Injectable dexamethasone-loaded peptide hydrogel for therapy of radiation-induced ototoxicity by regulating the mTOR signaling pathway.

Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA32-HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway.

Association of smoking with brain gray and white matter volume: a Mendelian randomization study.

BACKGROUND: Observational studies have found a significant association between smoking and smaller gray matter volume, but this finding was limited by the reverse causality bias and possible confounding factors. Therefore, we conducted a Mendelian randomization (MR) study to explore the causal association of smoking with brain gray and white matter volume from a genetic perspective, and to investigate the possible mediators influencing the association. METHODS: Smoking initiation (ever being a regular smoker) was used as the primary exposure from the GWAS & Sequencing Consortium of Alcohol and Nicotine use in up to 1,232,091 individuals of European descent. Their associations with brain volume were acquired from a recent genome-wide association study of brain imaging phenotypes conducted among 34,298 individuals of the UK Biobank. The random-effects inverse-variance weighted method was applied as the main analysis. Multivariable MR analysis was performed to assess the potential interference of confounding factors on causal effect. RESULTS: Genetic liability to smoking initiation was significantly associated with lower gray matter volume (beta, -0.100; 95% CI, -0.156 to -0.043; P=5.23×10-4) but not with white matter volume. Multivariable MR results suggested that the association with lower gray matter volume might be mediated by alcohol drinking. Regarding localized gray matter volume, genetic liability to smoking initiation was associated with lower gray matter volume in left superior temporal gyrus, anterior division and right superior temporal gyrus, posterior division. CONCLUSIONS: This MR study supports the association between smoking and lower gray matter volume, and highlights the importance of never smoking.

Study of the mechanism of ultrasound-induced enhanced therapeutic effects of a chitosan-based nanoplatform.

Ultrasound (US) has been used in drug delivery systems for controlling drug release and activation of US-sensitive drugs for sonodynamic therapy of cancer. In our previous work, we found that erlotinib-grafted chitosan nanocomplexes loading perfluorooctyl bromide and hematoporphyrin under US irradiation showed satisfactory therapeutic effects for non-small cell lung cancer treatment. However, the underlying mechanism of US-mediated delivery and therapy has not been fully explored. In this work, the underlying mechanisms of the US-induced effects of the nanocomplexes were evaluated at the physical and biological levels after the chitosan-based nanocomplexes were characterized. The results showed that US could activate the cavitation effects and promote nanocomplexes penetrating into the depth of three-dimensional multicellular tumor spheroids (3D MCTSs) when nanocomplexes were selectively uptaken by targeted cancer cells, but push the extracellular nanocomplexes out of the 3D MCTSs. US demonstrated strong tissue penetration ability to effectively induce obvious reactive oxygen species production deep inside the 3D MCTSs. Under the US condition of 0.1 W cm-2for 1 min, US caused little mechanical damage and weak thermal effect to avoid severe cell necrosis, whereas cell apoptosis could be induced by collapse of mitochondrial membrane potential and the nucleus damage. The present study indicates that US can potentially be used jointly with nanomedicine to improve targeted drug delivery and combination therapy of deep-seated tumors.

Bacteria-mediated metformin-loaded peptide hydrogel reprograms the tumor immune microenvironment in glioblastoma.

The tumor immune microenvironment (TIME) is one of the significant hallmarks of cancer and has the important role of largely determining the malignancy level of tumors. As an approach to break through this bottleneck of tumor treatment methods, the TIME can be reprogrammed by certain nanomaterials. Here, we coated C-novyi-spores with melittin-RADA32 nanofiber hybrid peptide and loaded the immunomodulator metformin to obtain MRM-coated spores as a powerful antitumor nanodrug against glioblastoma (GBM), which is based on the activation of the TIME. MRM-coated spores exhibit extended-release profiles and an enhanced killing effect on GBM both in vitro and in vivo. Furthermore, MRM-coated spores can educate the innate and adaptive immune system by inducing sustainable CD8+ T cell responses, promoting M1 macrophage polarization, and regulating the expression of HIF1-α, PDL1, and CXCL9 in TIME. In intracranial applications, MRM-coated spores showed excellent biosafety and a strong therapeutic effect. In summary, peptide hydrogels provide a promising strategy in which advantages of different treatment methods can be incorporated to synthesize potent antitumor drugs with mild side effects from bacteria-mediated nanomaterials.

Facile preparation of indocyanine green and tiny gold nanoclusters co-loaded nanocapsules for targeted synergistic sono-/photo-therapy.

Photothermal therapy (PTT) and sono-photodynamic therapy (SPDT) are fast growing local treatment modalities with minimal invasiveness and high safety. Gold nanoparticles and indocyanine green (ICG) have been used as sensitizers for PTT and SPDT. However, long resident time of gold nanoparticles in tissues and fast elimination of ICG hampered their further clinical applications. Herein, we developed nanocapsules formed by hyaluronic acid and chitosan loading with ICG and tiny gold nanoclusters (TAuNCs) to overcome the shortcomings of gold nanoparticles and ICG for combined PTT and SPDT. The nanocapsules exhibited good biological stability, favorable photothermal effects, and ultrasound/near-infrared light (NIR)-responsive release behaviors. The hyaluronic acid could mediate the specific delivery of cargos to CD44 protein over-expressing cancer cells. The in vitro and in vivo results showed that TAuNCs and ICG could act synergistically to obtain satisfactory anticancer effects under NIR laser and/or ultrasound exposure induced by thermal ablation and reactive oxygen species (ROS) generation. Biodistribution and excretion studies showed that the nanocapsules had longer ICG retention time in tumor and most of the TAuNCs could be effectively excreted from the body within one month. This study thus provides a facile strategy for the development of a safe and high-performance nanoplatform for synergistic PTT/SPDT.

3D Printing Tannic Acid-Based Gels via Digital Light Processing.

Photocurable 3D printing of polyphenol-based gels has been limited by the catechol groups, which can scavenge free radicals generated by photoinitiators during photopolymerization. Herein, a 3D-printed gel composed of poly-acrylamide (PAM) and tannic acid (TA) is presented, fabricated by using glycerol as shielding of TA and a commercial digital light processing printer. The printed gels are based on a polymeric network interpenetrated by TA-glycerol, enabling the printed objects with various favorable properties, such as improved toughness, anti-dehydration, antioxidant and antibacterial properties, etc. The proposed strategy enables photocurable 3D printing of polyphenol-based gels with complex architecture, paving the way for future applications in various fields, ranging from soft wearable devices to tissue engineering.

Drug-Eluting Bead Transarterial Chemoembolization versus Conventional Transarterial Chemoembolization Both Combined Apatinib for Hepatocellular Carcinoma: A Retrospective, Propensity-Score Matched Study.

PURPOSE: This study aims to compare the efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) versus conventional TACE (cTACE), both combined with apatinib, and to establish predictive nomograms to support individualized survival prediction in hepatocellular carcinoma (HCC) patients. PATIENTS AND METHODS: This retrospective study assessed HCC patients from June 2015 to December 2019. Patients were classified as DEB-TACE plus apatinib (D-apatinib) and cTACE plus apatinib (c-apatinib). The endpoints were overall survival (OS) and progression-free survival (PFS). The nomograms were constructed, and the C-index, receiver operating characteristic (ROC) curve, and calibration curves were used to validate the nomograms. Propensity score matching (PSM) analysis was applied to reduce patient selection bias. RESULTS: A total of 174 patients were included. After PSM analysis, 58 pairs of patients were selected. Before PSM analysis, the median OS and PFS were 21.0 and 8.0 months in the D-apatinib group, respectively, which were better than the 18.0 and 5.0 months observed in the c-apatinib group (P < 0.05). The complete response (CR) rate and objective response rate (ORR) of the D-apatinib group were higher than those of the c-apatinib group. The C-index values of the nomograms in the D-apatinib group and the c-apatinib group were 0.826 and 0.802, and the area under the curve (AUC) values in the ROC curve were 0.934 and 0.892. After PSM analysis, the survival of patients treated with D-apatinib was better than that of patients treated with c-apatinib (P < 0.05). The C-index values were 0.854 and 0.794 in the D-apatinib group and the c-apatinib group, respectively, and the AUC values were 0.960 and 0.890. The incidence of adverse events was higher in the c-apatinib group. CONCLUSION: DEB-TACE in combination with apatinib showed better treatment effectiveness for unresectable HCC. The nomograms can identify HCC patients who may benefit most from the treatment.

Survival analysis and prognostic factors of palliative radiotherapy in patients with metastatic colorectal cancer: a propensity score analysis.

BACKGROUND: Radiation therapy (RT) is known to have beneficial effects on the palliative treatment of patients with advanced cancer. However, valid data on this treatment method are limited, especially for patients with metastatic colorectal cancer (mCRC). This study aimed to identify prognostic factors and investigate the outcomes of mCRC patients who received palliative RT. METHODS: A total of 488 mCRC patients who underwent systemic therapy with or without palliative RT between 2014 and 2019 were included in the study. Of the 488 patients, 155 received systemic treatment combined with palliative RT (RT group), while 333 were only administered systemic treatment (non-RT group). Propensity score matching (PSM) was conducted to eliminate possible bias, and overall survival (OS) was calculated using the Kaplan-Meier (KM) method. A log-rank test was used to compare the survival outcomes of each group, and a multivariate analysis was conducted using a Cox proportional hazards model. RESULTS: The RT group had a higher OS than that of the non-RT group (P=0.001). After PSM, the median OS of the RT group was 50.8 months, and for the non-RT group it was 32.2 months (P=0.003). Subgroup analysis revealed that RT had a better effect on the OS of patients who had synchronous metastasis, or who didn't receive targeted therapy or local treatment (including surgery, ablation, and intervention). Multivariate analysis of the whole cohort showed that palliative RT was associated with improved OS. Moreover, multivariate analysis of the RT group showed that systemic therapy before RT, and the site of RT was in the liver and lung, were independent prognostic factors affecting survival time. CONCLUSIONS: We demonstrated that systemic treatment followed by palliative RT led to a better OS for mCRC patients. This combination method can therefore be seen as a suitable treatment approach for patients with mCRC.

An intelligent hypoxia-relieving chitosan-based nanoplatform for enhanced targeted chemo-sonodynamic combination therapy on lung cancer.

The clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based targeted molecular therapies (TMT) is inevitably hampered by the development of acquired drug resistance in non-small cell lung cancer (NSCLC) treatment. Sonodymanic therapy (SDT) is a promising new cancer treatment approach, but its effects are restricted by tumor hypoxia. Herein, a nanoplatform fabricated by erlotinib-modified chitosan loading sonosensitizer hematoporphyrin (HP) and oxygen-storing agent perfluorooctyl bromide (PFOB), namely CEPH, was developed to deliver HP to erlotinib-sensitive cells. CEPH with ultrasound could alleviate hypoxia inside the three-dimensional multicellular tumor spheroids, suppress NSCLC cell growth under normoxic or hypoxic condition, and enhance TMT/SDT synergistic effects through elevated production of reactive oxygen species, decrease of mitochondrial membrane potential, and down-regulation of the expression of the proteins EGFR, p-EGFR, and HIF-1α. Hence, CEPH could be a potential nanoplatform to improve the efficacy of oxygen-dependent SDT and overcome hypoxia-induced TMT resistance for enhanced synergistic TMT/SDT.

Prognostic Value of Plasma Epstein-Barr Virus DNA Levels Pre- and Post-Neoadjuvant Chemotherapy in Patients With Nasopharyngeal Carcinoma.

BACKGROUND: In this study, we evaluated the prognostic value of the plasma levels of Epstein-Barr virus (EBV) DNA in patients with nasopharyngeal carcinoma (NPC) at different treatment stages. METHODS: We retrospectively analyzed the Data of 206 patients with NPC. Pre-neoadjuvant chemotherapy (pre-NACT), post-NACT, post-radiotherapy, and post-treatment plasma EBV DNA levels were used to establish prognostic nomograms. The concordance index (C-index) and calibration curves were used to compare the prognostic accuracy of the nomograms. The results were confirmed in a validation cohort consisting of patients who were tested for EBV DNA levels at all four stages of treatment. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Survival differences were calculated using the log-rank test. RESULTS: EBV DNA-positive patients had worse 3-year PFS and 5-year OS than EBV DNA-negative patients; this was true for pre-NACT (PFS: 82.7% vs. 57.3%, P < 0.001; OS: 90.9% vs. 68.7%, P = 0.08) and post-NACT (PFS: 85.0% vs. 50.6%, P < 0.001; OS: 91.7% vs. 65.7%; P = 0.001) EBV DNA levels but not for post-radiotherapy (PFS: 72.2% vs. 60.9%, P = 0.192; OS: 73.1% vs. 77.2%, P = 0.472) or post-treatment (PFS: 77.3% vs. 59.2%, P = 0.063; OS: 77.5% vs. 79.7%, P = 0.644) levels. Nomograms combining pre-NACT and post-NACT EBV DNA levels had a superior prognostic ability than those of post-radiotherapy and post-treatment EBV DNA levels. CONCLUSION: Pre-NACT EBV DNA levels combined with post-NACT EBV DNA levels can more reliably predict survival outcomes in patients with NPC.

Comparison of TPF and TP Induction Chemotherapy for Locally Advanced Nasopharyngeal Carcinoma Based on TNM Stage and Pretreatment Systemic Immune-Inflammation Index.

PURPOSE: To evaluate the efficacy and toxicity of the two IC (induction chemotherapy) regimens, TPF (taxanes, cisplatin, and 5-fluorouracil) and TP (taxanes and cisplatin) combined with concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LA-NPC) patients. METHODS: Ultimately, we enrolled 213 patients at stage III-IVA in this retrospective study. The prognosis of TPF and TP was compared by Kaplan-Meier and Cox proportional hazard regression. The toxicities were evaluated according to CTCAE v4.0 and RTOG criteria. RESULTS: TPF was found to have a higher 5-year DMFS in stage IVA and N2-3 patients. The optimal value of pretreatment SII was 432.48. A further subgroup analysis revealed that patients in stage IVA combined with SII ≥432.48 showed superior OS (P=0.038) and DMFS (P=0.028) from TPF. Also, SII was proved to be a prognostic element for PFS (HR 2.801, P=0.018) and DMFS (HR 3.735, P=0.032) in multivariate analysis, and IC regimen (HR 2.182, P=0.049) for predicting DMFS. The rate of grade 3-4 leukopenia (P=0.038), neutropenia (P=0.021), radiation oral mucositis (P=0.048), diarrhea (P=0.036), and ear damage (P=0.046) were more common in TPF group. CONCLUSION: Our study revealed that TPF regimen showed a higher 5-year DMFS for stage IVA and N2-3 patients, while for stage III and N0-1, TP might be ample. In high-risk LA-NPC patients (stage IVA combined with pretreatment SII ≥432.48), TPF had a higher 5-year OS and DMFS, with more grade 3-4 toxicities, but most of them were endurable.

KIF18B as a regulator in tumor microenvironment accelerates tumor progression and triggers poor outcome in hepatocellular carcinoma.

BACKGROUND: The tumor microenvironment plays an important role in the progression and recurrence of tumors and immunotherapy outcomes. The use of immune checkpoint blockers to improve the overall survival rate of patients with advanced hepatocellular carcinoma has yielded inconsistent outcomes. We examined the tumor microenvironment-related genes for their clinical significance and biological functions in hepatocellular carcinoma. METHODS: Bioinformatic analysis was performed to screen the differentially expressed genes and to identify the core gene of the tumor microenvironment in hepatocellular carcinoma. The expression of KIF18B in hepatocellular carcinoma cell lines and tumor samples was determined using western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The malignancy-promoting ability of KIF18B was evaluated using Cell Counting Kit-8, colony formation, cell proliferation, migration and invasion, and xenograft tumor assays. RESULTS: KIF18B was identified as one of the core genes in the hepatocellular carcinoma microenvironment and was significantly associated with infiltrating immune cell subtypes and tumor cell stemness. Upregulation of KIF18B was associated with poor clinicopathological characteristics and poor patient outcomes; its downregulation inhibited the proliferation ability of hepatocellular carcinoma cells, which was consistent with the findings of in vivo experiments. Knockdown of KIF18B inhibited epithelial-mesenchymal transition which reduced the migration and invasion abilities of tumor cells. A pulmonary metastasis model confirmed that the downregulation of KIF18B inhibited hepatocellular carcinoma cell metastasis in vivo. CONCLUSION: KIF18B could be a useful marker for determining the treatment outcomes of immune checkpoint blockers in the context of hepatocellular carcinoma.

Emerging self-assembling peptide nanomaterial for anti-cancer therapy.

Recently it is mainly focused on anti-tumor comprehensive treatments like finding target tumor cells or activating immune cells to inhibit tumor recurrence and metastasis. At present, chemotherapy and molecular-targeted drugs can inhibit tumor cell growth to a certain extent. However, multi-drug resistance and immune escape often make it difficult for new drugs to achieve expected effects. Peptide hydrogel nanoparticles is a new type of biological material with functional peptide chains as the core and self-assembling peptide (SAP) as the framework. It has a variety of significant biological functions, including effective local inflammation suppression and non-drug-resistant cell killing. Besides, it can induce immune activation more persistently in an adjuvant independent manner when compared with simple peptides. Thus, SAP nanomaterial has great potential in regulating cell physiological functions, drug delivery and sensitization, vaccine design and immunotherapy. Not only that, it is also a potential way to focus on some specific proteins and cells through peptides, which has already been examined in previous research. A full understanding of the function and application of SAP nanoparticles can provide a simple and practical strategy for the development of anti-tumor drugs and vaccine design, which contributes to the historical transition of peptide nanohydrogels from bench to bedside and brings as much survival benefits as possible to cancer patients.

KIF18B is a Prognostic Biomarker and Correlates with Immune Infiltrates in Pan-Cancer.

Background: Cancer is one of the deadliest diseases at present. Although effective screening and treatment can save lives to a certain extent, our knowledge of the disease is far from sufficient. KIF18B is a member of the kinesin-8 superfamily and plays a conserved regulatory role in the cell cycle. KIF18B reportedly functions as an oncogene in some human cancers, but the correlations between KIF18B and prognosis and immune-infiltrates in different cancers remain unclear. Methods: Data were collected from the TCGA, GTEx, CCLE, TIMER, and GSEA databases. The expression difference, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs), tumor microenvironment (TME), immune cell infiltration, and gene co-expression of KIF18B were analyzed using the R language software. Results: KIF18B was widely upregulated in cancers, compared with normal tissues, and high KIF18B expression was associated with unfavorable prognoses. TMB, MSI, MMRs, and DNA methylation correlated with KIF18B dysregulation in cancers. KIF18B correlated closely with tumor immunity and interacted with different immune cells and genes in different cancer types. Conclusion: KIF18B could be used as a prognostic biomarker for determining prognosis and immune infiltration in pan-cancer.

The Expression of Three Negative Co-Stimulatory B7 Family Molecules in Small Cell Lung Cancer and Their Effect on Prognosis.

BACKGROUND: In recent years, immune checkpoint inhibitors have shown significant effects in a variety of solid tumors. However, due to the low incidence of small cell lung cancer (SCLC) and its unclear mechanism, immune checkpoints in SCLC have not been fully studied. METHODS: We evaluated the expression of PD-L1, B7-H3, and B7-H4 in 115 SCLC tissue specimens using immunohistochemistry. The clinical data of patients with SCLC were retrospectively reviewed to investigate three negative co-stimulatory B7 family molecules' ability to affect the prognosis of SCLC. RESULTS: Among the SCLC patients with complete follow-up data (n = 107), sixty-nine (64.49%) expressed moderate to high B7-H3 levels, which correlated positively with tumor sizes (P < 0.001). Eighty (74.77%) patients expressed moderate to high B7-H4 levels, which correlated positively with metastases (P = 0.049). The positive expression of B7-H3 and B7-H4 correlated significantly with shortened overall survival (OS) (B7-H3, P = 0.006; B7-H4, P = 0.019). PD-L1 was positively expressed only in 13.08% of cancer tissues, and there was no significant correlation with prognosis. The Cox proportional hazards regression showed that B7-H3 was an independent prognostic indicator of OS (P = 0.028; HR = 2.125 [95% CI = 0.985-4.462]). CONCLUSIONS: Our results suggest that B7-H3 has a negative predictive effect on SCLC. This outcome provides a theoretical basis for the subsequent research on immune checkpoint inhibitors targeting B7-H3.

Prognostic value of pretreatment prognostic nutritional index and lactated dehydrogenase in locally advanced nasopharyngeal carcinoma patients.

BACKGROUND: To evaluate the prognostic value of pretreatment prognostic nutritional index (PNI), lactated dehydrogenase (LDH) and their combination (PNI-LDH) in patients with locally advanced NPC receiving induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). METHODS: A total of 213 patients diagnosed with locally advanced (III-IVA) NPC between January 2013 and December 2017 were retrospectively reviewed. The optimal PNI and LDH cutoff values were determined by the quartiles. The association between PNI and LDH and the clinicopathological characteristics of the patients was examined. Survival curves were analyzed using the Kaplan-Meier method and compared by the log-rank test between the different PNI and LDH subgroups. Univariate and multivariate analyses were performed by the Cox proportional hazards regression model to evaluate the prognostic impact on overall survival (OS), progression-free survival (PFS), locoregional recurrence free survival (LRFS) and distant metastasis-free survival (DMFS). Furthermore, the prognostic values of the PNI, LDH, and PNI-LDH were evaluated by comparing the AUC area. RESULTS: The optimal cut-off values of PNI and LDH were 52 and 177, respectively. Multivariate analyses revealed that patients with a higher PNI had inferior OS (P=0.027), PFS (P=0.040), LRFS (P=0.015) and DMFS (P=0.040), and patients with a higher LDH level had poorer OS (P=0.040), PFS (P=0.001), LRFS (P=0.001) and DMFS (P=0.001). Furthermore, EBV DNA positive, stage IVA were independent prognostic factors for survival outcomes in the multivariate analyses. Moreover, we further demonstrated that low PNI-high LDH in locally advanced NPC patients was significantly related to poor OS (P=0.012), PFS (P=0.001), LRFS (P=0.001) and DMFS (P=0.001). The AUC of the PNI, LDH and PNI-LDH were 0.653 (P=0.021), 0.647 (P=0.028) and 0.751 (P=0.001), respectively, indicating that PNI-LDH is superior to either score alone. CONCLUSIONS: Pretreatment PNI and LDH could be considered as valuable predictors for survival outcomes in locally advanced NPC patients. The combination of them, superior to either score alone, can be used as a supplement to the traditional TNM staging system.

Prognostic efficacy of the combination of the pretreatment systemic Immune-Inflammation Index and Epstein-Barr virus DNA status in locally advanced Nasopharyngeal Carcinoma Patients.

Background: The systemic immune-inflammation index (SII) and Epstein-Barr virus DNA (EBV DNA) levels has been used as a prognostic marker for nasopharyngeal carcinoma (NPC) patients, but there is no in-depth study in locally advanced NPC patients and no research on the predictive value of their combination. Our study aimed to evaluate the prognostic efficacy of the pretreatment SII, EBV DNA levels and their combination in locally advanced NPC patients receiving induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). Materials and methods: 319 patients diagnosed with locally advanced NPC receiving IC followed by CCRT were retrospectively reviewed (213 in the training cohort and 106 in the validation cohort). The cut-off value for the SII was determined using receiver operating characteristic (ROC) curve. Correlations between characteristics of patients were assessed using the Pearson correlation coefficient. Survival curves for the SII, EBV DNA levels and their combination were analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed by the Cox proportional hazards regression model to evaluate the prognostic impact on overall survival (OS) and progression-free survival (PFS). A prognostic nomogram was generated and its prediction ability was measured by the concordance index (C-index). Results: The optimal cutoff point for the SII was 402.10. A higher SII and EBV DNA positivity were demonstrated to be related to poorer survival outcomes (P < 0.05). Multivariate analyses showed that a higher SII, EBV DNA positivity and their combination were powerful independent risk factors for OS and PFS (P < 0.05). The SII - EBV DNA had the largest area under the curve (AUC) compared to either score alone. The incorporation of the SII - EBV DNA into established nomogram achieved higher C-index in the prediction of OS and PFS, indicating its superior for predicting survival. All results were found in the training cohort and confirmed in the validation cohort. Conclusions: The pretreatment SII and EBV DNA levels are promising factors for predicting survival in locally advanced NPC patients. The combination of them, which was superior to either score alone, was a complement to the conventional TNM staging system.

Research on the circadian clock gene HNF4a in different malignant tumors.

Background: The circadian rhythm is produced by multiple feedback loops formed by the core clock genes after transcription and translation, thus regulating various metabolic and physiological functions of the human body. We have shown previously that the abnormal expression of 14 clock genes is related closely to the occurrence and development of different malignant tumors, and these genes may play an anti-cancer or pro-cancer role in different tumors. HNF4a has many typical properties of clock proteins involved in the clock gene negative feedback loop regulation process. We need to explore the function of HNF4a as a circadian clock gene in malignant tumors further. Methods: We used The Cancer Genome Atlas (TCGA) database to download the clinicopathological information of twenty malignant tumors and the corresponding RNA-seq data. The HNF4a RNA-seq data standardized by R language and clinical information were integrated to reveal the relationship between HNF4a and prognosis of patients. Results: Analysis of TCGA data showed that the prognosis of HNF4a was significantly different in BLCA, KIRC, LUSC, and READ. High HNF4a expression is correlated with good prognosis in BLCA, KIRC, and READ but poor prognosis in LUSC. However, HNF4a was associated with the stages, T stages, and lymph node status only in BLCA. Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA. The low expression of HNF4a could be a reference index for the metastasis, recurrence, and prognosis of BLCA.

Near-infrared/pH dual-responsive nanocomplexes for targeted imaging and chemo/gene/photothermal tri-therapies of non-small cell lung cancer.

Combination therapy offers promising opportunities for treating advanced non-small cell lung cancer (NSCLC). Here, we established a chitosan-based nanocomplex CE7Q/CQ/S to deliver molecular-targeted drug erlotinib (Er), Survivin shRNA-expressing plasmid (SV), and photothermal agent heptamethine cyanine dye (Cy7) in one platform for simultaneous near-infrared (NIR) fluorescence imaging and triple-combination therapy of NSCLC bearing epidermal growth factor receptor (EGFR) mutations. The obtained CE7Q/CQ/S exhibited favorable photothermal effects, good DNA binding ability, and pH/NIR dual-responsive release behaviors. The conjugated Er could mediate specific delivery of Cy7 to EGFR-mutated NSCLC cells to enable targeted NIR fluorescence imaging and photothermal therapy (PTT). The in vitro and in vivo results showed that downregulation of Survivin expression and the photothermal effects could act synergistically with Er to induce satisfactory anticancer effects in either Er-sensitive or Er-resistant EGFR-mutated NSCLC cells. By integrating chemo/gene/photothermal therapies into one theranostic nanoplatform, CE7Q/CQ/S could significantly suppress EGFR-mutated NSCLC, indicating its potential use in treating NSCLC. STATEMENT OF SIGNIFICANCE: The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved overall survival in patients with NSCLC driven by EGFR mutations. Unfortunately, the emergence of acquired resistance of EGFR-TKIs is almost inevitable after treatment. Here, we constructed a NIR/pH dual-responsive nanocomplex CE7Q/CQ/S based on chitosan which could integrate targeted near-infrared fluorescence imaging and chemo/gene/phototheramal tri-therapies together. We found that CE7Q/CQ/S possessed a promising outcome in fighting against EGFR-mutated NSCLC. The inhibition of Survivin expression and the application of photothermal therapy could act synergistically with erlotinib and reverse erlotinib resistance. The results of this work suggested that this chitosan-based combination therapeutic nanoplatform could be a promising candidate for NSCLC treatment.

Optimizing a Novel Au-Grafted Lipid Nanoparticle Through Chelation Chemistry for High Photothermal Biologic Activity.

Gold nanoparticles through nucleation of Au clusters have been extensively studied. However, due to low potency, prolonged tissue retention, and irreversible accumulation, the safety considerations have limited their therapeutic and diagnostic applications. Novel gold nanostructures with retained physical properties and higher biodegradability could be prepared by alternative approaches. Previously, a lipid nanoparticle (LNP) platform carrying gadolinium (Gd3+) has been reported to eliminate through the biliary without accumulation in the liver or kidney within 24 h. Inspired by this discovery, we investigated a new approach of forming gold nanoparticles using preformed LNPs grafting diethylenetriamine-pentaacetic acid as a chelating agent. Tiny Au nanoparticles are formed by simply mixing Au3+ with preformed diethylenetriamine-pentaacetic acid-LNP. The Au3+ associates stably to these LNPs after a systematic optimization. The Au-grafted LNPs are scalable and showed excellent photothermal effects when subjected to near-infrared light irradiation. They exhibit enhanced light-induced tumor cell killing at higher efficiency, compared with that of classical gold nanoparticles (citrated reduced). Given an additional small dose (2 Gy) of gamma irradiation, Au-grafted LNP could produce synergistic photothermal and radiotherapeutic effects under reduced light dose. The simple and adaptive nanoparticle design may enhance the margin of safety of gold nanoparticles in the treatment of cancers and other diseases.