Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

Non-invasive prediction model of axillary lymph node status in patients with early-stage breast cancer: a feasibility study based on dynamic contrast-enhanced-MRI radiomics.

OBJECTIVES: Accurate axillary evaluation plays an important role in prognosis and treatment planning for breast cancer. This study aimed to develop and validate a dynamic contrast-enhanced (DCE)-MRI-based radiomics model for preoperative evaluation of axillary lymph node (ALN) status in early-stage breast cancer. METHODS: A total of 410 patients with pathologically confirmed early-stage invasive breast cancer (training cohort, N = 286; validation cohort, N = 124) from June 2018 to August 2022 were retrospectively recruited. Radiomics features were derived from the second phase of DCE-MRI images for each patient. ALN status-related features were obtained, and a radiomics signature was constructed using SelectKBest and least absolute shrinkage and selection operator regression. Logistic regression was applied to build a combined model and corresponding nomogram incorporating the radiomics score (Rad-score) with clinical predictors. The predictive performance of the nomogram was evaluated using receiver operator characteristic (ROC) curve analysis and calibration curves. RESULTS: Fourteen radiomic features were selected to construct the radiomics signature. The Rad-score, MRI-reported ALN status, BI-RADS category, and tumour size were independent predictors of ALN status and were incorporated into the combined model. The nomogram showed good calibration and favourable performance for discriminating metastatic ALNs (N + (≥1)) from non-metastatic ALNs (N0) and metastatic ALNs with heavy burden (N + (≥3)) from low burden (N + (1-2)), with the area under the ROC curve values of 0.877 and 0.879 in the training cohort and 0.859 and 0.881 in the validation cohort, respectively. CONCLUSIONS: The DCE-MRI-based radiomics nomogram could serve as a potential non-invasive technique for accurate preoperative evaluation of ALN burden, thereby assisting physicians in the personalized axillary treatment for early-stage breast cancer patients. ADVANCES IN KNOWLEDGE: This study developed a potential surrogate of preoperative accurate evaluation of ALN status, which is non-invasive and easy-to-use.

Geometric Origin of Non-Bloch PT Symmetry Breaking.

The parity-time (PT) symmetry of a non-Hermitian Hamiltonian leads to real (complex) energy spectrum when the non-Hermiticity is below (above) a threshold. Recently, it has been demonstrated that the non-Hermitian skin effect generates a new type of PT symmetry, dubbed the non-Bloch PT symmetry, featuring unique properties such as high sensitivity to the boundary condition. Despite its relevance to a wide range of non-Hermitian lattice systems, a general theory is still lacking for this generic phenomenon even in one spatial dimension. Here, we uncover the geometric mechanism of non-Bloch PT symmetry and its breaking. We find that non-Bloch PT symmetry breaking occurs by the formation of cusps in the generalized Brillouin zone (GBZ). Based on this geometric understanding, we propose an exact formula that efficiently determines the breaking threshold. Moreover, we predict a new type of spectral singularities associated with the symmetry breaking, dubbed non-Bloch van Hove singularity, whose physical mechanism fundamentally differs from their Hermitian counterparts. This singularity is experimentally observable in linear responses.

Development and Validation of a Dual-Energy CT-Based Model for Predicting the Number of Central Lymph Node Metastases in Clinically Node-Negative Papillary Thyroid Carcinoma.

RATIONALE AND OBJECTIVES: This study aimed to develop and validate a dual-energy CT (DECT)-based model for preoperative prediction of the number of central lymph node metastases (CLNMs) in clinically node-negative (cN0) papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Between January 2016 and January 2021, 490 patients who underwent lobectomy or thyroidectomy, CLN dissection, and preoperative DECT examinations were enrolled and randomly allocated into the training (N = 345) and validation cohorts (N = 145). The patients' clinical characteristics and quantitative DECT parameters obtained on primary tumors were collected. Independent predictors of> 5 CLNMs were identified and integrated to construct a DECT-based prediction model, for which the area under the curve (AUC), calibration, and clinical usefulness were assessed. Risk group stratification was performed to distinguish patients with different recurrence risks. RESULTS: More than 5 CLNMs were found in 75 (15.3%) cN0 PTC patients. Age, tumor size, normalized iodine concentration (NIC), normalized effective atomic number (nZeff) and the slope of the spectral Hounsfield unit curve (λHu) in the arterial phase were independently associated with> 5 CLNMs. The DECT-based nomogram that incorporated predictors demonstrated favorable performance in both cohorts (AUC: 0.842 and 0.848) and significantly outperformed the clinical model (AUC: 0.688 and 0.694). The nomogram showed good calibration and added clinical benefit for predicting> 5 CLNMs. The KaplanMeier curves for recurrence-free survival showed that the high- and low-risk groups stratified by the nomogram were significantly different. CONCLUSION: The nomogram based on DECT parameters and clinical factors could facilitate preoperative prediction of the number of CLNMs in cN0 PTC patients.

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells.

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

The additional radiotherapy to adjuvant chemotherapy improves the prognosis of stage III-N2 with highest mediastinal lymph node metastasis in non-small cell lung cancer.

INTRODUCTION: The benefits of adjuvant chemoradiation therapy (CRT) for heterogeneous pathological N2 (pN2) diseases remain unclear in non-small cell lung cancer (NSCLC). This study aimed to investigate suitable pN2 patients for adjuvant CRT. MATERIAL AND METHODS: This study retrospectively reviewed the data of patients with pN2 NSCLC in Shanghai Pulmonary Hospital from January 2012 to December 2016. Included cases were subdivided as highest mediastinal lymph node (HM) (n = 732) metastasis and non-HM metastasis (n = 677) groups according to the International Association for the Study of Lung Cancer (IASLC). Furthermore, the Kaplan-Meier and Cox models were used to evaluate the prognostic benefits of adjuvant CRT in heterogeneous pN2 subgroups. RESULTS: A total of 1409 patients were enrolled in this study, with a median follow-up time of 63.8 months. Patients with HM involvement had worse prognoses (p < 0.001 for recurrence-free survival (RFS) and overall survival (OS)). Furthermore, the survival improvement of adjuvant CRT was significant for these patients (p < 0.001 for RFS and p = 0.032 for OS), regardless of whether it was single (p < 0.001 for RFS and p = 0.029 for OS) or multiple pN2 (p < 0.001 for RFS and p = 0.026 for OS) diseases. According to multivariable cox analysis, the long-term RFS and OS in the cancerous HM group were independently predicted by pathological N stage (p = 0.002 for RFS and p < 0.001 for OS) and adjuvant CRT (p < 0.001 for RFS and p = 0.011 for OS). CONCLUSION: Metastatic HM was associated with a worse prognosis in pN2 disease. Our analysis supported that adjuvant CRT significantly improved both RFS and OS for these patients.

MRI-based radiomics model for distinguishing Stage I endometrial carcinoma from endometrial polyp: a multicenter study.

BACKGROUND: Patients with early endometrial carcinoma (EC) have a good prognosis, but it is difficult to distinguish from endometrial polyps (EPs). PURPOSE: To develop and assess magnetic resonance imaging (MRI)-based radiomics models for discriminating Stage I EC from EP in a multicenter setting. MATERIAL AND METHODS: Patients with Stage I EC (n = 202) and EP (n = 99) who underwent preoperative MRI scans were collected in three centers (seven devices). The images from devices 1-3 were utilized for training and validation, and the images from devices 4-7 were utilized for testing, leading to three models. They were evaluated by the area under the receiver operating characteristic curve (AUC) and metrics including accuracy, sensitivity, and specificity. Two radiologists evaluated the endometrial lesions and compared them with the three models. RESULTS: The AUCs of device 1, 2_ada, device 1, 3_ada, and device 2, 3_ada for discriminating Stage I EC from EP were 0.951, 0.912, and 0.896 for the training set, 0.755, 0.928, and 1.000 for the validation set, and 0.883, 0.956, and 0.878 for the external validation set, respectively. The specificity of the three models was higher, but the accuracy and sensitivity were lower than those of radiologists. CONCLUSION: Our MRI-based models showed good potential in differentiating Stage I EC from EP and had been validated in multiple centers. Their specificity was higher than that of radiologists and may be used for computer-aided diagnosis in the future to assist clinical diagnosis.

Metabolomic differentiation of benign vs malignant pulmonary nodules with high specificity via high-resolution mass spectrometry analysis of patient sera.

Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening.

Prediction of placenta accreta spectrum with nomogram combining radiomic and clinical factors: A novel developed and validated integrative model.

OBJECTIVE: To develop and validate a clinicoradiomic nomogram based on sagittal T2WI images to predict placenta accreta spectrum (PAS). METHODS: Between October 2016 and April 2022, women suspected of PAS by ultrasound were enrolled. After taking into account exclusion criteria, 132 women were retrospectively included in the study. The variance threshold SelectKBest and the least absolute shrinkage and selection operator were applied to select radiomic features, which was further used to calculate the Rad-score. Multivariable logistic regression was used to screen clinical factor. RESULTS: Based on 13 radiomic features, five radiomic models were constructed. A clinical factor of intraplacental T2-hypointense bands was obtained by multivariate logistic regression. The area under the curve (AUC) value of the stochastic gradient descent (SGD) radiomic model was 0.82 in the training cohort and 0.78 in the test cohort. After adding clinical factors to the SGD radiomic model, the AUC value of the clinicoradiomic model was significantly increased from 0.82 and 0.78 to 0.84 in both the training and test cohorts. The nomogram of the clinicoradiomic model was constructed, which had good performance verified by calibration and a decision curve. CONCLUSION: The presented nomogram could be useful for predicting PAS.

Normalization Approach by a Reference Material to Improve LC-MS-Based Metabolomic Data Comparability of Multibatch Samples.

Large cohorts of samples from multiple batches are usually required for global metabolomic studies to characterize the metabolic state of human disease. As such, it is critical to eliminate systematic variation and truly reveal the biologically associated alterations. In this study, we proposed a reference material-based approach (Ref-M) for data correction by liquid chromatography-mass spectrometry and represented by an analysis of multibatch human serum samples. The reference material was generated by mixing serum from healthy donors and distributed to each extraction batch of subject samples. Pooled quality control samples and isotopic internal standards were then applied in each acquisition batch for data quality control. Finally, each metabolite in subject samples was normalized by its counterpart in the reference serum. We demonstrated that Ref-M significantly enhanced the numbers of efficient features and effectively eliminated the batch variation of 522 serum samples of healthy individuals, benign pulmonary nodules, and lung cancer patients. Twenty differential metabolites were identified to distinguish lung cancer from healthy controls in the training set. The discriminant model was validated in an independent data set with an area under the receiver operating characteristics (ROC) curve (AUC) of 0.853. Another 40 serum samples further tested with Ref-M were achieved an AUC of 0.843 by the established model. Our results showed that the reference material-based approach presents the potential to improve the data comparability and precision for biomarker discovery in large-scale metabolomic studies.

Developing Bi-Gold Compound BGC2a to Target Mitochondria for the Elimination of Cancer Cells.

Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.

Intraplacental T2-hypointense bands may help predict placental invasion depth and postpartum hemorrhage in placenta accrete spectrum disorders in high-risk gravid patients.

INTRODUCTION: Accurate noninvasive prenatal diagnosis of placenta accreta spectrum (PAS) disorder is critical for delivery management. PURPOSE: To evaluate the diagnostic ability of MRI features in predicting the PAS, invasive depth and postpartum hemorrhage (PPH) in high-risk gravid patients. MATERIALS AND METHODS: Between February 2019 and November 2020, women with ultrasound (US)-suspected PAS were enrolled. With the exclusion criteria, 80 women were included in the study. Two experienced genitourinary radiologists reviewed and recorded the MRI features. The chi square test was used to compare the effectiveness of MRI features. Relative risk ratios were computed to test the association of intraplacental T2-hypointense bands with poor outcomes of cesarean section. Receiver operating characteristic (ROC) analyses based on the number and area of intraplacental T2-hypointense bands were used to predict PAS, invasion depth, and PPH. RESULTS: PAS was diagnosed in 56 of 80 women (70%). At delivery, 24 of 80 women (30%) experienced PPH (≥1000 mL). Intraplacental T2-hypointense bands were detected at MRI in 28 of 56 women with PAS (50%). The relative risk ratio of intraplacental T2-hypointense bands was 1.51 for PAS, 3.17 for depth of PAS invasiveness and 4.74 for PPH. The largest areas of intraplacental T2-hypointense bands for predicting PAS, invasion depth and PPH were 0.66 cm2, 1.68 cm2 and 1.99 cm2, respectively. DISCUSSION: The appearance of intraplacental T2-hypointense bands has important diagnostic value for PAS, its invasion depth and PPH. The area of the largest T2-hypointense band in the placenta can predict poor outcomes of cesarean section.

Design and Synthesis of Dual EZH2/BRD4 Inhibitors to Target Solid Tumors.

EZH2 inhibitors that prevent trimethylation of histone lysine 27 (H3K27) are often limited to the treatment of a subset of hematological malignancies. In most solid tumors, EZH2 inhibitors induce reciprocal H3K27 acetylation that subsequently results in acquired drug resistance. The combination of EZH2 and BRD4 inhibitors to resensitize solid cancer cells to EZH2 inhibitors has proven to be effective, underlying the significance of developing dual inhibitors. Herein, we present the design, synthesis, and biological evaluation of first-in-class dual EZH2/BRD4 inhibitors. Our most promising compound, YM458, displays potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative capacity against 11 solid cancer cell lines. Its in vivo therapeutic potential is validated in both lung cancer and pancreatic cancer xenograft tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors to target a broad scope of EZH2 inhibitor-resistant solid tumors.

Flag leaf cell wall functional groups and components play a crucial role in the accumulation and translocation of Cd in rice grain via foliage application of humic acid.

Devising a low-cost and effective strategy to reduce Cd contamination of brown rice is critical to achieve the safe production of rice grain for human consumption. Accordingly, here field experiments were conducted at two sites to evaluate the effects of applying humic acid (HA) to foliage twice, at the booting and full heading stage, on diminishing the translocation of cadmium (Cd) into rice grains. Besides measuring the Cd subcellular distribution in the flag leaf and the polysaccharide composition of the cell wall, the latter's types and concentrations of functional groups were quantitatively analyzed by potentiometric titration and fitted by a surface complexation model. The results demonstrated that applying HA to leaves not only increased the rice yield but also reduced the Cd concentration in brown rice by 35.48-39.74% when using an application rate of just 600 g/ha. The HA treatment augmented Cd fixation in flag leaves, reduced the Cd translocation to rachis and brown rice, and increased the subcellular distribution of Cd in flag leaf cell wall. Furthermore, the Cd concentration in the pectin and hemicellulose 1 of cell wall increased by 33.00% and 25.73%, respectively. Besides those effects, foliar spraying of HA induced a greater abundance of carboxyl, hydroxyl, and amino groups on the cell wall, allowing for more sites to be involved in the binding of Cd, thereby promoting the immobilization of Cd in the flag leaf, and ultimately reducing the remobilization of Cd into the grain. Thus, foliage application of HA may offer a promising and cost-effective tactic for the remediation and continued use of Cd-contaminated paddy soils. CAPSULE: Foliage application of humic acid promoted the deposition of Cd in the cell wall of rice flag leaf, thereby enhancing the immobilization of Cd and ultimately reducing the remobilization of Cd into the grain.

Non-Hermitian Edge Burst.

We unveil an unexpected non-Hermitian phenomenon, dubbed edge burst, in non-Hermitian quantum dynamics. Specifically, in a class of non-Hermitian quantum walk in periodic lattices with open boundary condition, an exceptionally large portion of loss occurs at the system boundary. The physical origin of this edge burst is found to be an interplay between two unique non-Hermitian phenomena: non-Hermitian skin effect and imaginary gap closing. Furthermore, we establish a universal bulk-edge scaling relation underlying the non-Hermitian edge burst. Our predictions are experimentally accessible in various non-Hermitian systems including quantum-optical and cold-atom platforms.

Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.

Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U-13C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U-13C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo. Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future.

A triple enhanced permeable gold nanoraspberry designed for positive feedback interventional therapy.

Due to the unique microenvironment, nanoparticles cannot easily penetrate deeply into tumours, which decreases their therapeutic efficacy. Thus, new strategies should be developed to solve this problem and increase the efficacy of nanomedicine. In this study, gold nanoraspberries (GNRs) were constructed using ultrasmall gold nanospheres (UGNPs) with a matrix metalloproteinase (MMP)-2/9-sensitive peptide as a cross-linking agent. These UGNPs were then modified with trastuzumab (TRA) and mertansine derivatives (DM1) via the AuS bond. TRA targets the human epidermal growth factor receptor-2 (Her-2) which is overexpressed on Her-2+ breast cancer cells. The AuS bond in GNRs-DM1 can be replaced by the free sulfhydryl group of GSH, which could achieve GSH dependent redox responsive release of the drug. In the mouse model of Her-2+ breast cancer, a "positive feedback" triple enhanced penetration platform was construct to treat tumours. Firstly, near-infrared light-triggered photothermal conversion increased vascular permeability, resulting in nanoparticle penetration. Secondly, GNRs disintegrated into UGNPs in response to stimulation with MMPs. GNRs with larger particle sizes reached the tumour site through EPR effect and active targeting. Meanwhile, UGNPs with smaller particle sizes penetrated deeply into the tumour through diffusion. Thirdly, the UGNPs transformed activated cancer-associated fibroblasts to a quiescent state, which reduced intercellular pressure and promoted the penetration of the UGNPs into the interior of the tumour. In turn, an increase in the number of nanoparticles penetrating into the tumour led to a "positive feedback" loop of triple enhanced photothermal effects and further self-amplify the permeability in vivo. Interventional photothermal therapy (IPTT) was used to improve the therapeutic efficacy by reducing the laser power attenuation caused by percutaneous irradiation. The GNRs also showed excellent multimode imaging (computed tomography, photoacoustic imaging and photothermal imaging) capabilities and high anti-tumour efficacy due to efficient tumour targeting and triple enhanced deep penetration into the tumour site. Thus, these MMP-2/redox dual-responsive GNRs are promising carriers of drugs targeting human epidermal growth factor receptor 2+ breast cancer.

Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library.

Internal tandem duplication in the FLT3 receptor tyrosine kinase (FLT3/ITD mutation) occurs in approximately 25% of acute myeloid leukemia (AML) patients. To specifically target this driver mutation in AML, we assessed and compared the cell-based cytotoxicity of a diversity library (10,000 compounds) against the normal cell line BaF3 and the isogenic leukemic cell line BaF3/ITD. A benzoimidazole scaffold-based compound (HP1142) was identified as the most selective compound against a series of murine and human leukemia cells with FLT3/ITD. Novel benzoimidazole compounds were further designed to improve the aqueous solubility of HP1142. The most potent compound, HP1328, demonstrated desirable pharmaceutical and pharmacokinetic properties. Treatment with HP1328 significantly reduced the leukemia burden and prolonged the survival of mice with FLT3/ITD leukemia. Our findings establish the specific activity of the benzoimidazole compound against FLT3/ITD leukemia and warrant further investigation in this subset of leukemia patients with poor prognosis.

Emerging Antibacterial Strategies with Application of Targeting Drug Delivery System and Combined Treatment.

At present, some bacteria have developed significant resistance to almost all available antibiotics. One of the reasons that cannot be ignored is long-term exposure of bacteria to the sub-minimum inhibitory concentration (MIC) of antibiotics. Therefore, it is necessary to develop a targeted antibiotic delivery system to improve drug delivery behavior, in order to delay the generation of bacterial drug resistance. In recent years, with the continuous development of nanotechnology, various types of nanocarriers that respond to the infection microenvironment, targeting specific bacterial targets, and targeting infected cells, and so on, are gradually being used in the delivery of antibacterial agents to increase the concentration of drugs at the site of infection and reduce the side effects of drugs in normal tissues. Here, this article describes in detail the latest research progress on nanocarriers for antimicrobial, and commonly used targeted antimicrobial strategies. The advantages of the combination of nanotechnology and targeting strategies in combating bacterial infections are highlighted in this review, and the upcoming opportunities and remaining challenges in this field are rationally prospected.