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Objectives. Indoleamine 2,3-dioxygenase 1 (IDO1) acts as the key rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Its activity was primarily induced by interferon-γ (IFN-γ), which was reported to play a role in the development of acute radiation-induced pneumonitis. In this study, we aimed to investigate the correlation between IDO1 activity and radiation-induced lung toxicity (RILT) in stage III nonsmall cell lung cancer (NSCLC) patients who were treated with chemoradiotherapy (CRT). Materials and Methods. Systemic IDO1 activity was reflected by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 stage III NSCLC patients were measured by high-performance liquid chromatography (HPLC) before the initiation of radiotherapy. Dynamic change of IDO1 activity was followed in 23 patients before, during, and after radiotherapy. We also used RNA sequencing (RNA-seq) data from the Cancer Genome Atlas Program (TCGA) database and performed gene set enrichment analysis (GSEA) to explore how IDO1 was involved in the development of RILT. Results. 9.7% (11/113) of the whole group developed G 3 + (greater than or equal to Grade 3) RILT. Preradiation IDO1 activity was significantly higher in patients who developed G 3 + RILT than in non G 3 + RILT patients. ( P = 0.029 , AUC = 0.70). Univariate and multivariate analyses showed that high IDO1 activity was independently associated with the risk of G 3 + RILT ( P = 0.034 ). A predictive model combining both IDO1 activity and FEV1 was established for severe RILT and displayed a moderate predictive value (AUC = 0.83, P < 0.001 ). The incidence of G 3 + RILT was 2.6% (1/38) in patients with an IDO activity ≤0.069 and FEV1 > 59.4%, and 50.0% (6/12) in those with an IDO activity >0.069 and FEV1 ≤ 59.4%. Of 23 patients with dynamic tracking, the IDO1 activity of postradiation was significantly lower than midradiation ( P = 0.021 ), though no significant differences among the three time points were observed ( P = 0.070 ). Bioinformatic analysis using RNA-seq data from 1014 NSCLC patients revealed that IDO mainly functioned in the inflammatory response instead of the late fibrosis process in NSCLC patients. Conclusion. High baseline IDO1 activity combined with unfavorable baseline FEV1 was predictive of severe RILT in unresectable stage III NSCLC patients. IDO1 might play a role in the acute inflammatory response. Finding effective interventions to alleviate RILT using IDO inhibitors is warranted in the future.

On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms pDTD@M (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. STATEMENT OF SIGNIFICANCE: Compared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.

The unsatisfactory efficacy of conventional theranostic agents in ablating tumor poses urgent demands on the development of high-performance integrated theranostic agents utilizing rising nanotechnology. To cope with the existing limitations, here we presented an intelligent nanoplatform based on yolk-shell Fe

The COVID-19 pandemic has spread to every corner of the world and seriously affected our health and daily activities in the past three years; thereby, it is still urgent to develop various simple, quick, and accurate methods for early detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Nanozymes, a kind of nanomaterial with intrinsic enzyme-mimicking activity, have emerged as a suitable alternative for both therapy and diagnosis of SARS-CoV-2. Here, ultrasensitive and ultrafast MIL-101(CuFe)-CD147 biosensors are established for the detection of SARS-CoV-2 by a simple colorimetric method. A MIL-101(CuFe) metal-organic framework has excellent peroxidase-like activity due to the synergistic effect of Fe and Cu atoms. In addition, the MIL-101(CuFe)-CD147 biosensor shows great potential to detect the various variants of SARS-CoV-2 due to the universal receptor of CD147. The enzyme-based biosensor for the detection of SARS-CoV-2 achieves a very low limit of detection (about 3 PFU/mL) within 30 min. Therefore, the present method provides a new generation of an alternative approach for highly sensitive and visual diagnosis of COVID-19.

Purpose Chemotherapy and concurrent thoracic radiation therapy (CCTRT) followed by prophylactic cranial irradiation (PCI) is the standard of care for limited-stage small cell lung cancer (LS-SCLC). We aimed to compare the efficacy and toxicity of moderately hypofractionated once-daily CCTRT with that of a standard twice-daily regimen. Methods and Materials This multicenter, phase 2, randomized study enrolled patients aged 18 to 75 years old who had pathologically confirmed LS-SCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received 4 to 6 cycles of etoposide-cisplatin chemotherapy and were randomized to receive twice-daily CCTRT at 45 Gray (Gy) in 30 fractions or once-daily CCTRT at 65 Gy in 26 fractions, commencing with cycles 1 to 3 of chemotherapy. PCI was given to good responders. The primary endpoint was progression-free survival (PFS). Results The analyses included 182 patients, with 94 in the twice-daily group and 88 in the once-daily group. CCTRT started with cycle 3 of chemotherapy for most patients (80.2%). At a median follow-up of 24.3 months, the median PFS was 13.4 months (95% confidence interval [CI], 10.8-16.0) in the twice-daily group versus 17.2 months (95% CI, 11.8-22.6) in the once-daily group (P = .031), with 2-year PFS rates of 28.4% (95% CI, 18.2-38.6) and 42.3% (95% CI, 31.1-53.5), respectively. The estimated overall survival was 33.6 months in the twice-daily group versus 39.3 months in the once-daily group (P = .137). The median locoregional PFS was 23.9 months in the twice-daily group and was not reached in the once-daily group (P = .017). The incidences of most toxicities were similar in both groups, except for a higher incidence of ≥grade 3 acute lymphopenia in the once-daily group (71.7% vs 40.2% in the twice-daily group; P Conclusions Moderately hypofractionated, once-daily CCTRT showed improved PFS and similar toxicities compared with twice-daily CCTRT in LS-SCLC. This regimen should be evaluated for comparison in a phase 3 randomized trial.

BackgroundTo evaluate longitudinal changes of concurrent chemoradiotherapy (CCRT) related lymphopenia and its association with survival in locally advanced non-small cell lung cancer (LA-NSCLC) patients.MethodsTotal lymphocyte count (TLC) at baseline, weekly intervals during CCRT and monthly intervals up to 12 months after CCRT were documented. The Common Terminology Criteria for Adverse Events version 5.0 was used to grade the severity of lymphopenia. Cox regression analysis was performed to evaluate the association between overall survival (OS) and CCRT related lymphopenia at different timepoints. Logistic regression model was used to determine the clinical factors associated with TLC level.Results381 LA-NSCLC patients treated with definitive CCRT without consolidation therapy (NCT02573506/NCT02577341) between 2011 to 2020 were analyzed. With a median follow-up of 45.8 months, the median OS was 41.0 months for all patients. Univariable analysis demonstrated that the 3 weeks during CCRT Grade (G) 4 lymphopenia (P=0.018), 2 months after CCRT G1-4 lymphopenia (P=0.004), 6 months after CCRT (6m-post-CCRT) G1-4 lymphopenia (P=0.001), and TLC nadir (P=0.020) were significantly associated with poorer OS. Multivariable analysis suggested that 6m-post-CCRT G1-4 lymphopenia (HR 2.614; P=0.041) were one of the independent predictors of OS. Further analysis inferred that radiation dose (OR: 1.328; P=0.005), GTV volume (OR: 1.004; P=0.036), and baseline TLC (OR: 0.288; P=0.001) were associated with 6m-post-CCRT lymphopenia.ConclusionThe persistent lymphopenia at 6 months after CCRT was an independent prognostic factor of OS in LA-NSCLC patients. Higher radiation dose, larger gross tumor volume and lower baseline TLC were significantly related to 6m-post-CCRT lymphopenia.

Background Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown. Results NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis. Conclusions The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury. Graphical Abstract

Correction for ‘Controlled synthesis of water-dispersible and superparamagnetic Fe3O4 nanomaterials by a microwave-assisted solvothermal method: from nanocrystals to nanoclusters’ by Xunan Jing et al., CrystEngComm, 2017, 19, 5089–5099, https://doi.org/10.1039/C7CE01191A.

Nicotinamide adenine dinucleotide (NADH) is central to metabolism and implicated in various diseases. Herein, nanohybrids of gold nanostars and metal-organic frameworks are devised and demonstrated as a dual-mode NADH sensor, for which colorimetric detection is enabled by its peroxidase-like nanozyme property and Raman detection is realized by its surface-enhanced Raman scattering property with the detection limit as low as 28 pM. More importantly, this probe enables real-time SERS monitoring in living cells, providing a unique tool to investigate dynamic cellular processes involving NADH. Our experiments reveal that metabolism dynamics is accelerated by glucose and is much higher in cancerous cells. The SERS results can also be verified by the colorimetric detection. This sensor provides a new potential to detect biomarkers and their dynamics

BackgroundWe aimed to evaluate the efficacy and feasibility of concurrent weekly docetaxel-nedaplatin and hypo-fractionated radiotherapy (hypo-RT) in atypical histologic subtypes of primary and metastatic mediastinal malignancies.MethodsFifty-four patients diagnosed with atypical primary or metastatic mediastinal malignancies were retrospectively reviewed. 30 patients received concurrent weekly docetaxel and nedaplatin and hypo-RT (CChRT group) and 24 patients had hypo-RT alone (hRT group). Overall response rate (ORR), in-field locoregional progression-free survival (LPFS) and toxicities were analyzed. The radiobiological effect was evaluated by the LQRGC/TCP model, incorporating four “R”s of radiobiology, Gompertzian tumor growth and radio-sensitizing effect of chemotherapeutic agent. The biologically effective doses (BEDs) were calculated.ResultsThe median follow-up time was 29.2 months for all patients. The ORR was 86.7% in CChRT group, compared with 62.5% in hRT group (p=0.033). The 2-year in-field LPFS of CChRT and hRT group was 73.4% and 47.3%, respectively (p=0.003). There was no significant difference of any >=Grade 3 toxicities between the two groups (p=0.754). The mean total dose and mean BED by the LQRGC/TCP model in CChRT group were 58.2Gy and 72.34Gy, versus 52.6Gy and 67.25Gy in hRT group.ConclusionsConcurrent weekly docetaxel-nedaplatin and hypo-RT achieved promising in-field LPFS and tolerable toxicities compared with hypo-RT alone in different histologic subtypes of primary and metastatic mediastinal malignancies.

Purpose This phase I trial aimed to determine the maximal tolerated dose (MTD) of incorporating a twice-weekly docetaxel and nedaplatin regimen into definitive concurrent chemoradiotherapy (CCRT) as radiosensitizers in patients with inoperable esophageal squamous cell carcinoma (ESCC). Methods The CCRT regimen included docetaxel (5 mg/m2, 10 mg/m2, or 15 mg/m2) and nedaplatin (5 mg/m2, 10 mg/m2, or 15 mg/m2) twice-weekly based on the traditional 3 + 3 dose escalation strategy, and radiotherapy (64 Gy in 32 fractions). The primary goals were to determine the MTD of concurrent chemotherapy and the dose limiting toxicities (DLTs). In-field objective response rate (ORR) was investigated. Results Fifteen patients had been recruited and analyzed. DLT involving persistent grade 3 esophagitis over 1 week was observed in all three patients (3/3) at dose level 3 (15 mg/m2), and two patients (2/6) experienced DLTs in the dose level 2 (10 mg/m2) due to esophageal fistula and persistent grade 3 esophagitis over 1 week, while one patient (1/6) treated at dose level 1 (5 mg/m2) exhibited DLT owing to Grade 3 increased liver enzymes, suggesting a MTD of 5 mg/m2. The in-filed ORR was both 100% in all patients and those receiving MTD. The 1-year loco-regional recurrence-free survival rate was 83.3%, 83.3% and 66.7% in dose level 1, 2, and 3, respectively. Conclusions The MTD of twice-weekly docetaxel and nedaplatin regimen was 5 mg/m2 in inoperable ESCC patients treated with definitive CCRT. Low dose concurrent docetaxel and nedaplatin showed promising radiosensitizing effect on in-filed disease control and good tolerability.

This systematic review and meta-analysis aimed to evaluate the association between pretreatment body mass index (BMI) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs). Systematical searches of PubMed, Embase, and the Cochrane Library databases were carried out. Studies reporting on the association between BMI and outcomes of ICIs were included. The intended outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and immune-related adverse events (irAEs). Quantitative analyses and dose–response meta-analyses were performed under random effect models. Twenty-two eligible studies involving 5686 cancer patients treated with ICIs were identified. Compared to those with lower BMI, patients with higher BMI obtained a significant benefit on OS (HR = 0.698, 95% CI 0.614–0.794, P

ObjectiveHigh activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.Materials and methodsSystemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.ResultsIn 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).ConclusionFavorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.

Metal-organic frameworks (MOFs) are widely used to mimic enzymes for catalyzing chemical reactions; however, low enzyme activity limit their large-scale application. In this work, gold nanorods/metal-organic frameworks (Au NRs/Fe-MOF) hybrids were successfully synthesized for photo-enhanced peroxidase-like catalysis and surface-enhanced Raman spectroscopy (SERS). The enzyme-like activity of Au NRs/Fe-MOF hybrids was significantly enhanced under localized surface plasmon resonance (LSPR), because the hot electrons produced on Au NRs surface were transferred into Fe-MOF, activating the Fenton reaction by Fe

Objective The study aimed to compare the characteristics and prognosis between patients with second primary lung cancer following Hodgkin’s lymphoma and those with primary lung cancer. Materials and methods Using the SEER 18 database, the characteristics and prognosis were compared between the second primary non-small cell lung cancer following Hodgkin’s lymphoma (HL-NSCLC) (n = 466) and the first primary non-small cell lung cancer (n = 469,851)(NSCLC-1), as well as between the second primary small cell lung cancer following Hodgkin’s lymphoma (n = 93) (HL-SCLC) and the first primary small cell lung cancer (n = 94,168) (SCLC-1). Comparisons of categorical variables were performed using Chi-square or Fisher’s test. Continuous variables were compared using the Mann-Whitney U test. Overall survival (OS) was estimated using the Kaplan-Meier method, and the difference between groups was analyzed by log-rank test. Results HL-NSCLC group had more males than NSCLC-1 group, and the median age of HL-NSCLC group was younger than that of NSCLC-1 group. Patients with HL-NSCLC showed inferior OS than those with NSCLC-1 (median: 10 months vs. 11 months, P = 0.006). Both HL-SCLC and SCLC-1 groups had poor prognosis, with median OS of 7 months (P = 0.4). The 3-year cumulative risks of death from any cause for patients with the latencies from HL to NSCLC of 0 to 5 years, >5 to 10 years, >10 to 15 years, >15 to 20 years, and>20 years were 71.8%, 82.6%, 86.8%, 85.7% and 78.5%, respectively(P = 0.020). Conclusion HL-NSCLC patients had worse prognosis than NSCLC-1 patients, while HL-SCLC patients shared similar characteristics and survival with SCLC-1 patients.

This study aimed to quantitatively assess [The 60-min dynamic total-body [A total of 30 patients with stage IIIA-IV NSCLC were enrolled. Patients were divided into fast dynamic FDG metabolic group (F-DFM) and slow dynamic FDG metabolic group (S-DFM) by the unsupervised K-means classification of PTs. The F-DFM group showed significantly higher Patlak-Ki (P 0.001) and SUVThe dynamic total-body [

This prospective phase 2 study aimed to evaluate the efficacy and safety of hypofractionated radiation therapy (HRT) combined with concurrent weekly chemotherapy in patients with unresectable or recurrent thymic epithelial tumors (TETs).Patients with unresectable or recurrent intrathoracic TETs that could be encompassed within the radiation fields were enrolled. HRT using intensity modulated radiation therapy (IMRT) technique was administered with 3 different levels of radiation doses (51 Gy/17 fractions (fx), 48 Gy/12 fx, and 45 Gy/9 fx; biologically effective dose of 66.3-67.5Gy), combined with weekly docetaxel (25 mg/mFifty eligible patients enrolled from August 1, 2018, to July 1, 2020, were analyzed. Most patients (82.0%) had stage IVB tumors. Patients had IMRT-HRT (36-51 Gy in 9-17 fx, median biologically effective dose of 67.2 Gy) and concurrent weekly docetaxel/nedaplatin (2-4 cycles). During a median follow-up of 25.0 months (14.0-40.0), the ORR was 83.7%, the 2-year PFS was 59.1%, and the 2-year OS was 90.0%. There was 1 (2.0%) in-field recurrence while 19 (38.0%) patients developed out-of-field recurrence. Grade 3 pneumonitis was observed in 1 patient (2.0%). The ORR, 2-year PFS, 2-year OS, and toxicity were similar among 3 dose levels. Fourteen (28.0%) patients had 2 to 4 courses of radiation therapy because of recurrent diseases. Only 1 suffered from grade 1 pulmonary fibrosis during follow-up. Most patients (88%) maintained a stable QOL within 1 year after radiation therapy.IMRT-HRT and concurrent weekly docetaxel/nedaplatin was effective and well tolerated in unresectable or recurrent TETs. Considering the common out-of-field recurrence, this combined regimen could be an option for repeated radiation therapy. Thymosin α1 might help lower the incidence of pneumonitis and maintain the QOL.

In the past decades, polymer-drug conjugates of anticancer agents have gained much attention due to their enhanced aqueous solubility, improved pharmacokinetics, and better drug utilization than their conventional insoluble counterparts. Several polymer-drug conjugates have entered the third phase of clinical trials yet suffer from inherent deficiencies, including uncontrolled drug release and unclear degradation mechanisms. In this study, a pH/reactive oxygen species (ROS) dual-responsive PEG-doxorubicin (DOX) conjugate (denoted as TPD) was synthesized through acyl alkynyl-amine click reaction by PEG dipropiolate (PEGB), amine-terminated thioketal (TKL), and doxorubicin (DOX). Due to the generated ene-amine and thioketal in the backbone, the prepared amphiphilic TPD not only has a high drug loading ratio for photosensitizer chlorin e6 (Ce6) but also has the sensitivity to the acidic tumor microenvironment (TME) and ROS. Considering the complex conditions of TME, the prepared TPD@Ce6 nanoparticles (NPs) might respond to the relatively low pH and release Ce6 initially, and upon laser radiation, Ce6 produces abundant singlet oxygen (

As an emerging antitumor strategy, photodynamic therapy (PDT) has attracted intensive attention for the treatment of various malignant tumors owing to its noninvasive nature and high spatial selectivity in recent years. However, the therapeutic effect is unsatisfactory on some occasions due to the presence of some unfavorable factors including nonspecific accumulation of PS towards malignant tissues, the lack of endogenous oxygen in tumors, as well as the limited light penetration depth, further hampering practical application. To circumvent these limitations and improve real utilization efficiency, various enhanced strategies have been developed and explored during the past years. In this review, we give an overview of the state-of-the-art advances progress on versatile nanoplatforms for enhanced PDT considering the enhancement from targeting or responsive, chemical and physical effect. Specifically, these effects mainly include organelle-targeting function, tumor microenvironment responsive release photosensitizers (PS), self-sufficient O2 (affinity oxygen and generating oxygen), photocatalytic water splitting, X-rays light stimulate, surface plasmon resonance enhancement, and the improvement by resonance energy transfer. When utilizing these strategies to improve the therapeutic effect, the advantages and limitations are addressed. Finally, the challenges and prospective will be discussed and demonstrated for the future development of advanced PDT with enhanced efficacy.

Nanozymes are a new generation of artificial enzymes that address the limitations of natural enzymes, with numerous reports on the development of high performance nanozymes for various applications. Herein, the phase regulation of network-like MoSe2 from the metal 1T phase to semiconductor 2H phase was achieved under different reaction conditions by a facile but efficient microwave-assisted solvothermal method. The coexisting 1T/2H-MoSe2 with edge enriched and defective nanostructures showed great enhancement of the peroxidase-like properties. This high enzymatic activity may arise from optimized active sites of 1T/2H-MoSe2, effectively leading to a rapid charge transfer within the substrate. In addition, chitosan functionalization not only greatly improves the dispersion stability of MoSe2, but also significantly increases its peroxidase-like activity, probably due to its enhanced affinity to hydrogen peroxide (H2O2). Based on these results we have established a highly sensitive colorimetric assay for the detection of H2O2 and glucose in human serum.

In order to improve the therapeutic efficacy and reduce the side effects of anticancer drugs, stimuli-responsive and biodegradable drug-delivery systems have attracted significant attention in the past three decades. Herein, we report acid-responsive and degradable polyphosphazene nano-prodrugs synthesized via a one-pot cross-linking reaction of 4-hydroxybenzhydrazide-modified doxorubicin (BMD) with hexachlorocyclotriphosphazene (HCCP). The phenol groups in the as-synthesized BMD exhibited a high reactivity towards HCCP and in the presence of a basic catalyst the determined drug loading ratio of the nanoparticles, denoted as HCCP-BMD, was up to 85.64%. Interestingly, the hydrazone bonds in BMD and the skeleton of polyphosphazene tended to break down in acidic environments, and the antitumor active drug DOX was found to be released in an acidic tumor microenvironment (pH ∼ 6.8 for extracellular, and pH ∼ 5.0 for endosomes and lysosomes). The resulting HCCP-BMD prodrug exhibited high cytotoxicity to HeLa cells and could effectively suppress tumor growth, with negligible damage to normal tissues. We therefore believe that this acid- degradable polyphosphazene prodrug may offer great potential in various biomedical fields.

Aim: Adequate lymph node evaluation is recommended in patients with malignant tumors. However, the role of negative lymph nodes (NLNs) remains unclear in breast cancer (BC), especially in patients who have received neoadjuvant chemotherapy and mastectomy. Materials & methods: A total of 435 patients were included in the analysis. On multivariate analysis, NLN count was an independent predictor of 5 year disease-free survival and 5 year overall survival. Results: Patients with NLN count

This study aimed to explore the role of a modified criteria for assessing tumor response to concurrent chemoradiotherapy (CCRT) in locally advanced non-small cell lung cancer (LA-NSCLC), using the combined modalities of anatomical and functional MRI and CT.One hundred and fifty-three patients with LA-NSCLC who underwent CCRT with continuous chest MRI and CT follow-up were analyzed. The tumor response to CCRT was evaluated two months after the completion of CCRT. The RECIST criteria (CT imaging) and modified criteria (combined chest MRI and CT imaging) were compared and validated on follow-up imaging. The chest MRI scan analysis included T1C, T2fs, DWI imaging and the apparent diffusion coefficient values. Progression free survival (PFS) ≥ 18 months was used as a surrogate endpoint of complete response to analyze the accuracy of tumor response assessment.Eight (5.2%) patients were considered to have complete response (CR) by the RECIST criteria while fifty-five (35.9%) were considered to have CR (CT + MRI) by the modified criteria. Using PFS ≥ 18 months as a surrogate for CR, the sensitivity and specificity of the modified criteria were 71.2% and 90.8% (AUC = 0.810, 95%CI 0.735-0.885), but were 9.1% and 97.7%, respectively, for the RECIST criteria (AUC = 0.534, 95%CI 0.441-0.627). The median PFS was 58.4 months for patients with CR (CT + MRI) and 9.7 months for those with non-CR (P 0.001). Multivariate analysis showed that the tumor response evaluated by the modified criteria [CR (CT + MRI) vs. non-CR] was an independent factor for both PFS (HR 0.182, 95%CI 0.088-0.373, P 0.001) and overall survival (HR 0.134, 95%CI 0.044-0.410, P 0.001).Combined multi-parameter MRI and CT imaging could improve the accuracy of tumor response assessment in LA-NSCLC patients after definitive CCRT, therefore contributed to the risk stratification and survival prediction for clinical practice.

Retraction of ‘A tumor-microenvironment fully responsive nano-platform for MRI-guided photodynamic and photothermal synergistic therapy’ by Daquan Wang et al., J. Mater. Chem. B, 2020, 8, 8271–8281, https://doi.org/10.1039/D0TB01373K.

Purpose The study aimed to evaluate the efficacy and safety of concurrent chemoradiation therapy (CCRT) combined with nimotuzumab in patients with unresectable stage III squamous cell lung cancer (SqCLC). Methods and Materials A prospective, single-center, open-label, randomized phase 2 trial was performed in patients with unresectable stage III SqCLC. Patients were randomized to receive 65 Gy thoracic radiation over 5 weeks concurrent with docetaxel and cisplatin or the same CCRT regimen combined with 200 mg of nimotuzumab (NIMO-CCRT), administered weekly by intravenous infusion. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, objective response rate, failure patterns, and treatment-related toxicity. Results From August 2015 to June 2020, 126 patients with SqCLC were randomized. Four patients withdrew consent before the start of treatment, and 122 patients were included for analysis, including 57 in the NIMO-CCRT group and 65 in the CCRT group. The median OS was 24.9 months in the NIMO-CCRT group and 23.5 months in the CCRT group (P = .655). The median PFS was 12.1 months in the NIMO-CCRT group and 13.7 months in the CCRT group (P = .968). The NIMO-CCRT group had a significantly lower risk of brain metastasis, with adjusted subdistribution hazard ratio of 0.099 (95% confidence interval, 0.012-0.81; P = .031). The incidence of grade ≥3 pneumonitis (P = .894) and esophagitis (P = .974) was similar between the 2 arms. There was no grade 2 or higher skin toxicity in NIMO-CCRT group. Conclusions The coincident application of nimotuzumab with CCRT was well tolerated for locally advanced SCCL. The NIMO-CCRT group had an OS and PFS similar to that in the CCRT group, but a lower risk of brain metastasis. Further investigations are warranted.

To explore the efficacy and toxicities of split-course hypo-fractionated radiotherapy with concurrent chemotherapy (HFRT-CHT) with intensity modulated radiotherapy (IMRT) technique in non-small cell lung cancer (NSCLC) patients with postoperative locoregional recurrence (LRR).NSCLC patients were eligible if confirmed as LRR disease without distant metastasis after complete resection. HFRT-CHT using IMRT technique was administered with 51 Gy in 17 fractions or 40 Gy in 10 fractions as the first course followed by a break. Patients with no disease progression and no persistent Grade ≥2 toxicities had the second course of 15 Gy in 5 fractions or 28 Gy in 7 fractions as a boost. The primary endpoint was progression-free survival (PFS).Fifty-eight patients were enrolled and analyzed. With a median follow-up of 23.9 months for all, the 2-year and 3-year PFS rate was 59.7 % and 46.4 %, the 2-year and 3-year OS rate was 72.5 % and 52.2 %, respectively, and a favorable objective response rate of 95.9 % was obtained after the whole courses protocol. Grade 3 acute pneumonitis and esophagitis occurred in 2 (3.4 %) and 7 (12.1 %) patients, and fatal pneumonitis was reported in one case (1.7 %). Exploratory subgroup analysis showed that performance status (PS) (PS 0 vs. 1: 2-year PFS, 88.1 % vs. 46.9 %,P = 0.001; 2-year OS, 100 % vs. 59.4 %, P 0.001), recurrence site (single vs. multiple: 2-year PFS, 93.8 % vs. 47.4 %, P = 0.008; 2-year OS, 100 % vs. 63.0 %, P = 0.001), and gross tumor volume (GTV) (50cmSplit-course HFRT-CHT with IMRT technique achieved promising disease control and satisfactory survival with moderate toxicities in postoperative LRR of NSCLC. Good PS, a single recurrence site and GTV50cm

To enhance the therapeutic effects and reduce the damage to normal tissues in cancer chemotherapy, it is indispensable to develop drug delivery carriers with controllable release and good biocompatibility. In this work, acid-responsive and degradable polyphosphazene (PPZ) nanoparticles were synthesized by the reaction of hexachlorotripolyphosphonitrile (HCCP) with 4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide (HBHBH) and anticancer drug doxorubicin (DOX). The controlled release of DOX could be realized based on the acid responsiveness of acylhydrazone in HBHBH. Experimental results showed that polyphosphazene nanoparticles remained stable in the body's normal fluids (pH ∼ 7.4), while they were degraded and controllable release of DOX in an acidic environment such as tumors (pH ∼ 6.8) and lysosome and endosome (∼5.0) in cancer cells In particular, the doxorubicin (DOX)-loading ratio was fair high and could be tuned from 10.6 to 52.6% by changing the dosing ratio of DOX to HBHBH. Meanwhile, the polyphosphazene nanodrugs showed excellent toxicity to tumor cells and reduced the side effect to normal cells both in vitro and in vivo due to their enhanced permeability and retention (EPR) effect and pH-sensitive degradation properties. Therefore, the constructed pH-sensitive drug delivery system has great potential for cancer chemotherapy.

In order to maximize the therapeutic effect and and minimize the systemtic side effect of the small molecule anticancer drugs, biodegradable drug delivery systems (DDSs) that respond to tumor microenvironment (TME) have attracted significant attention. Herein, a novel redox/pH dual-responsive and biodegradable polyphosphazene (PPZ) nano-prodrugs have been prepared via one-pot crosslinking of vanillin modified DOX (VMD, acid-sensitive) and 4,4'-dihydroxydiphenyl disulfide (HPS, GSH-responsive) with hexachlorocyclotriphosphazene (HCCP). The phenol groups of the as-synthesized VMD and HPS have high nucleophilic substitution activity towards HCCP under base catalyst and afforded PPZ nano-prodrugs, denoted as HCCP-VMD-HPS, with a high drug loading ratio of up to 56.4 %. As expected, the skeleton of the PPZ consisting of imine bonds in VMD and the disulfide bonds in HPS and cyclotriphosphazenes inclined to be decomposed in low pH conditions and high level of GSH environments. The antitumor drug DOX was found to be controlled released in TME conditions (extracellular, pH∼6.8 and endosomes, lysosomes pH∼5.0 with ∼10 mM GSH), rather than neutral physiological conditions (pH 7.4 with ∼20 μM GSH). Moreover, the resulting HCCP-VMD-HPS nano-prodrug have obvious cytotoxicity to cancer cells while a negligible side effect to normal cells. We therefore believe that the prepared redox/pH dual-responsive and biodegradable PPZ DDSs have great potential in various field.

PurposeThe gross tumor volume (GTV) could be an independent prognostic factor for unresectable locally advanced non-small cell lung cancer (LANSCLC). We aimed to develop and validate a novel integrated GTV-TNM stratification system to supplement LANSCLC sub-staging in patients treated with concurrent chemoradiotherapy (CCRT).MethodsWe performed a retrospective review of 340 patients with unresectable LANSCLC receiving definitive CCRT. All included patients were divided into two randomized cohorts. Then the Kaplan-Meier method and Cox regression were calculated to access the prognostic value of the integrated GTV-TNM stratification system, which was further validated by the area under the receiver operating characteristic curve (AUC) score and F1-score.ResultsThe optimal outcome-based GTV cut-off values (70 and 180 mL) of the modeling cohort were used to determine each patient’s integrated GTV-TNM stratum in the whole cohort. Our results indicated that a lower integrated GTV-TNM stratum could had better overall survival and progression-free survival (all PP=0.027) and F1-score (0.655 vs. 0.615, PConclusionsWe proposed a novel integrated GTV-TNM stratification system to supplement unresectable LANSCLC sub-staging due to its prognostic value independent of TNM stage and other clinical characteristics, suggesting that it could be considered in pretreatment assessment and individual treatment decision-making process.

Multifunctional intelligent theranostics agents are promising for next-generation oncotherapy. We fabricated a tumor-microenvironment (TME)-responsive carbon nanotube (CNT)-based nanoplatform for T1 weighted magnetic resonance imaging (MRI)-guided synergistic photodynamic and photothermal therapy (PDT and PTT). CNTs convert near infrared (NIR) radiation into hyperthermia for PTT, and can effectively deliver their cargo into cells due to their unique 1D nanostructure. The CNT@MnO2-PEG@Ce6 nanomedicine was internalized into tumor cells, and rapidly released the photosensitizer (Ce6) in response to the low pH and high glutathione (GSH) levels characteristic of the TME. The degradation of the MnO2 layer under the same conditions released Mn2+ for T1-MRI. Furthermore, catalytic decomposition of the excess H2O2 into oxygen by MnO2 enhanced the efficacy of PDT, relieved hypoxia, and increased consumption of superfluous GSH to mitigate the effects of excessive reactive oxygen species (ROS) generation during PDT. MRI-guided PDT and PTT synergistically inhibited tumor cell growth in vitro, and ablated tumors in vivo. The side effects were negligible due to specific tumor cell targeting via surface modification with folic-PEG, and enhanced permeability and retention. Taken together, CNT@MnO2-PEG is a fully TME-responsive theranostics nanoplatform for targeted tumor ablation and real-time disease tracking.

Daquan Wang,1,* Jiayun Chen,1,* Xiaodong Zhang,2 Tao Zhang,1 Luhua Wang,1 Qinfu Feng,1 Zongmei Zhou,1 Jianrong Dai,1 Nan Bi1 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this workCorrespondence: Nan BiDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuannanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel +86 10 87788995Email binan_email@163.comBackground: The technique of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) has been widely used in locally advanced non-small cell lung cancer; however, its dosimetric advantages are seldom reported. This study aimed to quantify dosimetric advantages of SIB-VMAT.Methods: Forty patients with stage III non-small cell lung cancer in our hospital were retrospectively included. SIB-VMAT and conventional VMAT (C-VMAT) plans were generated for every patient using the automatic treatment planning system. A reduced dose was delivered to PTV in SIB-VAMT plans compared to C-VMAT plans (50.4Gy vs 60Gy). The prescribed dose was 50.4 Gy in 28 fractions to PTV and 59.92 Gy in 28 fractions to PGTV in SIB-VMAT plans, while 60 Gy in 30 fractions to PTV in C-VMAT plans. Dose-volume metrics of PTV, total lung, heart, esophagus and spinal cord were recorded. The quality score was used to evaluate organs at risk (OAR) protection for two type prescription plans.Results: Conformal coverage of the targets (PGTV/PTV) by 95% of the prescription dose was well achieved in radiation plans. SIB-VMAT plans achieved significantly higher quality score than C-VMAT plans (Mean: 68.15± 13.32 vs 49.15± 13.35, P< 0.001). More plans scored above sixty in SIB-VMAT group compared to C-VMAT group (72.5% vs 20%, P< 0.001). Notable reductions in mean dose, V30, V40 and V50 of total lung were observed in SIB-VMAT plans compared to C-VMAT plans, with median decreased proportions of 6.5%, 8.7%, 19.6% and 32.1%, respectively. Statistically significant decrease in heart V30 and V40 was also achieved in SIB-VMAT plans, with median decreased proportions of 26.1% and 38.8%. SIB-VMAT plans achieved significant reductions in the maximum doses to both esophagus and spinal cord. Patients with CTV/(GTV+GTVnd) ≥ 8.6 showed more notable decrease in total lung V50 (median, 33.6% vs 28.8%, P=0.001) in SIB-VMAT plans compared to those with the ratio being less than 8.6.Conclusion: SIB-VMAT technique could lead to a substantial sparing of normal organs, including lung, heart, esophagus and cord, mainly through reducing high and inter-median dose exposure. Patients with CTV/(GTV+GTVnd) ≥ 8.6 might benefit more from SIB-VMAT.Keywords: lung cancer, simultaneous integrated boost, radiotherapy, automatic planning, organ at risks

Nanozymes are a new generation of artificial enzymes that address the limitations of natural enzymes, with numerous reports on the development of high performance nanozymes for various applications. Herein, the phase regulation of network-like MoSe2 from the metal 1T phase to semiconductor 2H phase was achieved under different reaction conditions by a facile but efficient microwave-assisted solvothermal method. The coexisting 1T/2H-MoSe2 with edge enriched and defective nanostructures showed great enhancement of the peroxidase-like properties. This high enzymatic activity may arise from optimized active sites of 1T/2H-MoSe2, effectively leading to a rapid charge transfer within the substrate. In addition, chitosan functionalization not only greatly improves the dispersion stability of MoSe2, but also significantly increases its peroxidase-like activity, probably due to its enhanced affinity to hydrogen peroxide (H2O2). Based on these results we have established a highly sensitive colorimetric assay for the detection of H2O2 and glucose in human serum.

Dual fuel of biomass and natural gas can provide a cost effective and reliable method of simultaneously using renewable energy and fossil energy, and it offers advantages such as flexibility and environmental friendliness. In this paper, a dual fuel combined cooling, heating, and power (CCHP) system primarily composed of a gasifier, gas conditioning unit, gas storage tank, internal combustion engine (ICE), absorption chiller/heater, and heat exchanger is proposed as an energy supply system for a hypothetical hotel. The system is analyzed and evaluated from the viewpoint of thermodynamics and exergoeconomics under design conditions in summer and winter seasons. The exergy efficiencies, exergy losses, and exergoeconomic behaviors of each component in the system are calculated and analyzed; then, the exergoeconomic costs of chilled water, heating water, electricity, and domestic hot water are calculated. Furthermore, a sensitivity analysis is performed to evaluate the impact of fuel prices on the unit exergy cost of the products. The results indicate that the exergy efficiencies of the system in summer and winter are 8.06% and 12.23%, respectively. Exergy loss analyses indicate that the largest loss occurs in the gasifier and accounts for more than 60% of the total exergy losses. Exergoeconomic analysis shows that the unit exergoeconomic cost of the products is higher in winter than in summer. Sensitivity analysis demonstrates that the products are more sensitive to the price of natural gas than biomass.

Hollow microporous nanostructures (HMNs) are powerful platforms for multiple promising applications, including energy storage, drug/gene delivery, nanoreactors/catalysis, adsorption, and separation. Herein, we report a facile one-step method to synthesize highly cross-linked organic-inorganic hybrid poly(cyclotriphosphazene-co-4,4'-sulfonyldiphenol) (PZS) HMNs via a salt-induced liquid-liquid separation process. The size of inner cavities can be properly tuned by modulating the concentration of the NaOH solution. The regulation mechanism of the PZS HMNs was further confirmed by encapsulating water-dispersed Pt nanoclusters into the cavities. Interestingly, the resulting yolk-shell Pt@PZS serves as nanoreactors and exhibits excellent substrate selectivity and recyclability for the catalytic oxidation of 1,3,5-trimethylbenzene.

Although the collaborative therapy of chemotherapy (CT) and photodynamic therapy (PDT) is much more efficient for tumor treatment than monotherapies, premature leakage of drugs from nanocarriers and hypoxia in the tumor microenvironment (TME) result in systemic toxicity and suboptimal therapy efficiency. To overcome these limitations, we developed an intelligent nanoflower composite (termed FHCPC@MnO2) by coating functionalized polyphosphazene on superparamagnetic Fe3O4 nanoclusters and then growing MnO2 nanosheets as an outer shell. The FHCPC@MnO2 nanoflowers with multistage H2O2/pH/GSH-responsive properties could fully exploit TME characteristics, including supernormal glutathione (GSH) levels, low pH and high H2O2, to realize the specific release of drugs in tumors and maximum synergetic therapeutic effects. The MnO2 nanosheets can elevate O2 concentration by catalytic decomposition of H2O2 and can be simultaneously reduced to Mn2+ by overexpressed GSH in the acidic TME. Meanwhile, the inner polyphosphazene containing (bis-(4-hydroxyphenyl)-disulfide) is GSH- and pH-sensitively biodegradable to release the anticancer drug curcumin (CUR) and photosensitizer chlorin e6 (Ce6) in the TME. Therefore, the "triple-responsive" and synergetic strategy simultaneously endows the nanoflowers with specific drug release, relieving hypoxia and the antioxidant capability of the tumor and achieving significant optimization of CT and PDT. In addition, the resulting Mn2+ ions and Fe3O4 core enable in vivo T1/T2 magnetic resonance imaging (MRI), while the released Ce6 can simultaneously provide a fluorescence imaging (FL) function. Unsurprisingly, the intelligent nanoflowers exhibited remarkable multimodal theranostic performance both in vitro and in vivo, suggesting their great potential for precision medicine.

Background : The technique of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) have been widely used in locally advanced non-small cell lung cancer, however, its dosimetric advantages are seldom reported. This study aimed to investigate the dosimetric benefit of SIB-VMAT compared to conventional VMAT plans (C-VMAT). Methods : Forty patients with stage III non-small cell lung cancer in our hospital were randomly selected for the two type prescriptions. SIB-VMAT and C-VMAT plans were generated for each patient with the same optimization parameter by the automatic treatment planning system (TPS). The prescribed dose was 50.4 Gy in 28 fractions to PTV and 59.92 Gy in 28 fractions to PGTV in SIB-VMAT plans, with 60 Gy in 30 fractions to PTV in C-VMAT plans. Dose-volume metrics for the planning target volume, lung, heart, esophagus and spinal cord were recorded. The quality score (S D ) was used to evaluate organ at risks (OARs) protection for two type prescription plans. Results : Conformal coverage of the PGTV/PTV by the 95% of the prescription dose was well achieved in automated plans. SIB-VMAT plans achieved significantly lower S D values than C-VMAT plans (Mean: 0.064±0.106 vs. 0.145±0.181, P=0.001). Obvious reductions in mean dose, V 30 , V 40 and V 50 of total lung were observed in SIB-VMAT plans compared to C-VMAT plans, with median decreased proportions of 6.5%、8.7%、19.6% and 32.1%. Statistically significant decrease in heart V 30 and V 40 were also achieved in SIB-VMAT plans, with median decreased proportions of 26.1% and 38.8%. SIB-VMAT plans achieved significant reductions in the maximum doses to both esophagus and spinal cord. Conclusions : SIB-VMAT technique could lead to a substantial sparing of normal organs, including lung, heart, esophagus and cord, mainly through reducing high and inter-median dose exposure.

Combining doxorubicin with thermal therapy in the clinic has led to startling results in the treatment of problematic cancers. Here, we describe a multimo dal multi-walled carbon nanotube material that combines tumor targeting, doxorubicin delivery, and photothermal therapy for localized cancer treatment. The agent was constructed layer-by-layer from polypyrrole and gold nanoparticles on multi-walled carbon nanotubes. The gold surface was modified with tumor targeting folic acid terminated PEGylated chains, which also provide water-dispersibility, biocompatibility and should extend the half-life in blood. The material has a high loading/unloading capacity for the cytotoxic agent doxorubicin. Release of the doxorubicin, combined with the photothermal properties of the material that induces localized hyperthermia, leads to efficient cancer cell death.

Background Baseline lung immune prognostic index (LIPI) was reported as a potential predictive biomarker of immune checkpoint inhibitor treatment and a prognostic biomarker for metastatic non-small cell lung cancer (NSCLC). However, it remains unclear whether LIPI is associated with outcomes in locally advanced NSCLC (LA-NSCLC). Materials/methods Patients with LA-NSCLC receiving radiotherapy between 2000 to 2017 were retrospectively reviewed. Based on pretreatment dNLR and LDH level made up LIPI per previous publications, patients were divided into good group (0 score) and intermediate-poor group (1 or 2 scores). Propensity score matching (PSM) was conducted to balance confounding variables. Results A total of 1079 patients were eligible for analysis. Patients with intermediate-poor pretreatment LIPI had inferior overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) than those with good LIPI. Multivariate analysis suggested that LIPI was an independent prognostic marker for OS (hazard ratio [HR] = 1.19, 95% CI: 1.02–1.40), PFS (HR = 1.18, 95% CI: 1.02–1.36), and LRRFS (HR = 1.22, 95% CI: 1.05–1.41) in patients with inoperable LA-NSCLC. PSM analysis further verified that intermediate-poor LIPI was an independent prognostic factor for shorter survivals (OS, PFS and LRRFS). Conclusions LIPI is a simple and promising prognostic marker for patients with unresectable LA-NSCLC. Further prospected studies are warranted to validated these findings.