYNC1H1 was high frequently alteration in GC and was positively associated with TMB-H and MSI-H. Mutant DYNC1H1 may be accompanied with down-regulation of MTIs-related genes in GC or change the binding pocket to sensitize MTIs. Overall, this study suggested that some MTIs may be the best candidate drugs to treat GC with high immune activity, especially patients with DYNC1H1 mutated.

Identification of prognostic chromatin-remodeling genes in clear cell renal cell carcinoma.

The aim of this study was to investigate the effects of chromatin-remodeling genes on the prognosis of patients with clear cell renal cell carcinoma (ccRCC). In TCGA-KIRC patients, two subgroups based on 86 chromatin-remodeling genes were established. The random forest algorithm was used for feature selection to identify BPTF, SIN3A and CNOT1 as characterized chromatin remodelers in ccRCC with good prognostic value. YY1 was indicated to be a transcription factor of genes highly related to BPTF, SIN3A and CNOT1. Functional annotations indicated that BPTF, SIN3A, CNOT1 and YY1 are all involved in the ubiquitin-mediated proteolysis process and that high expression of any of the five associated E3 ubiquitin ligases found in the pathway suggests a good prognosis. Protein network analysis indicated that BPTF has a targeted regulatory effect on YY1. Another independent dataset from International Cancer Genome Consortium (ICGC) showed a strong consistency with results in TCGA. In conclusion, we demonstrate that BPTF, SIN3A and CNOT1 are novel prognostic factors that predict good survival in ccRCC. We predicted that the good prognostic value of chromatin-remodeling genes BPTF and SIN3A is related to the regulation of YY1 and that YY1 regulates E3 ubiquitin ligases for further degradation of oncoproteins in ccRCC.

Prognostic value of fibrinogen-to-albumin ratio in patients with gastric cancer receiving first-line chemotherapy.

The fibrinogen-to-albumin ratio (FAR), reflecting the systemic coagulation, nutritional and inflammation status of patients, has matured into a prognostic marker for several tumor types. However, only a few studies have assessed the utility of the FAR as a prognostic indicator in patients with advanced gastric cancer (GC) receiving first-line chemotherapy. In the present study, 273 patients with advanced GC who received first-line chemotherapy between January 2014 and January 2019 at the Cancer Hospital of China Medical University (Shenyang, China) were retrospectively analyzed. Using the cut-off values determined by receiver operating characteristic (ROC) analysis, the patients were divided into low-FAR (≤10.03) and high-FAR (>10.03), low-fibrinogen (<3.8 g/l) and high-fibrinogen (≥3.8 g/l), and low-albumin (<40.55 g/l) and high-albumin (≥40.55 g/l) groups. The associations of the pretreatment FAR and clinicopathological characteristics with progression-free survival (PFS) and overall survival (OS) were evaluated. In order to estimate the prognostic value of the FAR for patients with poor prognosis or normal fibrinogen and albumin levels, subgroup analyses were performed. The FAR had a higher area under the ROC curve (0.690; 95% CI: 0.628-0.752; P<0.001) compared with either fibrinogen or albumin alone, which are common indicators of coagulation, nutritional and inflammatory indices. A high FAR was significantly associated with a more advanced stage, peritoneal metastasis, increased CA72-4 levels and anemia (all P<0.05). On survival analysis, a low FAR was associated with a longer PFS and OS compared with a high FAR (202 vs. 130 days and 376 vs. 270 days, respectively; both P<0.001), while the hazard ratio (HR) and P-values of the FAR were lower compared with those of fibrinogen and albumin alone on multivariate analysis (PFS: HR=0.638, 95% CI: 0.436-0.932, P=0.020; OS: HR=0.568, 95% CI: 0.394-0.819, P=0.002). Subgroup analysis indicated that among patients with poor prognosis, including multiple metastases, TNM stage IV and abnormal CA72-4 levels, the FAR may be used as an accurate prognostic marker (all P<0.05), and may also reliably identify patients with poor prognosis among those with normal fibrinogen and albumin levels (all P<0.001). The FAR was indicated to be a valuable marker for predicting PFS and OS in patients with advanced GC receiving first-line chemotherapy and is superior to either fibrinogen or albumin alone.

An Immune Cell Signature Is Associated With Disease-Free Survival and Adjuvant Chemosensitivity of Patients With Resectable Gastric Cancer.

Increasing evidence has indicated that current tumor-node-metastasis (TNM) stage alone cannot predict prognosis and adjuvant chemotherapy benefits accurately for stages II and III gastric cancer (GC) patients after surgery. In order to improve the predictive ability of survival and adjuvant chemotherapy benefits of GC patients after surgery, this study aimed to establish an immune signature based on the composition of infiltrating immune cells. Twenty-eight types of immune cell fractions were evaluated based on the expression profiles of GC patients from the Gene Expression Omnibus (GEO) database using single-sample gene set enrichment analysis (ssGSEA). The immunoscore (IS) was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression model. Through the LASSO model, an IS classifier consisting of eight immune cells was constructed. Significant difference was found between high-IS and low-IS groups in the training cohort in disease-free survival (DFS, P < 0.0001) and overall survival (OS, P < 0.0001). Multivariate analysis showed that the IS classifier was an independent prognostic indicator. Moreover, a combination of IS and TNM stage exhibited better prognostic value than TNM stage alone. Further analysis demonstrated that low-IS patients who had more tumor-infiltrating lymphocytes had better response to adjuvant chemotherapy. More importantly, we found that patients with high-IS were more likely to benefit from a Xeloda plus cisplatin regimen after surgery. Finally, we established two nomograms to screen the stage II and III GC patients who benefitted from adjuvant chemotherapy after surgery. The combination of IS classifier and TNM stage could predict DFS and OS of GC patients. The IS model has been proven as a promising tool that can be used to identify the patients with stages II and III GC who may benefit from adjuvant chemotherapy.

A nomogram based on a gene signature for predicting the prognosis of patients with head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors. The purpose of this study was to establish and validate a gene-expression-based prognostic signature in non-metastatic patients with HNSCC. MATERIALS AND METHODS: All the patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We randomly divided the GSE65858 samples into 70% (training cohort, n = 190) and 30% (internal validation cohort, n = 72). A total of 36 samples collected from the TCGA HNSCC databases were selected as an independent external validation cohort. The oligo package in R was used to normalize the raw data before analysis. Data characteristics were extracted, and a gene signature was built via the least absolute shrinkage and selection operator regression model. The predictive model was developed by multivariable Cox regression analysis. T stage, N stage, human papilloma virus status, and the gene signature were incorporated in this predictive model, which was shown as a nomogram. Calibration and discrimination were performed to assess the performance of the nomogram. The clinical utility of this nomogram was assessed by the decision curve analysis. RESULTS: Overall, 2001 significant messenger RNAs in HNSCC samples were identified compared with normal samples. The gene signature contained seven genes and significantly correlated with overall survival. The gene signature was also significant in subgroup analysis of the primary cohort. The calibration was plotted in the external cohort (C-index 0.90, 95% CI 0.85, 0.95) compared with the training (C-index 0.76, 95% CI 0.73, 0.79) and internal (C-index 0.71, 95% CI 0.66, 0.77) cohorts. In clinic, a decision curve analysis demonstrated that the model including the prognostic gene signature score status was better than that without it. CONCLUSION: This study developed and validated a predictive model, which can promote the individualized prediction of overall survival in non-metastatic patients with HNSCC.

FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling.

Flap endonuclease 1 (FEN1) is recognized as a pivotal factor in DNA replication, long-patch excision repair, and telomere maintenance. Excessive FEN1 expression has been reported to be closely associated with cancer progression, but the specific mechanism has not yet been explored. In the present study, we demonstrated that FEN1 promoted breast cancer cell proliferation via an epigenetic mechanism of FEN1-mediated up-regulation of DNA methyltransferase (DNMT)1 and DNMT3a. FEN1 was proved to interact with DNMT3a through proliferating cell nuclear antigen (PCNA) to suppress microRNA (miR)-200a-5p expression mediated by methylation. Furthermore, miR-200a-5p was identified to repress breast cancer cell proliferation by inhibiting the expression of its target genes, hepatocyte growth factor (MET), and epidermal growth factor receptor (EGFR). Overall, our data surprisingly demonstrate that FEN1 promotes breast cancer cell growth via the formation of FEN1/PCNA/DNMT3a complex to inhibit miR-200a expression by DNMT-mediated methylation and to recover the target genes expression of miR-200a, MET, and EGFR. The novel epigenetic mechanism of FEN1 on proliferation promotion provides a significant clue that FEN1 might serve as a predictive biomarker and therapeutic target for breast cancer.-Zeng, X., Qu, X., Zhao, C., Xu, L., Hou, K., Liu, Y., Zhang, N., Feng, J., Shi, S., Zhang, L., Xiao, J., Guo, Z., Teng, Y., Che, X. FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling.

NPTX1 promotes metastasis via integrin/FAK signaling in gastric cancer.

PURPOSE: This study aimed to investigate the effect of NPTX1 on the prognosis of gastric cancer (GC), as well as the metastatic process in GC. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the association between NPTX1 expression and prognosis in GC. Quantitative real-time polymerase chain reaction and Western blots were applied to examine the expression of NPTX1 in GC cell lines and expression of genes in downstream pathways. The role of NPTX1 on the migration, invasion, adhesion, and proliferation of GC cell lines was investigated with the transwell assay, the adhesion assay, and the MTT assay. Immunofluorescence staining was used to observe the effect of NPTX1 knockdown on the morphology of cells. RESULTS: According to the review of TCGA and GEO databases of GC, we found that the expression of NPTX1 increased in cancer tissues and high NPTX1 expression was correlated with poor overall survival, which was associated with lymph node stage in clinicopathologic parameters. Knockdown of NPTX1 attenuated the migration, invasion, and adhesion abilities of GC cells. According to gene set enrichment analysis, NPTX1 was found to be positively related to integrin and focal adhesion (FA). Additionally, NPTX1 knockdown decreased the expression of integrin α1 and integrin α7, followed by deregulation of the expression of p-Src, p-Akt, p-Erk, MMP2, and MMP7, as well as inhibiting the formation of FA complexes and decreasing the length of pseudopods in GC cells. CONCLUSION: Our study provides strong evidence that NPTX1 plays a crucial role in promoting metastasis and acts as a prognostic indicator in GC.

Preparation of PEGylated liposomes incorporating lipophilic lomeguatrib derivatives for the sensitization of chemo-resistant gliomas.

Liposomal delivery is a well-established approach to increase the therapeutic index of drugs, mainly in the field of cancer chemotherapy. Here, we report the preparation and characterization of a new liposomal formulation of a derivative of lomeguatrib, a potent O6-methylguanine-DNA methyltransferase (MGMT) inactivator. The drug had been tested in clinical trials to revert chemoresistance, but was associated with a low therapeutic index. A series of lomeguatrib conjugates with distinct alkyl chain lengths - i.e. C12, C14, C16, and C18 - was synthesized, and the MGMT depleting activity as well as cytotoxicity were determined on relevant mouse and human glioma cell lines. Drug-containing liposomes were prepared and characterized in terms of loading and in vitro release kinetics. The lipophilic lomeguatrib conjugates did not exert cytotoxic effects at 5 µM in the mouse glioma cell line and exhibited a similar MGMT depleting activity pattern as lomeguatrib. Overall, drug loading could be improved by up to 50-fold with the lipophilic conjugates, and the slowest leakage was achieved with the C18 derivative. The present data show the applicability of lipophilic lomeguatrib derivatization for incorporation into liposomes, and identify the C18 derivative as the lead compound for in vivo studies.

Porous Pd nanoparticles with high photothermal conversion efficiency for efficient ablation of cancer cells.

Nanoparticle (NP) mediated photothermal effect shows great potential as a noninvasive method for cancer therapy treatment, but the development of photothermal agents with high photothermal conversion efficiency, small size and good biocompatibility is still a big challenge. Herein, we report Pd NPs with a porous structure exhibiting enhanced near infrared (NIR) absorption as compared to Pd nanocubes with a similar size (almost two-fold enhancement with a molar extinction coefficient of 6.3 × 10(7) M(-1) cm(-1)), and the porous Pd NPs display monotonically rising absorbance from NIR to UV-Vis region. When dispersed in water and illuminated with an 808 nm laser, the porous Pd NPs give a photothermal conversion efficiency as high as 93.4%, which is comparable to the efficiency of Au nanorods we synthesized (98.6%). As the porous Pd NPs show broadband NIR absorption (650-1200 nm), this allows us to choose multiple laser wavelengths for photothermal therapy. In vitro photothermal heating of HeLa cells in the presence of porous Pd NPs leads to 100% cell death under 808 nm laser irradiation (8 W cm(-2), 4 min). For photothermal heating using 730 nm laser, 70% of HeLa cells were killed after 4 min irradiation at a relative low power density of 6 W cm(-2). These results demonstrated that the porous Pd nanostructure is an attractive photothermal agent for cancer therapy.

Triple-functional core-shell structured upconversion luminescent nanoparticles covalently grafted with photosensitizer for luminescent, magnetic resonance imaging and photodynamic therapy in vitro.

Upconversion luminescent nanoparticles (UCNPs) have been widely used in many biochemical fields, due to their characteristic large anti-Stokes shifts, narrow emission bands, deep tissue penetration and minimal background interference. UCNPs-derived multifunctional materials that integrate the merits of UCNPs and other functional entities have also attracted extensive attention. Here in this paper we present a core-shell structured nanomaterial, namely, NaGdF(4):Yb,Er@CaF(2)@SiO(2)-PS, which is multifunctional in the fields of photodynamic therapy (PDT), magnetic resonance imaging (MRI) and fluorescence/luminescence imaging. The NaGdF(4):Yb,Er@CaF(2) nanophosphors (10 nm in diameter) were prepared via sequential thermolysis, and mesoporous silica was coated as shell layer, in which photosensitizer (PS, hematoporphyrin and silicon phthalocyanine dihydroxide) was covalently grafted. The silica shell improved the dispersibility of hydrophobic PS molecules in aqueous environments, and the covalent linkage stably anchored the PS molecules in the silica shell. Under excitation at 980 nm, the as-fabricated nanomaterial gave luminescence bands at 550 nm and 660 nm. One luminescent peak could be used for fluorescence imaging and the other was suitable for the absorption of PS to generate singlet oxygen for killing cancer cells. The PDT performance was investigated using a singlet oxygen indicator, and was investigated in vitro in HeLa cells using a fluorescent probe. Meanwhile, the nanomaterial displayed low dark cytotoxicity and near-infrared (NIR) image in HeLa cells. Further, benefiting from the paramagnetic Gd(3+) ions in the core, the nanomaterial could be used as a contrast agent for magnetic resonance imaging (MRI). Compared with the clinical commercial contrast agent Gd-DTPA, the as-fabricated nanomaterial showed a comparable longitudinal relaxivities value (r(1)) and similar imaging effect.