[Retracted] Paclitaxel inhibits breast cancer metastasis via suppression of Aurora kinase­mediated cofilin­1 activity.

[This retracts the article DOI: 10.3892/etm.2017.5588.].

Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases.

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer's disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

Mechanism and effectiveness of enzymatically induced phosphate precipitation (EIPP) in stabilizing coexisting lead, zinc, and cadmium in tailings.

Lead-zinc (Pb-Zn) tailings ponds carry the risk of multiple heavy metals (HMs) contamination and pile destabilization. This poses requirements for in-situ applicable, low-distribution, and effective stabilization/solidification (S/S) methods. For this, the novel enzymatically induced phosphate precipitation (EIPP) method was implemented in this study. Its mechanism and performance on stabilization of composite Pb, Zn, and cadmium (Cd) in tailings were explored and evaluated under typical erosion conditions for the first time. Results show that the EIPP stabilized HMs by chemically transforming the unstable carbonate-bound HMs to stable phosphate precipitates and by physically encapsulating tailings particles with newberyite precipitates. The stabilization effect on the three HMs was ranked as Pb > Zn > Cd. Comparing magnesium resources for the EIPP reactants, the EIPP utilizing Mg(CH3COO)2 was more effective at decontamination than MgCl2 because its special pre-activation and re-precipitation function enhanced the chemical transformation function of EIPP. The EIPP stabilization was confirmed to reduce simulated acid rain-leachable and bio-extractive HMs by about 90% and 60%, respectively. Under the prolonged acid attack, treated HMs were ultimately leached through the dissolution mechanism. Zn exhibited significant instability in highly acidic conditions (pH = 2.5-3.5), where its cumulative leaching toxicity after long-term dissolution warrants attention. Overall, EIPP presents a novel and effective strategy for on-site mitigation of composite HMs pollution.

Genetic labeling reveals spatial and cellular expression pattern of neuregulin 1 in mouse brain.

BACKGROUND: Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. METHODS: Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. RESULTS: In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. CONCLUSIONS: Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.

Comparison of Diagnostic Value for Chronic Kidney Disease between 640-Slice Computed Tomography Kidney Scan and Conventional Computed Tomography Scan.

Objective: To explore the diagnostic value for chronic kidney disease (CKD) between 640-slice computed tomography (CT) kidney scan and conventional CT scan. Methods: A total of 120 CKD patients who received kidney plain scan plus enhanced examination in the CT room of the Medical Imaging Department of our hospital from June 2019 to September 2019 were selected and randomly divided into the experimental group (n = 60) and the control group (n = 60). Patients in the control group received the conventional CT plain scan and enhanced scan, and for patients in the experimental group, CT plain scan was performed first, the range of 640-slice CT dynamic volume scan was determined, and after bolus injection of contrast agent, dynamic volume scan was performed for scanning in the cortical phase, myeloid phase, and secretory phase. The imaging quality and effective scanning dose were compared between the two modalities, and the relationship between CT values obtained from 640-slice CT scan and conventional CT scan and the renal impairment was analyzed. Results: Compared with the control group, the image quality of 640-slice CT scan conducted in the experimental group was significantly better (P < 0.05); the effective radiation doses of the experimental group and the control group were, respectively, (1.89 ± 0.32) mSv and (3.26 ± 0.47) mSv, indicating that the dose was significantly lower in the experimental group than in the control group (t = 18.664, P < 0.001), and the correlation analysis showed that the relationship between the sum of CT values in the cortical phase of both kidneys and kidney injury in the experimental group was r = 0.835, P < 0.001. Conclusion: Both 640-slice CT kidney scan and conventional CT scan can be used in the diagnosis of CKD. 640-slice CT has a lower radiation dose, better image quality, and higher application value.

Dehydration effect of freeze-thaw on sludge: Temperature spatio-temporal distribution and multi-scale evaluation.

The freeze-thaw vacuum method for conditioning pretreated sludge has been proved that it not only has greater dewatering efficiency but also is more ecologically friendly. In this paper, the experiment is improved to address shortcomings in previous freeze-thaw vacuum approach for sludge treatment. The spatio-temporal distribution relationship of distance-time-temperature is developed and divided into two stages by numerically fitting the temperature change of freezing tubes in the sludge. It is expected to guide the time control of large-scale frozen sludge in practical engineering applications to achieve optimal dewatering treatment. Furthermore, the performance of dehydration after the model test is evaluated on multi-scale: settlement and mechanical properties (macroscopic perspective), mean particle size (mesoscopic perspective), and SEM microstructure (microscopic perspective). The results reveal that the improved sludge treatment method of alternating freeze-thaw vacuum procedures, using both prefabricated horizontal drains (PHDs) and prefabricated vertical drains (PVDs), substantially benefits the sludge dewatering and reduction. This method results in an unparalleled volume reduction of 63.51% and a water content reduction to 58.54%. Moreover, in-situ vane shearing strength of the sludge obtained from the improved test meets the strength requirement for the landfill final cover soil, demonstrating that the method is superior in improving mechanical properties.

Comparison of the Application Value for Diagnosis of Chronic Kidney Disease between Color Doppler Flow Quantification Technique and Computed Tomography.

Objective: The aim of this study is to compare the application value for diagnosis of chronic kidney disease (CKD) between the color Doppler flow quantification (CDFQ) technique and computed tomography (CT). Methods: The clinical data of 88 hospitalized patients treated in the Renal Medicine of our hospital and diagnosed with CKD after pathological examination from June 2020 to June 2021 were selected for the retrospective analysis, and 32 individuals with normal physical examination results in the same period were selected as the control group. All study subjects received CDFQ and 640-slice volume CT examination, and by plotting the ROC curves, the clinical value of different diagnostic modalities was analyzed. Results: The 3D renal volumes between the stage 1 group and control group were significantly different (P < 0.05); the 3D renal volumes between the stage 2 group and control group and between the stage 2 group and stage 1 group were significantly different (P < 0.05); in the comparison between the stage 3 group versus control group/stage 2 group, the RI values, 3D renal volumes, and cortical thicknesses were significantly different (P < 0.05); in the comparison between the stage 4 group versus control group/stage 1 group, the RI values, 3D renal volumes, and cortical thicknesses were significantly different, and between the stage 4 group and stage 2 group, the RI values and cortical thicknesses were significantly different (P < 0.05); in the comparison between the stage 5 group versus control group/stage 1 group/stage 2 group/stage 3 group, the RI values, 3D renal volumes, and cortical thicknesses were significantly different, and between the stage 5 group and stage 4 group, the RI values and 3D renal volumes were significantly different (P < 0.05); among various groups, the measurement indicators of 640-slice volume CT scan were significantly different (P < 0.05); and in terms of disease classification, the AUC value, positive predictive value, negative predictive value, sensitivity, and specificity of 640-slice volume CT were higher than those of CDFQ diagnosis. Conclusion: 640-slice volume CT has a higher efficacy in diagnosing CKD and can provide a reliable basis for the selection of treatment schemes for CKD patients.

Insights into vacuum preloading consolidation of landfill sludge based on Fe2+-activated sodium persulfate.

To further reduce the in-situ sludge from landfill, Fe2+-activated sodium persulfate combined with vacuum preloading was first proposed. Firstly, the effects of optimal Na2S2O8 dosage on the landfill sludge (LS) were investigated by the vacuum filtration experiments. Then, vacuum preloading experiments were conducted on the sludge with different Na2S2O8 dosages to study the water content, water discharge, and settlement. Besides, sludge particle size diversification was carried out by particle size distribution and scanning electron microscopy (SEM) tests. The results were summarized as follows: the specific resistance of filtration (SRF) of LS could be reduced by 98.5% mostly when the Na2S2O8 dosage was 30%; the particle size became significantly smaller, and large particles were converted to small particles; the water content dropped from 86.9 to 58.3%; and the SEM test manifested the oxidation of sodium persulfate caused the destruction of the glial structure of the sludge and the recombination of partial particles.

Freeze-thaw vacuum treatment of landfill sludge: Mechanism of uneven frost heaving and dewatering performance.

The method of freeze-thaw combined with vacuum pretreatment for landfill sludge (LS) has attracted extensive attention. However, most of the existing approaches are based on small-scale laboratory testing, and further testing studies must be performed to realize in situ treatment. To enhance the practicality of such approaches, the range of temperature effects on LS was analysed after field freeze-thaw model testing. After the freeze-thaw model test, samples were transported to the laboratory for unidirectional oedometer tests, and the remaining samples were retained in the field to continue vacuum model testing for exploring the differences in the consolidation and drainage effect of the LS. Results show that temperature changes during freeze-thaw process affect the distribution of sludge and water in the model boxes, resulting in frost heave and the appearance of "extrusion rings". In addition, the coefficient of consolidation obtained from the unidirectional oedometer test shows that the consolidation coefficient is generally larger near the freezing tubes at a lower temperature. The settlement determined from the field vacuum preloading test shows that the subsequent vacuum consolidation settlement is larger at the position with a lower elevation of the frozen sludge surface. The comparison indicates that the consolidation and drainage effect in the field is not as significant as that in the laboratory. The findings can provide reference to optimize the field conditions during the in situ engineering practice of sludge treatment.

Co-treatment with miR-21-5p inhibitor and Aurora kinase inhibitor reversine suppresses breast cancer progression by targeting sprouty RTK signaling antagonist 2.

Numerous studies have reported the regulatory effects of miR-21-5p and reversine in human breast cancer (HBC). However, the mechanism of reversine and miR-21-5p has not been fully investigated in HBC. The aim of the current study was to assess the mechanism of action of reversine, with or without miR-21-5p, in HBC progression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot results confirmed the upregulation of miR-21-5p and downregulation of sprouty RTK signaling antagonist 2 (SPRY2) in HBC. Bioinformatics analysis and luciferase assay identified the correlation between miR-21-5p and SPRY2. Cell function experiment results indicated a decrease in migration, proliferation, and invasion of HBC cells treated with miR-21-5p inhibitor and reversine; however, an increase in apoptosis was observed in these cells. Apoptotic ability was more enhanced and migration, proliferation, and invasion were more impaired in HBC cells treated with both miR-21-5p inhibitor and reversine than in those treated individually with either inhibitors. SPRY2, downstream of miR-21-5p, participated in HBC progression with reversine. Overall, our study proved that combining the miR-21-5p inhibitor with reversine produced a synergistic effect by regulating SPRY2, thereby limiting HBC progression. This knowledge might offer insights into the clinical therapy of HBC.

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition.

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.

An urchin-like helical polypeptide-asparaginase conjugate with mitigated immunogenicity.

The use of asparaginase (ASNase), a first line drug for lymphoma treatment, is impaired by short circulation and notoriously high immunogenicity. Although PEGylation can prolong the circulating half-life of ASNase, however, it also induces anti-PEG antibodies that lead to accelerated blood clearance (ABC) and hypersensitivity reactions. Here, we create an urchin-like polypeptide-ASNase conjugate P(CB-EG3Glu)-ASNase, in which the surface of ASNase is sufficiently shielded by an array of zwitterionic helical polypeptides through the labeling of the ε-amine of lysine. The conjugate is fully characterized with size exclusion chromatography, SDS-PAGE, dynamic light scattering, and circular dichroism. In vitro, P(CB-EG3Glu)-ASNase retains full activity based on the enzymatic assay using the Nessler's reagent and cell viability assay. In vivo, examination of the enzyme activity in serum indicates that P(CB-EG3Glu)-ASNase prolongs the circulating half-life of ASNase for ~20 fold. Moreover, P(CB-EG3Glu)-ASNase significantly inhibits tumor growth in a xenografted mouse model using human NKYS cells. Importantly, P(CB-EG3Glu)-ASNase elicits almost no antidrug or antipolymer antibodies without inducing ABC effect, which is in sharp contrast with a similarly produced PEG-ASNase conjugate that develops both antidrug/antipolymer antibodies and profound ABC phenomenon. Our results demonstrate that urchin-like conjugates are outstanding candidates for reducing immunogenicity of therapeutic proteins, and P(CB-EG3Glu)-ASNase holds great promises for the treatment of various lymphoma diseases.

Dynamic Functional Connectivity Alterations and Their Associated Gene Expression Pattern in Autism Spectrum Disorders.

Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that are highly heritable and are associated with impaired dynamic functional connectivity (DFC). However, the molecular mechanisms behind DFC alterations remain largely unknown. Eighty-eight patients with ASDs and 87 demographically matched typical controls (TCs) from the Autism Brain Imaging Data Exchange II database were included in this study. A seed-based sliding window approach was then performed to investigate the DFC changes in each of the 29 seeds in 10 classic resting-state functional networks and the whole brain. Subsequently, the relationships between DFC alterations in patients with ASDs and their symptom severity were assessed. Finally, transcription-neuroimaging association analyses were conducted to explore the molecular mechanisms of DFC disruptions in patients with ASDs. Compared with TCs, patients with ASDs showed significantly increased DFC between the right dorsolateral prefrontal cortex (DLPFC) and left fusiform/lingual gyrus, between the DLPFC and the superior temporal gyrus, between the right frontal eye field (FEF) and left middle frontal gyrus, between the FEF and the right angular gyrus, and between the left intraparietal sulcus and the right middle temporal gyrus. Moreover, significant relationships between DFC alterations and symptom severity were observed. Furthermore, the genes associated with DFC changes in ASDs were identified by performing gene-wise across-sample spatial correlation analysis between gene expression extracted from six donors' brain of the Allen Human Brain Atlas and case-control DFC difference. In enrichment analysis, these genes were enriched for processes associated with synaptic signaling and voltage-gated ion channels and calcium pathways; also, these genes were highly expressed in autistic disorder, chronic alcoholic intoxication and several disorders related to depression. These results not only demonstrated higher DFC in patients with ASDs but also provided novel insight into the molecular mechanisms underlying these alterations.

Early Intervention of Gastrodin Improved Motor Learning in Diabetic Rats Through Ameliorating Vascular Dysfunction.

The mechanism of cognitive dysfunction in diabetes is still unclear. Recently, studies have shown that the cerebellum is involved in cognition. Furthermore, diabetes-induced cerebellar alterations is related to vascular changes. Therefore, we aimed to explore the roles of vascular function in diabetes-induced cerebellar damage and motor learning deficits. Type 1 diabetes was induced by a single injection of streptozotocin in Sprague-Dawley rats. Motor learning was assessed by beam walk test and beam balance test. The pathological changes of the cerebellum were assessed by Hematoxylin and eosin staining and Nissl staining. Apoptosis was evaluated by anti-caspase-3 immunostaining. Protein expression was evaluated by western blotting and double immunofluorescence. Our results have shown that motor learning was impaired in diabetic rats, coupled with damaged Purkinje cells and decreased capillary density in the cerebellum. In addition, the protein expression of neuronal NOS, inducible NOS, endothelial NOS, total nitric oxide, vascular endothelial growth factor and its cognate receptor Flk-1 was decreased in the cerebellum. Gastrodin treatment ameliorated neuronal damage and restored protein expression of relevant factors. Arising from the above, it is suggested that vascular dysfunction and NO signaling deficits in the cerebellum may be the underlying mechanism of early manifestations of cognitive impairment in diabetes, which could be ameliorated by gastrodin intervention.

Evaluation of the Chinese version of the swallowing screen in stroke patients with dysphagia.

OBJECTIVE: The purpose of this study was to validate a Chinese version of the modified Standardized Swallowing Assessment (SSA) instrument used by nurses in stroke patients with dysphagia and explore the feasibility of the simplified instrument. MATERIALS AND METHODS: This study involved a cross-sectional design. Nurses independently applied the modified SSA to 127 patients with stroke before a complete dysphagia evaluation conducted by a speech-language pathologist. Factor analysis of eight dysphagia variables in the modified SSA was performed to evaluate construct validity. The accuracy of the screening instrument was assessed through receiver operating characteristic (ROC) analysis. RESULTS: The comprehensive swallowing assessment revealed that 49.6% of the stroke patients had dysphagia. The modified SSA had an acceptable internal consistency coefficient. The inter-rater agreement between nurses using the modified SSA showed a Kappa coefficient of 0.509. All items had a communality loading of >0.5, and two factors accounted for 73.89% of the response variance. The area under the ROC curve was 0.79 (95% confidence interval: 0.71-0.87). The sensitivity and specificity derived for dysphagia detection were satisfactory according to the results obtained from the original 8-item and simplified 6-item scales (sensitivities = 82.50% and 81.00% and specificities = 59.40% and 64.10%, respectively; accuracy = 70.87% and 72.44%, respectively). CONCLUSION: This preliminary study suggests that the modified SSA is a potentially reliable and valid nurse-administered screening instrument for dysphagia detection in patients with stroke.

Gastrodin Ameliorates Motor Learning Deficits Through Preserving Cerebellar Long-Term Depression Pathways in Diabetic Rats.

Cognitive dysfunction is a very severe consequence of diabetes, but the underlying causes are still unclear. Recently, the cerebellum was reported to play an important role in learning and memory. Since long-term depression (LTD) is a primary cellular mechanism for cerebellar motor learning, we aimed to explore the role of cerebellar LTD pathways in diabetic rats and the therapeutic effect of gastrodin. Diabetes was induced by a single injection of streptozotocin into adult Sprague-Dawley rats. Motor learning ability was assessed by a beam walk test. Pathological changes of the cerebellum were assessed by Hematoxylin-Eosin (HE) and Nissl staining. Cellular apoptosis was assessed by anti-caspase-3 immunostaining. Protein expression levels of LTD pathway-related factors, including GluR2, protein kinase C (PKC), NR2A, and nNOS, in the cerebellar cortex were evaluated by western blotting and double immunofluorescence. The NO concentration was measured. The cellular degeneration and the apoptosis of Purkinje cells were evident in the cerebellum of diabetic rats. Protein expression levels of GluR2 (NC9W: 1.26 ± 0.12; DM9W + S: 0.81 ± 0.07), PKC (NC9W: 1.66 ± 0.10; DM9W + S: 0.58 ± 0.19), NR2A (NC9W: 1.40 ± 0.05; DM9W + S: 0.63 ± 0.06), nNOS (NC9W: 1.26 ± 0.12; DM9W + S: 0.68 ± 0.04), and NO (NC9W: 135.61 ± 31.91; DM9W + S: 64.06 ± 24.01) in the cerebellum were significantly decreased in diabetic rats. Following gastrodin intervention, the outcome of motor learning ability was significantly improved (NC9W: 6.70 ± 3.31; DM9W + S: 20.47 ± 9.43; DM9W + G: 16.04 ± 7.10). In addition, degeneration and apoptosis were ameliorated, and this was coupled with the elevation of the protein expression of the abovementioned biomarkers. Arising from the above, we concluded that gastrodin may contribute to the improvement of motor learning by protecting the LTD pathways in Purkinje cells.

Genetic labeling reveals temporal and spatial expression pattern of D2 dopamine receptor in rat forebrain.

The D2 dopamine receptor (Drd2) is implicated in several brain disorders such as schizophrenia, Parkinson's disease, and drug addiction. Drd2 is also the primary target of both antipsychotics and Parkinson's disease medications. Although the expression pattern of Drd2 is relatively well known in mouse brain, the temporal and spatial distribution of Drd2 is lesser clear in rat brain due to the lack of Drd2 reporter rat lines. Here, we used CRISPR/Cas9 techniques to generate two knockin rat lines: Drd2::Cre and Rosa26::loxp-stop-loxp-tdTomato. By crossing these two lines, we produced Drd2 reporter rats expressing the fluorescence protein tdTomato under the control of the endogenous Drd2 promoter. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Drd2 in adult and postnatal rat forebrain. Strikingly, the Drd2 expression pattern differs between Drd2 reporter rats and Drd2 reporter mice generated by BAC transgene in prefrontal cortex and hippocampus. These results provide fundamental information needed for the study of Drd2 function in rat forebrain. The Drd2::Cre rats generated here may represent a useful tool to study the function of neuronal populations expressing Drd2.

Paclitaxel inhibits breast cancer metastasis via suppression of Aurora kinase-mediated cofilin-1 activity.

The main problem in breast cancer treatment is the recurrence of tumor growth and metastases. Previous studies have suggested that Paclitaxel is widely used to treat various cancers. The present study analyzed the potential signaling pathway of Paclitaxel-inhibited breast cancer metastasis. It was demonstrated that Paclitaxel treatment significantly inhibited growth of breast cancer cell lines including MCF-7 and SKBR3 cells. Results demonstrated that Paclitaxel significantly inhibited breast cancer cell migration and invasion. Results additionally demonstrated that Paclitaxel treatment suppressed Aurora kinase and cofilin-1 activity in breast cancer cells. The potential mechanism indicated that activation of Aurora kinase activity stimulated cofilin-1 activity, which canceled Paclitaxel-inhibited growth and aggressiveness of breast cancer cells. An in vivo assay revealed that Paclitaxel treatment significantly inhibited breast cancer growth. Immunohistochemistry demonstrated that Paclitaxel treatment increased apoptosis of tumor cells in tumor tissue. Notably, Aurora kinase and cofilin-1 activity were downregulated by Paclitaxel in tumor tissues. In conclusion, these results indicated that Paclitaxel inhibited breast cancer cell growth and metastasis via suppression of Aurora kinase-mediated cofilin-1 activity, suggesting Paclitaxel may be an efficient anticancer agent for the treatment of this disease.

A S-Sn Lewis Pair-Mediated Ring-Opening Polymerization of α-Amino Acid N-Carboxyanhydrides: Fast Kinetics, High Molecular Weight, and Facile Bioconjugation.

The rapid and controlled generation of polypeptides with ultrahigh molecular weight (MW) and well-defined chain end functionality has been a great challenge. To tackle this problem, we report here an initiation system based on a S-Sn Lewis pair, trimethylstannyl phenyl sulfide (PhS-SnMe3), for the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs). This initiator displays a strong solvent effect, and can yield polypeptides with high MW (>1.0 × 105 g·mol-1) and low polydispersity index within a few hours. The MWs of the obtained polypeptides are strongly dependent on the THF/DMF ratio. The polymerization follows a typical first-order kinetic character with respect to the monomer concentration in mixed THF and DMF. Moreover, a highly reactive phenyl thioester is in situ generated at the C-terminus of the polypeptides, which is readily accessible for native chemical ligation affording high MW and site-specific protein-polypeptide conjugates. Together, this initiator sheds light on regulating the ROP of NCAs via appropriate Lewis pair and solvent selection, and is particularly useful in preparing ultrahigh MW polypeptides within a short period of time.

Harnessing Phosphato-Platinum Bonding Induced Supramolecular Assembly for Systemic Cisplatin Delivery.

To improve the therapeutic index of cisplatin (CDDP), we present here a new paradigm of drug-induced self-assembly by harnessing phosphato-platinum complexation. Specifically, we show that a phosphato-platinum cross-linked micelle (PpY/Pt) can be generated by using a block copolymer methoxy-poly(ethylene glycol)-block-poly(l-phosphotyrosine) (mPEG-b-PpY). Coating of PpY/Pt with a R9-iRGD peptide by simple mixing affords a targeting micelle with near neutral-charged surface (iPpY/Pt). The micelles feature in well-controlled sizes below 50 nm and high stability under physiological conditions, and can withstand various environmental stresses. Importantly, the micelles demonstrate on-demand drug release profiles in response to pathological cues such as high ATP concentration and acidic pH. In vitro, the micelles are efficiently internalized and almost equally potent compared to CDDP. Moreover, iPpY/Pt induce greater cytotoxicity than PpY/Pt in a 3D tumor spheroid model likely due to its deeper tumor penetration. In vivo, the micelles exhibit prolonged circulation half-lives, enhanced tumor accumulation, excellent tumor growth inhibition in a xenograft HeLa model and an orthotropic mammary 4T1 model, and improved safety profiles evidenced by the reduced nephrotoxicity. Together, this work demonstrates for the first time that phosphato-platinum complexation can be exploited for effective delivery of CDDP, and suggests a paradigm shift of constructing nanosystems for other anticancer metallodrugs.