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Accurately distinguishing tumor cells from normal cells is a key issue in tumor diagnosis, evaluation, and treatment. Fluorescence-based immunohistochemistry as the standard method faces the inherent challenges of the heterogeneity of tumor cells and the lack of big data analysis of probing images. Here, we have demonstrated a machine learning-driven imaging method for rapid pathological diagnosis of five types of cancers (breast, colon, liver, lung, and stomach) using a perovskite nanocrystal probe. After conducting the bioanalysis of survivin expression in five different cancers, high-efficiency perovskite nanocrystal probes modified with the survivin antibody can recognize the cancer tissue section at the single cell level. The tumor to normal (T/N) ratio is 10.3-fold higher than that of a conventional fluorescent probe, which can successfully differentiate between tumors and adjacent normal tissues within 10 min. The features of the fluorescence intensity and pathological texture morphology have been extracted and analyzed from 1000 fluorescence images by machine learning. The final integrated decision model makes the area under the receiver operating characteristic curve (area under the curve) value of machine learning classification of breast, colon, liver, lung, and stomach above 90% while predicting the tumor organ of 92% of positive patients. This method demonstrates a high T/N ratio probe in the precise diagnosis of multiple cancers, which will be good for improving the accuracy of surgical resection and reducing cancer mortality.

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [ 68 Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [ 68 Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sonodynamic therapy (SDT) has promising application prospects in tumor therapy. However, SDT does not eradicate metastatic tumors. Herein, Cu-substituted ZnAl ternary layered double hydroxide nanosheets (ZCA NSs) were developed as both sonosensitizers and copper nanocarriers for synergistic SDT/cuproptosis cancer therapy. An optimized electronic structure more conducive to the sonodynamic process was obtained from ZCA NSs via the Jahn-Teller effect induced by the introduction of Cu 2+ , and the synthesized ZCA NSs regulated the intricate tumor microenvironment (TME) by depleting endogenous glutathione (GSH) to amplify oxidative stress for further enhanced SDT performance. Furthermore, cuproptosis was evoked by intracellular overload of Cu 2+ and amplified by SDT, leading to irreversible proteotoxicity. In vitro results showed that such synergetic SDT/cuproptosis triggered immunogenic cell death (ICD) and promoted the maturation of dendritic cells (DCs). Furthermore, the as-synthesized ZCA NS-mediated SDT/cuproptosis thoroughly eradicated the in vivo solid tumors and simultaneously elicited antitumor immunity to suppress lung and liver metastasis. Overall, this work established a nanoplatform for synergistic SDT/cuproptosis with a satisfactory antitumor immunity.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy., (© 2023 Wu et al.)

Bioactive inorganic nanomaterials and the biological effects of metal ions have attracted extensive attention in tumor therapy in recent years. Vanadium (V), as a typical bioactive metal element, regulates a variety of biological functions. However, its role in antitumor therapy remains to be revealed. Herein, biodegradable vanadium disulfide (VS 2 ) nanosheets (NSs) were prepared as a responsive gas donor and bioactive V source for activating cancer immunotherapy in combination with immune-checkpoint blockade therapy. After PEGylation, VS 2 -PEG exhibited efficient glutathione (GSH) depletion and GSH-activated hydrogen sulfide (H 2 S) release. Exogenous H 2 S caused lysosome escape and reduced adenosine triphosphate (ATP) synthesis in tumor cells by interfering with the mitochondrial membrane potential and inducing acidosis. In addition, VS 2 -PEG degraded into high-valent vanadate, leading to Na + /K + ATPase inhibition, potassium efflux, and interleukin (IL)-1β production. Together with further induction of ferroptosis and immunogenic cell death, a strong antitumor immune response was stimulated by reversing the immunosuppressive tumor microenvironment. Moreover, the combined treatment of VS 2 -PEG and α-PD-1 amplified antitumor therapy, significantly suppressed tumor growth, and further elicited robust immunity to effectively defeat tumors. This work highlights the biological effects of vanadium for application in cancer treatment.

Oxygen-deficient molybdenum oxide (MoO X ) nanomaterials are prepared as novel nanosensitizers and TME-stimulants for ultrasound (US)-enhanced cancer metalloimmunotherapy. After PEGylation, MoO X -PEG exhibits efficient capability for US-triggered reactive oxygen species (ROS) generation and glutathione (GSH) depletion. Under US irradiation, MoO X -PEG generates a massive amount of ROS to induce cancer cell damage and immunogenic cell death (ICD), which can effectively suppress tumor growth. More importantly, MoO X -PEG itself further stimulates the maturation of dendritic cells (DCs) and triggeres the activation of the cGAS-STING pathway to enhance the immunological effect. Due to the robust ICD induced by SDT and efficient DC maturation stimulated by MoO X -PEG, the combination treatment of MoO X -triggered SDT and aCTLA-4 further amplifies antitumor therapy, inhibits cancer metastases, and elicits robust immune responses to effectively defeat abscopal tumors., (© 2023 Wiley-VCH GmbH.)

The further bioapplications of sonodynamic therapy (SDT) were hindered by the inadequate efficiency and poor degradability of sonosensitizers and the hypoxic tumor microenvironment (TME). Therefore, it is ideal to develop pH-sensitive sonosensitizers that generate abundant reactive oxygen species (ROS) and rapidly degrade in a neutral environment while slowly degrading in an acidic environment to reduce their long-term toxicity. Herein, the defective tungsten oxide nanobelts (WO x NBs) were developed as a type of pH-sensitive and biodegradable sonosensitizers with a high SDT efficiency and low toxicity for enhanced SDT. The defective oxygen sites of WO x NBs could inhibit the recombination of electrons and holes, making WO x NBs promising sonosensitizers that could generate abundant ROS under ultrasound (US) irradiation. Enhanced by the catalase (CAT) that reacted with H 2 O 2 to generate O 2 , the WO x NBs exhibited better SDT performance against 4T1 cells in both normoxic and hypoxic environments. In addition, the WO x NBs could degrade by releasing protons (H + ), resulting in intracellular acidification and inhibited cell motility that further enhanced the therapeutic effects of SDT. Assisted with CAT and ALG for hypoxia refinement and better retention, the WO x NBs enabled effective SDT and antimetastasis against 4T1 tumors in vivo . Most importantly, the WO x NBs could degrade rapidly in normal tissues but slowly in an acidic TME, which was favorable for their fast clearance, without any obvious long-term toxicity. Our work developed defective WO x NBs with a high SDT efficiency and pH-sensitive degradation for enhanced SDT, which extended the biomedical application of tungsten-based nanomaterials and the further development of SDT.

Gas-mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiS X NSs) are prepared as cascade bioreactors for sequential gas-sonodynamic cancer therapy. TiS X NSs themselves as hydrogen sulfide (H 2 S) donors can burst release H 2 S gas. Following H 2 S generation, TiS X NSs are gradually degraded to become S-defective and partly oxidized into TiO X on their surface, which endows TiS X NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiS X NSs. In detail, large amounts of H 2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H 2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiS X NSs are excreted out of the body without inducing any significant long-term toxicity. Collectively, this work establishes a cascade bioreactor of TiS X NSs with satisfactory H 2 S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Multiple amplification of tumor oxidative stress has been demonstrated as efficient strategy to enhance the reactive oxygen species (ROS)-mediated cancer therapy. Herein, vanadium-based nanocatalysts, hydrogen vanadium bronzes (H X V 2 O 5 , for short HVO), were constructed and employed as novel biocatalysts for amplifying tumor oxidative stress and enhancing cancer catalytic therapy. Such HVO nanocatalysts harboring multivalent V element possessed multi-functional catalytic activity in decomposing H 2 O 2 into ⋅OH and depleting endogenous glutathione (GSH) to dually amplify tumor oxidative stress. Meanwhile, HVO nanocatalysts could also be activated by ultrasound to further triply amplify oxidative stress. The massive intracellular ROS caused mitochondrial dysfunction, DNA damage, cell cycle arrest, and cell proliferation inhibition, further realizing cancer cell death and tumor growth inhibition. Collectively, HVO nanocatalysts highlight the remarkable value of ROS-mediated cancer therapies., (© 2022 Wiley-VCH GmbH.)

Objective: To study whether ACT exerts anti-fatigue activity against CRF by inducing skeletal muscle mitophagy via suppressing PHD2 to upregulate the HIF-1α/BNIP3 signaling pathway., Methods: In this study, the molecular docking virtual screening technique was used to screen active components in Cistanche tubulosa that act as potential PHD2 inhibitors; the preliminary verification was carried out by Surface plasmon resonance (SPR) technology. BALB/c mice were treated with Paclitaxel (PTX, 10 mg/kg) and ACT (50, 100 mg/kg) alone or in combination for 20 days. Fatigue-related behaviors, energy metabolism and skeletal muscle mitochondria were assessed. Murine C2C12 myoblast was cultured and differentiated; then, a C26 tumor cell-conditioned medium was added to induce cachexia. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential, mitochondrial microstructure and function, autophagy, PHD2/HIF-1 and PINK1/Parkin signal pathway proteins were analyzed. Then, interfering RNA technology was used to silence PHD2 and observe the efficacy of ACT., Results: We demonstrated that ACT exerted good binding activity with PHD2; ACT administration ameliorated PTX-induced muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing mitophagy, upregulating COXIV, CytoC, PINK1, Parkin, HIF-1α and BNIP3 expression and inhibiting p62, LC3B, PHD2 and Beclin-1 expression. The protective effect of ACT disappeared after transfection with the PHD2 gene knockdown plasmid Egln-1-RNAi., Conclusions: These results suggest that ACT can improve CRF by promoting mitophagy via suppression of PHD2 to remove dysfunctional mitochondria, demonstrating that ACT has huge prospects for clinical application in CRF treatment., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The rapid development of single-cell DNA sequencing (scDNA-seq) technology has greatly enhanced the resolution of tumor cell profiling, providing an unprecedented perspective in characterizing intra-tumoral heterogeneity and understanding tumor progression and metastasis. However, prominent algorithms for constructing tumor phylogeny based on scDNA-seq data usually only take single nucleotide variations (SNVs) as markers, failing to consider the effect caused by copy number alterations (CNAs). Here, we propose BiTSC$^2$, Bayesian inference of Tumor clonal Tree by joint analysis of Single-Cell SNV and CNA data. BiTSC$^2$ takes raw reads from scDNA-seq as input, accounts for the overlapping of CNA and SNV, models allelic dropout rate, sequencing errors and missing rate, as well as assigns single cells into subclones. By applying Markov Chain Monte Carlo sampling, BiTSC$^2$ can simultaneously estimate the subclonal scCNA and scSNV genotype matrices, subclonal assignments and tumor subclonal evolutionary tree. In comparison with existing methods on synthetic and real tumor data, BiTSC$^2$ shows high accuracy in genotype recovery, subclonal assignment and tree reconstruction. BiTSC$^2$ also performs robustly in dealing with scDNA-seq data with low sequencing depth and variant missing rate. BiTSC$^2$ software is available at https://github.com/ucasdp/BiTSC2., (© The Author(s) 2022. Published by Oxford University Press.)

Hydrogen can be used as an anti-cancer treatment. However, the continuous generation of H 2 molecules within the tumor is challenging. Magnesium (Mg) and its alloys have been extensively used in the clinic as implantable metals. Here we develop, by decorating platinum on the surface of Mg rods, a Mg-based galvanic cell (MgG), which allows the continuous generation of H 2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H 2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH) 2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors, including murine tumor models, patient-derived xenografts (PDX), as well as VX 2 tumors in rabbits. Our research suggests that the galvanic cells for hydrogen therapy based on implantable metals may be a safe and effective cancer treatment., (© 2022. The Author(s).)

Gallium indium (GaIn) alloy as a kind of liquid metal (LM) with unique chemical and physical properties has attracted increasing attention for its potential biomedical applications. Herein, a series of core-shell GaIn@Metal (Metal: Pt, Au, Ag, and Cu) heterogeneous nanoparticles (NPs) are obtained by a simple in-situ reduction method. Take core-shell GaIn@Pt NPs for example, the synthesized GaIn@Pt NPs after Pt growth on their surface showed significantly improved photothermal conversion efficiency (PCE) and thermal stability under near-infrared (NIR) II light irradiation. Moreover, the core-shell GaIn@Pt NPs also exhibited good Fenton-like catalytic effect due to the presence of Pt on their surface, and could convert tumor endogenous H 2 O 2 to generate reactive oxygen species (ROS) for cancer cell killing. With biocompatible polyethylene glycol (PEG) modification, such GaIn@Pt-PEG NPs showed efficient tumor homing after intravenous injection, and could lead to effective NIR II triggered photothermal-chemodynamic synergistic therapy of tumors as evidenced in a mouse tumor model. Our work highlights the ingenious use of the chemical properties of metals, providing a rather simple route for the surface engineering of LM-based multifunctional nanoplatforms to achieve a variety of functionalities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Radiodynamic therapy (RDT), an emerging therapeutic approach for cancer treatment by employing ionizing irradiation to induce localized photodynamic therapy (PDT) can overcome the drawbacks of the limited penetration depth for traditional PDT and the unconcentrated energy in the tumor for traditional radiotherapy (RT). Taking advantage of aggregation-induced emission (AIE) photosensitizers with bright fluorescence and efficient singlet oxygen production in the aggregate state, Hf-AIE coordination polymer nanoparticles (CPNs), which show both strong RT and RDT effect under X-ray irradiation, are developed. Furthermore, to enhance the tumor accumulation and prolong the tumor retention of the CPNs, bioorthogonal click chemistry is applied in the system through coupling between dibenzocyclooctyne (DBCO)-modified CPNs (Hf-AIE-PEG-DBCO) (PEG: poly(ethylene glycol)) and azide groups on the cell membrane formed by metabolic glycoengineering. Thanks to the high penetration of X-ray irradiation, the bioorthogonal-assisted RT and RDT combination therapy realizes significant killing of cancer cells without showing noticeable biotoxicity after intravenous administration of CPNs., (© 2021 Wiley-VCH GmbH.)

Sonodynamic therapy (SDT), which can generate reactive oxygen species (ROS) based on sonosensitizers under ultrasound (US) to kill tumor cells, has emerged as a noninvasive therapeutic modality with high tissue-penetration depth. Herein, ultrasmall iron-doped titanium oxide nanodots (Fe-TiO 2 NDs) are synthesized via a thermal decomposition strategy as a type of sonosensitizers to enhance SDT. Interestingly, the Fe doping in this system appears to be crucial in not only enhancing the US-triggered ROS generation of those NDs but also offering NDs the Fenton-catalytic function to generate ROS from tumor endogenous H 2 O 2 for chemodynamic therapy (CDT). After polyethylene glycol (PEG) modification, Fe-TiO 2 -PEG NDs demonstrate good physiological stability and biocompatibility. With efficient tumor retention after intravenous injection as revealed by in vivo magnetic resonance (MR) and fluorescent imaging, our Fe-TiO 2 NDs demonstrate much better in vivo therapeutic performance than commercial TiO 2 nanoparticles owing to the combination of CDT and SDT. Moreover, most of those ultrasmall Fe-TiO 2 NDs can be effectively excreted within one month, rendering no obvious long-term toxicity to the treated mice. Our work thus presents a type of multifunctional sonosensitizer for highly efficient cancer treatment via simply doping TiO 2 nanostructures with metal ions.

Background: pH-sensitive peptides are a relatively new strategy for conquering the poor endosomal release of cationic polymer-mediated transfection. Modification of antimicrobial peptides by exchanging positively-charged residues with negatively-charged glutamic acid residues (Glu) greatly improves its lytic activity at the endosomal pH, which could improve cationic polymer-mediated transfection., Methods: In the present study, we investigated the effect of the number of Glu substituted for positively-charged residues on the endosomal escape activity of AR-23 and the ability of mutated AR-23 with respect to enhancing cationic polymer-mediated transfection. Three analogs were synthesized by replacing the positively-charged residues in the AR-23 sequence with Glu one-by-one., Results: The pH-sensitive lysis ability of the peptides, the effect of peptides on the physicochemical characteristics, the intracellular trafficking, the transfection efficiency and the cytotoxicity of the polyplexes were determined. Increased lytic activity of peptides was observed with the increased number of Glu replacement in the AR-23 sequence at acidic pH. The number of Glu substituted for positively-charged residues of AR-23 dramatically affects its lysis ability at neutral pH. Triple-Glu substitution in the AR-23 sequence greatly improved poly(l-lysine)-mediated gene transfection efficiency at the same time as maintaining low cytotoxicity., Conclusions: The results indicate that replacement of positively-charged residues with sufficient Glu residues may be considered as a method for designing pH-sensitive peptides, which could be applied as potential enhancers for improving cationic polymer-mediated transfection., (© 2020 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.)

Nanozymes with high catalytic activity and great stability have attracted increasing interests as the promising alternative to natural enzymes for applications in various fields. In this study, a new type of highly efficient peroxidase-like nanozymes based on FeWO X nanosheets (NSs) synthesized by a thermal-decomposition method is reported. Owing to the sheet-structure with maximized utilization of catalytic sites (Fe atoms and oxygen vacancies), such FeWO X NSs exert efficient enzyme activity to trigger catalytic decomposition of hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (•OH). A nanozyme-based ratio-metric nanoprobe is then fabricated by co-loading of 3,3,5,5-tetramethylbenzidine (TMB) and IR780 dye on FeWO X NSs to enable ratio-metric photoacoustic (PA) imaging of endogenous H 2 O 2 , as verified by imaging of the subcutaneous 4T1 xenograft tumor model and lipopolysaccharide (LPS)-induced inflammation model. Moreover, FeWO X NSs could also be employed as promising nanoagents for multimodal computed tomography (CT) and magnetic resonance (MR) imaging of tumors, due to the strong X-ray attenuation ability of W element and high MR contrast ability of Fe element, respectively. Importantly, FeWO X NSs with good biodegradability could be cleared out from the body without any significant biotoxicity. This work highlights bimetallic oxide FeWO X NSs as an enzyme-mimetic nanoplatform for imaging of the tumor microenvironment., (© 2020 Wiley-VCH GmbH.)

Motivation: Single-cell sequencing (SCS) data provide unprecedented insights into intratumoral heterogeneity. With SCS, we can better characterize clonal genotypes and reconstruct phylogenetic relationships of tumor cells/clones. However, SCS data are often error-prone, making their computational analysis challenging., Results: To infer the clonal evolution in tumor from the error-prone SCS data, we developed an efficient computational framework, termed RobustClone. It recovers the true genotypes of subclones based on the extended robust principal component analysis, a low-rank matrix decomposition method, and reconstructs the subclonal evolutionary tree. RobustClone is a model-free method, which can be applied to both single-cell single nucleotide variation (scSNV) and single-cell copy-number variation (scCNV) data. It is efficient and scalable to large-scale datasets. We conducted a set of systematic evaluations on simulated datasets and demonstrated that RobustClone outperforms state-of-the-art methods in large-scale data both in accuracy and efficiency. We further validated RobustClone on two scSNV and two scCNV datasets and demonstrated that RobustClone could recover genotype matrix and infer the subclonal evolution tree accurately under various scenarios. In particular, RobustClone revealed the spatial progression patterns of subclonal evolution on the large-scale 10X Genomics scCNV breast cancer dataset., Availability and Implementation: RobustClone software is available at https://github.com/ucasdp/RobustClone., Contact: lwan@amss.ac.cn or maliang@ioz.ac.cn., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

2D nanomaterials with unique nanosheet structures, large surface areas, and extraordinary physicochemical properties have attracted tremendous interest. In the area of nanomedicine, research on graphene and its derivatives for diverse biomedical applications began as early as 2008. Since then, many other types of 2D nanomaterials, including transition metal dichalcogenides, transition metal carbides, nitrides and carbonitrides, black phosphorus nanosheets, layered double hydroxides, and metal-organic framework nanosheets, have been explored in the area of nanomedicine over the past decade. In particular, a large surface area makes 2D nanomaterials highly efficient drug delivery nanoplatforms. The unique optical and/or X-ray attenuation properties of 2D nanomaterials can be harnessed for phototherapy or radiotherapy of cancer. Furthermore, by integrating 2D nanomaterials with other functional nanoparticles or utilizing their inherent physical properties, 2D nanomaterials may also be engineered as nanoprobes for multimodal imaging of tumors. 2D nanomaterials have shown substantial potential for cancer theranostics. Herein, the latest progress in the development of 2D nanomaterials for cancer theranostic applications is summarized. Current challenges and future perspectives of 2D nanomaterials applied in nanomedicine are also discussed., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Vasculogenic mimicry (VM) formed by tumor cells plays a vital role in the progress of tumor, because it provides nutrition for tumor cells and takes away the metabolites. Therefore, the inhibition of VM is crucial to the clinical treatment of tumors. In this study, we investigated the anti-tumor effect of a novel peptide, KVEPQDPSEW (AATP), isolated from abalone ( Haliotis discus hannai ) on HT1080 cells by migration, invasion analysis and the mode of action. The results showed that AATP effectively inhibited MMPs by blocking MAPKs and NF-κB pathways, leading to the downregulation of metastasis of tumor cells. Moreover, AATP significantly inhibited VM and pro-angiogenic factors, including VEGF and MMPs by suppression of AKT/mTOR signaling. In addition, molecular docking was used to study the interaction of AATP and HIF-1α, and the results showed that AATP was combined with an active site of HIF-1α by a hydrogen bond. The effect of AATP on anti-metastatic and anti-vascular in HT1080 cells revealed that AATP may be a potential lead compound for treatment of tumors in the future.

Novel type of multifunctional polymeric micelles (PMs) designated as HM-PMss/CTX micelles were developed in the present study for tumor-targeted and glutathione (GSH)-responsive delivery of cabazitaxel (CTX). The surface of the vehicles was modified with piloting molecules (HM-3 peptide), which targets α v β 3 integrin overexpressed on cancer cells, and the micelle core was cross-linked by GSH-disintegrable disulfide linkages for controlled drug release. HM-PMss/CTX micelles were prepared using a mixture of two functionalized amphiphilic block copolymers and found to physically encapsulate CTX with excellent entrapment efficiency (93.94 ± 4.19%), drug-loading capacity (8.39 ± 2.28%), and a narrow size distribution. In vitro release profiles showed that CTX remained stably entrapped in the micelles in a release medium without GSH or with GSH of low concentration, while undergoing a rapid release in a highly reductive environment. Cellular uptake experiments showed that the conjugation of the targeting peptide, containing an arginine-glycine-aspartate sequence, enhanced the cellular uptake of HM-PMss/CTX micelles via α v β 3 integrin-mediated endocytosis. In vitro cell viability measurements revealed that blank micelles were biocompatible, while HM-PMss/CTX micelles, owing to their tumor-targeting ability and GSH sensitivity, effectively inhibited the proliferation of MDA-MB-231 breast cancer cells. These results indicate that HM-PMss/CTX micelles could be a promising platform for future intelligent drug delivery in cancer therapy.

Background: Red blood cell distribution width (RDW) is a clinical index used to make early diagnosis and to monitor treatment effects in iron deficiency anemia. Recently, several studies have suggested that RDW was associated with mortality from various cancers; however, there has been little evidence regarding RDW and cancer as a whole. Therefore, the purpose of our study was to investigate the relationship of RDW and overall cancer mortality in hospital., Methods: We extracted patient data from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3 (MIMICIII.1.3). RDW was measured prior to hospital admission. Patients older than 18 who were diagnosed with malignant tumors were included. The primary outcome was cancer mortality in hospital. Logistic regression and multivariate analysis were used to assess the association between the RDW and hospital mortality., Result: A total of 3384 eligible patients were enrolled. A positive correlation was observed between RDW and overall cancer mortality. Patients with higher RDW (14.4-16.3%, 16.4-30.5%) were at greater risk of death than the patients with RDW in the reference range (11.5-14.3%). On multivariate analysis, when adjusted for age and gender, the adjusted OR (95% CIs) in the mid-RDW group and high-RDW group were 1.61 (1.28, 2.03) and 2.52 (2.03, 3.13), respectively, with the low-RDW group set as the baseline. Similar trends were also observed in the model adjusted for other clinical characteristics. This suggested that elevated RDW was related to increased risk of cancer mortality, and RDW may play an important role in the prediction of short-term mortality after hospitalization in cancer patients., Conclusion: Elevated RDW was associated with overall cancer mortality. To a certain extent, RDW may predict the risk of mortality in patients with cancers; it was an independent prognostic indicator of short-term mortality after hospitalization in cancer patients.

Accurate imaging of glutathione (GSH) in vivo is able to provide real-time visualization of physiological and pathological conditions. Herein, we successfully synthesize bimetallic oxide MnMoO X nanorods as an intelligent nanoprobe for in vivo GSH detection via photoacoustic (PA) imaging. The obtained MnMoO X nanoprobe with no near-infrared (NIR) absorption in the absence of GSH would exhibit strong GSH-responsive NIR absorbance, endowing PA imaging detection of GSH. Due to the up-regulated GSH concentration in the tumor microenvironment, our MnMoO X nanoprobe could be utilized for in vivo tumor-specific PA imaging. Moreover, MnMoO X nanorods with GSH-responsive NIR absorbance could also be employed to achieve tumor-specific photothermal therapy (PTT). Importantly, such MnMoO X nanorods show inherent biodegradability and could be rapidly cleared out from the body, minimizing their long-term body retention and potential toxicity. Our work presents a new type of GSH-responsive nanoprobe based on bimetallic oxide nanostructures, promising for tumor-specific imaging and therapy.

Objective: To investigate the relationship between UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 polymorphisms and irinotecan-induced severe adverse reactions(grade 3-4 delayed diarrhea and neutropenia) in Chinese cancer patients. Methods: A total of 141 cancer patients treated with irinotecan were enrolled in this study. Peripheral venous blood was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 were analyzed by PCR and direct sequencing. The adverse reactions during chemotherapy were observed and recorded. The incidence of severe adverse reactions was compared among patients with different genotypes. Results: Among 141 patients, the cases with UGT1A1*6 GG, GA and AA genotypes were 71, 54 and 16, while those with UGT1A1*28 TA6/6, TA6/7 and TA7/7 genotypes were 105, 33 and 3, respectively. The cases with UGT1A1*60 AA, AC and CC genotypes were 52, 80 and 9, while those with UGT1A1*93 GG, GA and AA genotypes were 105, 32 and 4, respectively. The patients with grade 3-4 delayed diarrhea and neutropenia were 23 and 56, respectively. Multivariate logistic regression analysis showed that UGT1A1*6 and UGT1A1*60 genetic polymorphisms were independent factors influencing the occurrence of grade 3-4 delayed diarrhea. The risk of grade 3-4 delayed diarrhea in homozygous AA carriers of UGT1A1*6 increased 3.79 times compared with that in wild-type GG carriers (95% CI: 1.35-10.67). Moreover, the risk of grade 3-4 delayed diarrhea in homozygous CC carriers of UGT1A1*60 was 20.42 times compared with that in wild-type AA carriers (95% CI: 3.52-118.33). In addition, UGT1A1*28 genetic polymorphism was an independent factor of the occurrence of grade 3-4 neutropenia. The patients with homozygous TA7/7 carriers of UGT1A1*28 had an 1.61 times higher risk of grade 3-4 neutropenia compared with those with wild-type TA6/6 carriers (95% CI: 1.44-12.65). There was no correlation between UGT1A1*93 genetic polymorphism and severe adverse reactions caused by irinotecan. Conclusion: The cancer patients who carried UGT1A1*6, UGT1A1*28 and UGT1A1*60 gene polymorphisms have high risk of severe adverse events caused by irinotecan-based chemotherapy.

Our genetic information is organized into chromatin, which consists of histones and proteins involved in regulating DNA compaction, accessibility and function. Chromatin is decorated by histone modifications, which provide signals that coordinate DNA-based processes including transcription and DNA damage response (DDR) pathways. A major signal involved in these processes is acetylation, which when attached to lysines within proteins, including histones, can be recognized and read by bromodomain-containing proteins. We recently identified the bromodomain protein ZMYND8 (also known as RACK7 and PRKCBP1) as a critical DNA damage response factor involved in regulating transcriptional responses and DNA repair activities at DNA double-strand breaks. Other studies have further defined the molecular details for how ZMYND8 interacts with chromatin and other chromatin modifying proteins to exert its DNA damage response functions. ZMYND8 also plays essential roles in regulating transcription during normal cellular growth, perturbation of which promotes cellular processes involved in cancer initiation and progression. In addition to acetylation, histone methylation and demethylase enzymes have emerged as important regulators of ZMYND8. Here we discuss our current understanding of the molecular mechanisms that govern ZMYND8 function within chromatin, highlighting the importance of this protein for genome maintenance both during the DDR and in cancer.

Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD). Acetylation dynamics occur upon DNA damage in part to regulate chromatin and BRD protein interactions that mediate key DDR activities. In cancer, DDR and acetylation pathways are often mutated or abnormally expressed. DNA damaging agents and drugs targeting epigenetic regulators, including HATs, HDACs, and BRD proteins, are used or are being developed to treat cancer. Here, we discuss how histone acetylation pathways, with a focus on acetylation reader proteins, promote genome stability and the DDR. We analyze how acetylation signaling impacts the DDR in the context of cancer and its treatments. Understanding the relationship between epigenetic regulators, the DDR, and chromatin is integral for obtaining a mechanistic understanding of genome and epigenome maintenance pathways, information that can be leveraged for targeting acetylation signaling, and/or the DDR to treat diseases, including cancer., Competing Interests: The authors have declared that no competing interests exist.

Single-walled carbon nanotubes (SWNTs) are promising heating agents in cancer photothermal therapy when under near infrared radiation, yet few efforts have been focused on the quantitative understanding of the photothermal energy conversion in biological systems. In this article, a mesoscopic study that takes into account SWNT morphologies (diameter and aspect ratio) and dispersions (orientation and concentration), as well as thermal boundary resistance, is performed by means of an off-lattice Monte Carlo simulation. Results indicate that SWNTs with orientation perpendicular to the laser, smaller diameter and better dispersion have higher heating efficiency in cancer photothermal therapy. Thermal boundary resistances greatly inhibit thermal energy transfer away from SWNTs, thereby affecting their heating efficiency. Through appropriate interfacial modification around SWNTs, compared to the surrounding healthy tissue, a higher temperature of the cancer cell can be achieved, resulting in more effective cancer photothermal therapy. These findings promise to bridge the gap between macroscopic and microscopic computational studies of cancer photothermal therapy.

Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics. A promising cancer treatment modality is gene therapy, which is a form of molecular medicine designed to introduce into target cells genetic material with therapeutic intent. The history of RNA interference (RNAi) has only a dozen years, however, further studies have revealed that it is a potent method of gene silencing that has developed rapidly over the past few years as a result of its extensive importance in the study of genetics, molecular biology and physiology. RNAi is a natural process by which small interfering RNA (siRNA) duplex directs sequence specific post-transcriptional silencing of homologous genes by binding to its complementary mRNA and triggering its elimination. RNAi has been extensively used as a novel and effective gene silencing tool for the fundamental research of cancer therapeutics, and has displayed great potential in clinical treatment.

The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) exists naturally in two forms, a 26 kDa transmembrane form (TM-TNFalpha), and a 17 kDa secretory form (S-TNFalpha). The biological roles for each of these forms of TNFalpha in tumor killing have not been completely elucidated. Therefore, in this study, three different recombinant retroviral vectors, wild-type TNFalpha, solely secretable TNFalpha mutant, and uncleavable transmembrane TNFalpha mutant, were constructed by molecular techniques and stably transfected into a murine hepatic carcinoma cell line (H22). TNFalpha, either secreted in cell culture supernatants by secretable TNFalpha mutant- or wild-type TNFalpha-producing tumor cells, or as a treansmembrane form expressed on the cell surface of uncleavable TNFalpha mutant- or wild-type TNFalpha-synthesizing tumor cells, was demonstrated to be cytotoxic against the TNF sensitive L929 cell line. The H22 cells transfected with the three different forms of TNFalpha were shown to kill parental H22 cells in an in vitro cytotoxicity assay [effect/target (E/T) ratio-dependent manner], and their maximal killing rates were approximately 38-43% at E/T ratio of 5:1. The injection of total 2.5 x 10(5) mixed cells containing transfected and parental H22 tumor cells at different ratios into syngeneic mice resulted in the inhibition of tumor growth with a maximal inhibition rates of approximately 57 approximately 72% at E/T ratio of 5:1. A transient weight loss was found in mice bearing solely secretable TNFalpha mutant producing tumors, whereas no obvious side effects were seen in mice bearing uncleavable TNFalpha mutant or wild-type TNFalpha expressing tumors. Finally, we demonstrate that tumors secreting S-TNFalpha promoted the subsequent infiltration of CD4(+) T cells, and to a lesser extent CD8(+) T cells, to the tumor site. The TM-TNFalpha expressing tumors up-regulated Fas (CD95) expression and inhibited the expression of tumor metastasis associated molecule CD44v3. These results suggest that S-TNFalpha and TM-TNFalpha kill cancer cells in vivo through different mechanisms of action. We conclude that the non-secreted form of TNFalpha may be an ideal candidate for cancer gene therapy due to its therapeutic potential and lowered side effect profile.