Sonic hedgehog-heat shock protein 90ß axis promotes the development of nonalcoholic steatohepatitis in mice.

Sonic hedgehog (SHH) and heat shock protein 90ß (HSP90ß) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90ß is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90ß ubiquitylation through deubiquitylase USP31, thus preventing HSP90ß degradation and promoting hepatic lipid synthesis. HSP90ß significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90ß axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90ß-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

Lipid-polymer hybrid nanoparticle with cell-distinct drug release for treatment of stemness-derived resistant tumor.

Drug resistance presents one of the major causes for the failure of cancer chemotherapy. Cancer stem-like cells (CSCs), a population of self-renewal cells with high tumorigenicity and innate chemoresistance, can survive conventional chemotherapy and generate increased resistance. Here, we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent, all-trans retinoic acid and the chemotherapeutic drug, doxorubicin to overcome the CSC-associated chemoresistance. The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation. In the hypoxic CSCs, ATRA is released to induce differentiation of the CSCs, and in the differentiating CSCs with decreased chemoresistance, DOX is released upon elevation of reactive oxygen species to cause subsequent cell death. In the bulk tumor cells, the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect. This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism. We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.

A carrier-free metal-organic hybrid nanoassembly with combination anti-viral and hepato-protective activity for hepatitis B treatment.

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.

A scoping review of malnutrition in patients undergoing interventions for peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is associated with comorbid conditions and frailty. The role of preoperative nutrition in patients with PAD has not been well characterized. In the present scoping review, we sought to describe the prevalence and prognostic implications of preoperative malnutrition in patients undergoing vascular interventions for claudication or chronic limb-threatening ischemia (CLTI). METHODS: We systematically searched for studies across six databases from inception to August 2021. Studies that had focused on patients with claudication or CLTI who had undergone open or endovascular procedures were included if preoperative nutrition had been measured and correlated with a clinical outcome. RESULTS: Of 4186 records identified, 24 studies had addressed the prevalence or prognostic effects of malnutrition in patients who had undergone interventions for PAD. The proportion of women included in these studies ranged from 6% to 58%. The prevalence of preoperative malnutrition ranged from 14.6% to 72%. Seven different malnutrition assessments had been used in these studies. Across all the scales, preoperative malnutrition was associated with at least one of the following outcomes: mortality, postoperative complications, length of stay, readmission rates, and delayed wound healing. CONCLUSIONS: A variety of tools were used to measure malnutrition in patients undergoing interventions for PAD. Our findings suggest that preoperative malnutrition is associated with adverse clinical outcomes for patients undergoing open and endovascular procedures for claudication or CLTI and that consensus is lacking regarding which tool to use. Clinicians and surgeons should be sensitized to the importance of assessing for malnutrition preoperatively in adults undergoing interventions for PAD.

Combating Cancer Stem-Like Cell-Derived Resistance to Anticancer Protein by Liposome-Mediated Acclimatization Strategy.

Antibody-based therapeutics, which induce apoptosis of malignant cells by selectively binding to their receptors, hold tremendous promise for clinical cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable interest due to its favorable capability of activating apoptosis in cancer cells by interacting with death receptors (DRs). However, cancer stem-like cells (CSCs) show deficient or lower DR and are highly resistant to TRAIL-mediated apoptosis limiting the therapeutic efficacy. Here, we report a liposome-mediated acclimatization strategy to overcome the CSC-emanated TRAIL resistance. The liposomal assemblies coencapsulating plasmid DNA encoding TRAIL and salinomycin enable cancer cells as protein generators to express TRAIL, and more importantly, can acclimatize resistant CSCs to be sensitized to the TRAIL-triggered apoptosis by salinomycin-induced upregulation of DR expression on CSCs. This programmable liposome-based drug codelivery system shows the potential to efficiently eliminate CSCs and inhibit CSC-enriched tumor growth in the orthotopic colon tumor mouse model.

Calculation of Stokes vector of laser backscattering from typical geometric rough surfaces at a long distance.

The polarization bidirectional reflectance distribution function is key to establishing the relationships between incident and backscattering Stokes vectors. For analytical calculation of Stokes vectors of backscattering light from rough surfaces of objectives at long distances, we treat complicated objectives as a combination of several typical geometric surfaces. The analytical calculation forms of Mueller matrices of typical geometric rough surfaces at different sizes and geometric parameters are presented using a microfacet model, and thus, the backscattering Stokes vectors are determined. Experimental results of four types of geometric forms show good agreement with theoretical simulation, except when the incident angle is larger than about 60° at a wavelength of 532 nm. Further studies should be focused on improving the microfacet model for fitting the experimental results at large incident angles, and effects of multiple reflections between different geometric surfaces cannot be neglected when the combination of typical geometric surfaces is considered.

Jolkinolide B inhibits proliferation or migration and promotes apoptosis of MCF-7 or BT-474 breast cancer cells by downregulating the PI3K-Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The diterpenoids extracted from Euphorbia kansui S.L. Liou ex S.B.Ho, Euphorbia fischeriana Steud. have good antitumor effects. Jolkinolide B has anti-breast cancer effect, but it is unclear whether it has different therapeutic effects between luminal A subtype and luminal B subtype breast cancer. AIM OF THE STUDY: This study investigated the Jolkinolide B has different therapeutic, important targets and pathways effects between luminal A subtype and luminal B subtype breast cancer. MATERIALS AND METHODS: We used bioinformatics to predict the biological process and molecular mechanism of Jolkinolide B in treating two types of breast cancer. Then, in vitro, cultured MCF-7 cells and BT-474 cells were divided into control group, PI3K inhibitor + control group, Jolkinolide B group and PI3K inhibitor + Jolkinolide B group. The CCK-8 assay, Flow cytometric analysis and Transwell cell migration assay was used to detect the cell proliferation, apoptosis, and migration in each group, respectively. ELISA was used to measure the content of Akt and phosphorylated Akt (p-Akt) in cell lysis buffer. RESULTS: Compared to luminal A breast cancer, Jolkinolide B had more targets, proliferation, migration processes and KEGG pathways when treating luminal B subtype breast cancer. Jolkinolide B significantly prolonged the survival time of luminal B subtype breast cancer patients. Compared to the control group, the cell proliferation absorbance value (A value) and migration number of the two kinds of breast cancer cells in the Jolkinolide B group were decreased (P < 0.01, n = 6), and the number of apoptotic cells was increased (P < 0.01, n = 6). Compared to the Jolkinolide B group, the A value and migration number of the two types of breast cancer cells were significantly decreased in the PI3K inhibitor + Jolkinolide B group (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). In addition, compared to MCF-7 cells, the A value and migration number of BT-474 cells stimulated with Jolkinolide B were significantly decreased (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). Akt and p-Akt protein levels in the two breast cancer cell lines in the Jolkinolide B group were all decreased (P < 0.01, n = 6), especially in BT-474 cells stimulated by Jolkinolide B. CONCLUSION: Jolkinolide B regulates the luminal A and luminal B subtypes of breast cancer through PI3K-Akt, EGFR and other pathways. Jolkinolide B has more significant therapeutic effect on luminal B subtype breast cancer. In vitro, experiments verified that Jolkinolide B significantly inhibited the proliferation and migration activity of BT-474 breast cancer cells by downregulating the PI3K-Akt pathway.

Paracrine interleukin-8 affects mesenchymal stem cells through the Akt pathway and enhances human umbilical vein endothelial cell proliferation and migration.

Interleukin-8 (IL-8) promotes cell homing and angiogenesis, but its effects on activating human bone marrow mesenchymal stem cells (BMSCs) and promoting angiogenesis are unclear. We used bioinformatics to predict these processes. In vitro, BMSCs were stimulated in a high-glucose (HG) environment with 50 or 100 µg/ml IL-8 was used as the IL-8 group. A total of 5 µmol/l Triciribine was added to the two IL-8 groups as the Akt inhibitor group. Cultured human umbilical vein endothelial cells (HUVECs) were cultured in BMSCs conditioned medium (CM). The changes in proliferation, apoptosis, migration ability and levels of VEGF and IL-6 in HUVECs were observed in each group. Seventy processes and 26 pathways were involved in vascular development, through which IL-8 affected BMSCs. Compared with the HG control group, HUVEC proliferation absorbance value (A value), Gap closure rate, and Transwell cell migration rate in the IL-8 50 and IL-8 100 CM groups were significantly increased (P<0.01, n=30). However, HUVEC apoptosis was significantly decreased (P<0.01, n=30). Akt and phospho-Akt (P-Akt) protein contents in lysates of BMSCs treated with IL-8, as well as VEGF and IL-6 protein contents in the supernatant of BMSCs treated with IL-8, were all highly expressed (P<0.01, n=15). These analyses confirmed that IL-8 promoted the expression of 41 core proteins in BMSCs through the PI3K Akt pathway, which could promote the proliferation and migration of vascular endothelial cells. Therefore, in an HG environment, IL-8 activated the Akt signaling pathway, promoted paracrine mechanisms of BMSCs, and improved the proliferation and migration of HUVECs.

A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells.

Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all-trans retinoic acid, and the chemotherapeutic drug, camptothecin. All-trans retinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis.

Self-regulated hirudin delivery for anticoagulant therapy.

Pathological coagulation, a disorder of blood clotting regulation, induces a number of cardiovascular diseases. A safe and efficient system for the delivery of anticoagulants to mimic the physiological negative feedback mechanism by responding to the coagulation signal changes holds the promise and potential for anticoagulant therapy. Here, we exploit a "closed-loop" controlled release strategy for the delivery of recombinant hirudin, an anticoagulant agent that uses a self-regulated nanoscale polymeric gel. The cross-linked nanogel network increases the stability and bioavailability of hirudin and reduces its clearance in vivo. Equipped with the clot-targeted ligand, the engineered nanogels promote the accumulation of hirudin in the fibrous clots and adaptively release the encapsulated hirudin upon the thrombin variation during the pathological proceeding of thrombus for potentiating anticoagulant activity and alleviating adverse effects. We show that this formulation efficiently prevents and inhibits the clot formation on the mouse models of pulmonary embolism and thrombosis.

Atmospheric effect study of continuous-variable quantum key distribution.

We proposed a data acquisition method to monitor local oscillator (LO) intensity in real time in unidimensional continuous-variable quantum key distribution protocol. Based on this proposed method, the influence of weather conditions on the average transmittance and excess noise is studied, such as relative wetness, visibility, and beam jitter.

Liposomal 9-Aminoacridine for Treatment of Ischemic Stroke: From Drug Discovery to Drug Delivery.

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.

Advances in Engineering Cells for Cancer Immunotherapy.

Cancer immunotherapy aims to utilize the host immune system to kill cancer cells. Recent representative immunotherapies include T-cell transfer therapies, such as chimeric antigen receptor T cell therapy, antibody-based immunomodulator therapies, such as immune checkpoint blockade therapy, and cytokine therapies. Recently developed therapies leveraging engineered cells for immunotherapy against cancers have been reported to enhance antitumor efficacy while reducing side effects. Such therapies range from biologically, chemically and physically -engineered cells to bioinspired and biomimetic nanomedicines. In this review, advances of engineering cells for cancer immunotherapy are summarized, and prospects of this field are discussed.

Sequentially Site-Specific Delivery of Apoptotic Protein and Tumor-Suppressor Gene for Combination Cancer Therapy.

Nanocarrier-mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome-based nanoassembly (p53/C-rNC/L-FA) is developed for intracellular site-specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor-suppressing p53 protein (p53 DNA). p53/C-rNC/L-FA consists of an acid-activated fusogenic liposomal membrane shell modified with folic acid (L-FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC-encapsulated redox-responsive nanocapsule (C-rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C-rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C-rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C-rNC/L-FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.

The Relationship Between Level of Catastrophizing and Mental Health Comorbidity in Individuals With Whiplash Injuries.

OBJECTIVES: Pain catastrophizing has been shown to be correlated with measures of mental health problems such as depression and post-traumatic stress disorder (PTSD). However, the clinical implications of findings reported to date remain unclear. To date, no study has been conducted to determine meaningful cut-scores on measures of catastrophizing indicative of the heightened risk of mental health comorbidity. One objective of the present study was to identify the cut-score on the Pain Catastrophizing Scale (PCS) indicative of the heightened risk of the comorbidity of depression and PTSD. A second objective was to determine whether mental health comorbidity mediated the relationship between catastrophizing and occupational disability. MATERIALS AND METHODS: The sample consisted of 143 individuals with whiplash injuries. Pain severity, pain catastrophizing, depression, and post-traumatic stress symptoms were assessed after admission to a rehabilitation program. Mental health comorbidity was operationally defined as obtaining a score above the clinical threshold on measures of depressive and/or post-traumatic stress symptom severity. RESULTS: A receiver operating characteristic curve analysis revealed that a PCS score of 22 best distinguished between participants with and without mental health comorbidity. Results also revealed that mental health comorbidity mediated the relationship between catastrophizing and occupational disability. DISCUSSION: The findings suggest that a score of ≥22 on the PCS should alert clinicians to the possibility that patients might also be experiencing clinically significant symptoms of depression or PTSD. Greater attention to the detection and treatment of mental health conditions associated with whiplash injury might contribute to more positive recovery outcomes.

Cancer and fertility: optimizing communication between patients and healthcare providers.

PURPOSE OF REVIEW: This article reviews the status of guidelines and recommendations for communication between patients with cancer and healthcare providers (HCPs) concerning fertility issues. RECENT FINDINGS: The timing, the type of information provided, and the openness of HCPs can all affect how patients with cancer perceive discussions regarding fertility concerns and preservation. In addition, whether such discussions occur is associated with intrinsic factors, such as age and sex of the patients as well as HCP's knowledge level. It has also been found that the patients have different needs for information regarding fertility preservation and preferences for types of communication strategies regarding the impact of their disease and treatments on options for family planning. SUMMARY: Although discussions about fertility concerns in the context of cancer between physicians and patients are occurring more frequently, there are inconsistent findings regarding satisfaction with these discussions. Recent research has found that the timing, type of information given, and level of openness of the HCP can impact how patients perceive communications regarding the risks of cancer treatment on fertility preservation options and future family planning. Age, sex, and HCP's knowledge of fertility risks and fertility preservation services are also notable factors associated with whether and how extensively discussions about fertility take place. More women than men report having a fertility discussion with an HCP. However, men are more likely to report satisfaction with the fertility discussion than women.

Enhanced Transdermal Drug Delivery by Transfersome-Embedded Oligopeptide Hydrogel for Topical Chemotherapy of Melanoma.

Topical administration of anticancer drugs provides a potential chemotherapeutic modality with high patient compliance for cutaneous melanoma. However, the drug delivery efficiency is highly limited by physiological barriers from the skin to the tumor, which cannot acquire desired therapeutic efficacy. Herein, we propose a paintable oligopeptide hydrogel containing paclitaxel (PTX)-encapsulated cell-penetrating-peptide (CPP)-modified transfersomes (PTX-CTs) to enhance transdermal PTX delivery for topical melanoma treatment. After being plastered on the skin above the melanoma tumor, the PTX-CTs-embedded hydrogel (PTX-CTs/Gel) as a patch provided prolonged retention capacity of the PTX-CTs on the skin. The PTX-CTs with superior deformability could efficiently squeeze through the channels in the stratum coreum, and the surfactant components improved the fluidity of the lipid molecules in the stratum corneum to further enhance the skin permeation. Moreover, the CPP modification rendered the PTX-CT-enhanced penetration in the skin and tumor stroma as well as efficient transportation in the tumor cells. The PTX-CTs were shown to effectively slow the tumor growth in combination with the systemic chemotherapy using Taxol, the commercial PTX formulation on the xenograft B10F16 melanoma mouse model.

Rational Design and Bioimaging Applications of Highly Specific "Turn-On" Fluorescent Probe for Hypochlorite.

Hypochlorite (OCl-), an essential part of reactive oxygen species (ROS), plays a crucial role in cellular redox balance. OCl- has been shown to be implicated in many physiological and pathological processes, including liver injury and cancer. Exploitation of fluorescent probes for the OCl- helps to reveal its function in the genesis and progression of the aforementioned diseases. Here we propose an easy-to-fabricate coumarin-based fluorescent probe incorporated with an aryl dihydrazide linker for highly specific detection and biological imaging of OCl- in living cells and tissues. The p-nitrophenyl-modified dihydrazide-linked coumarin derivative (Cou-dhz-Ph-NO2) was screened from a series of candidate molecules and served as a "turn-on" probe with a low background fluorescence interference due to the nitro-group-based quenching on the coumarin fluorescence. The Cou-dhz-Ph-NO2 probe showed high selectivity and fast response with excellent linear relationship for detection of OCl-. A specific OCl--responsive mechanism that the dihydrazide linker could be oxidatively cleaved by OCl- was deduced. The exogenous OCl- and endogenous OCl- were successfully visualized using the Cou-dhz-Ph-NO2 probe in living cells, such as MDA-MB-231 cells, RAW 264.7 cells and neutrophils, and the pathologic tissues, including the tumor tissue and the acutely injured liver tissue. This study paves the way for utilizing the aryl dihydrazide linker as OCl--responsive module, which can aid the evolution of increasingly specific probes for detection of OCl- and diagnosis of OCl--coupled diseases.

Hierarchical Nanoassemblies-Assisted Combinational Delivery of Cytotoxic Protein and Antibiotic for Cancer Treatment.

Protein therapeutics hold increasing interest with the promise of revolutionizing the cancer treatment by virtue of a potent specific activity and reduced adverse effects. Nonetheless, the therapeutic efficacy of anticancer proteins is highly compromised by multiple successive physiological barriers to protein delivery. In addition, concurrent elimination of bulk tumor cells and highly tumorigenic cancer stem-like cells (CSCs) as a promising strategy has been evidenced to significantly improve cancer therapy. Here we show that a hierarchically assembled nanocomposite can self-adaptively transform its particulate property in response to endogenous tumor-associated signals to overcome the sequential barriers and achieve an enhanced antitumor efficacy by killing CSCs and bulk tumor cells synchronously. The nanoassemblies preferentially accumulate in tumors and dissociate under tumor microenvironmental acidity accompanied by the extracellular release of small-sized ribonuclease A (RNase A)-encapsulated nanocapsule (R-rNC) and small-molecule anti-CSC doxycycline (Doc), which exhibit increased tumor penetration and intracellular accumulation. The endocytosed R-rNC rapidly releases RNase A within both CSCs and tumor cells at intracellular reductive conditions, causing cell death by catalyzing RNA degradation, while Doc eradicates CSCs by inhibiting the mitochondrial biogenesis. The hierarchical assemblies show enhanced cytotoxicity on the CSC-enriched MDA-MB-231 mammospheres and an enhanced antitumor efficacy on the xenograft tumor mouse model.