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Pico- and nano-eukaryotic plankton are important members of marine ecosystems. To understand their community structure and spatio-temporal variations in the Beibu Gulf, and to study the impact of Changjiang Nuclear Power Plant (CNPP) located in the northwest coast of the Hainan Island on the eukaryotic plankton, we studied these issues in the coastal water near CNPP bimonthly from February 2018 to January 2019 via 18S Illumina sequencing. The results reveal a higher genetic alpha-diversity and less beta-diversity of the plankton community in small-size (0.45–5 µm and 5–20 µm) fractions than in large-size (20–200 µm and >20 µm) fractions. The small-sized phytoplankton, including Micromonas (Chlorophyta) and Minutocellus (Bacillariophyta), as well as heterotrophic plankton, including Paraphysomonas (Chrysophyceae), Ellobiopsis (Dinoflagellates), and Syndiniales (Dinoflagellates), took up a considerable proportion in eukaryotic plankton community. In addition, it showed a slight temperature increase and no significant difference in eukaryotic plankton community between the outfall of CNPP and other sampling sites, suggesting that the impact of the thermal discharge from the CNPP on local eukaryotic plankton community was limited.

The condensed tumor extracellular matrix (ECM) consisting of cross-linked hyaluronic acid (HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase (HAase)-modified layered double hydroxide (LDH) nanoplatform loaded with anticancer drug doxorubicin (DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.

Development of innovative nanomedicine enabling enhanced theranostics of multidrug-resistant (MDR) tumors remains to be challenging. Herein, we report the development of a newly designed multifunctional yellow-fluorescent carbon dot (y-CD)/dendrimer nanohybrids as a platform for ultrasound (US)-enhanced fluorescence imaging and chemotherapy of MDR tumors. Generation 5 (G5) poly(amidoamine) dendrimers covalently modified with efflux inhibitor of d-α-tocopheryl polyethylene glycol 1000 succinate (G5-TPGS) were complexed with one-step hydrothermally synthesized y-CDs via electrostatic interaction. The formed G5-TPGS@y-CDs complexes were then physically loaded with anticancer drug doxorubicin (DOX) to generate (G5-TPGS@y-CDs)-DOX complexes. The developed nanohybrids display a high drug loading efficiency (40.7%), strong y-CD-induced fluorescence emission, and tumor microenvironment pH-preferred DOX release profile. Attributing to the DOX/TPGS dual drug design, the (G5-TPGS@y-CDs)-DOX complexes can overcome the multidrug resistance (MDR) of cancer cells and effectively inhibit the growth of cancer cells and tumors. Furthermore, the introduction of US-targeted microbubble destruction technology was proven to render the complexes with enhanced intracellular uptake and anticancer efficacy in vitro and improved chemotherapeutic efficacy and fluorescence imaging of tumors in vivo due to the produced sonoporation effect. The developed multifunctional dendrimer/CD nanohybrids may represent an advanced design of nanomedicine for US-enhanced theranostics of different types of MDR tumors., Graphical abstract Image 1, Highlights • Dendrimer and y-CDs can form nanohybrids via electrostatic interaction. • The nanohybrids loaded with two drugs display strong y-CD-induced fluorescence emission. • DOX-loaded nanohybrids have acidic pH-triggered fast release profile. • The dual-drug design can make the nanohybrids overcome the MDR of tumors. • The nanohybrids enables ultrasound-enhanced fluorescence imaging and chemotherapy of MDR tumors.

Studies have determined that ultrasound-activated microbubbles can increase the membrane permeability of tumor cells by triggering membrane perforation (sonoporation) to improve drug loading. However, because of the distinct cavitation events adjacent to each cell, the degree of drug loading appeared to be heterogeneous. The relationship between the long-term fate trend and the degree of drug loading remains unclear. To investigate the time-lapse viability of diversity loading cells, fluorescein isothiocyanate-dextran (FITC-dextrans) was used as a molecular model mixed with 2% v/v SonoVue microbubbles (Bracco, Milan, Italy) and exposed to various peak negative pressures (0.25 MPa, 0.6 MPa, 1.2 MPa), 1 MHz frequency and 300 μs pulse duration. To select a suitable parameter, the cavitation activity was measured, and the cell analysis was performed by flow cytometry under these acoustic pressures. The sonoporated cells were then categorized into 3 sub-groups by flow cytometry according to the various fluorescence intensity distributions to analyze their long-term fate. We observed that the stable cavitation occurred at 0.25 MPa and microbubbles underwent ultra-harmonic emission, and obvious broadband signals were observed at 0.6 MPa and 1.2 MPa, suggesting the occurs of inertial cavitation. The cell analysis further showed the maximum delivery efficiency and cell viability at 0.6 MPa, and it was selected for the following experiment. The categorization displayed that the fluorescence intensity of FITC-dextrans in sub-groups 2 and 3 were approximate 5.62-fold and 19.53-fold higher than that in sub-group 1, respectively. After separation of these sub-groups, the apoptosis and necrosis ratios in all 3 sub-groups of sonoporated cells gradually increased with increasing culture time and displayed no significant difference in either the apoptosis (p > 0.05) or necrosis (p > 0.05) ratio after 6 h and 24 h of culture, respectively. Further analysis using Western blot verified that the long-term fate of sonoporated cells involves the mitochondrial signaling proteins. These results provide better insight into the role of cavitation-enhanced permeability and a critical guide for acoustic cavitation designs.

Development of versatile nanoplatforms that simultaneously integrate therapeutic and diagnostic features for stimuli-responsive delivery to tumors remains a great challenge. In this work, we report a novel intelligent redox-responsive hybrid nanosystem composed of MnO2 nanoparticles (NPs) and doxorubicin (DOX) co-loaded within poly(N-vinylcaprolactam) nanogels (PVCL NGs) for magnetic resonance (MR) imaging-guided and ultrasound-targeted microbubble destruction (UTMD)-promoted tumor chemotherapy. Methods: PVCL NGs were first synthesized via a precipitation polymerization method, decorated with amines using ethylenediamine, and loaded with MnO2 NPs through oxidation with permanganate and DOX via physical encapsulation and Mn-N coordination bonding. The as-prepared DOX/MnO2@PVCL NGs were well characterized. UTMD-promoted cellular uptake and therapeutic efficacy of the hybrid NGs were assessed in vitro, and a xenografted tumor model was used to test the NGs for MR imaging and UTMD-promoted tumor therapy in vivo. Results: The as-prepared DOX/MnO2@PVCL NGs with a size of 106.8 nm display excellent colloidal stability, favorable biocompatibility, and redox-responsiveness to the reductive intracellular environment and tumor tissues having a relatively high glutathione (GSH) concentration that can trigger the synchronous release of Mn2+ for enhanced T1-weighted MR imaging and DOX for enhanced cancer chemotherapy. Moreover, the DOX/MnO2@PVCL NGs upon the UTMD-promotion exhibit a significantly enhanced tumor growth inhibition effect toward subcutaneous B16 melanoma owing to the UTMD-improved cellular internalization and tumor penetration. Conclusion: Our work thereby proposes a promising theranostic nanoplatform for stimuli-responsive T1-weighted MR imaging-guided tumor chemotherapy.

The dense extracellular matrix (ECM) and hypovascular networks were often found in solid pancreatic tumors form an impenetrable barrier, leading to limited uptake of chemotherapeutics and thus undesirable treatment outcomes. Methods: A biodegradable nanoplatform based on hollow mesoporous organosilica nanoparticle (HMON) was designed as an effective delivery system for pirfenidone (PFD) to overcome the challenges in pancreatic tumor treatment. By varying pH producing a mildly acidic environment to emulate tumor cells, results in cleavage of the acetal bond between HMON nanoparticle and gating molecular, gemcitabine (Gem), enabling its controlled release. Results: The in vitro and in vivo immunocytochemistry evaluations demonstrated an excellent ECM regulation efficacy of the nanoplatform and therefore the improved penetration of drug into the cells. The technique employed was especially enhanced when mediated with ultrasound target microbubble destruction (UTMD). Evaluations culminated with pancreatic cancer bearing mice and demonstrated therapeutic efficacy, good biodegradability, and negligible systemic toxicity. Conclusion: the designed Gem gated biodegradable nanosystem is expected to provide an alternative way of improving antitumor efficacy by down-regulation of ECM levels and offers a passive-targeted therapy for pancreatic cancer treatment.

Emerging noninvasive treatments, such as sonodynamic therapy (SDT) and chemodynamic therapy (CDT), have developed as promising alternatives or supplements to traditional chemotherapy. However, their therapeutic effects are limited by the hypoxic environment of tumors. Here, a biodegradable nanocomposite-mesoporous zeolitic-imidazolate-framework@MnO

Microcystis blooms are an environmental and ecological concern that has received a serious attention. Hydrogen peroxide (H2O2) is an environment-friendly cyanocide that is commonly used to control Microcystis blooms. While the ecological safety of H2O2 has been previously studied, its influence on bacterioplankton has not been investigated to date. In this study, we used mesocosm experiments to determine the influence of H2O2 on the dynamic changes of the community structure of bacterioplankton. By using deep-sequencing and metagenomics strategy we determined the community structures of phytoplankton and bacterioplankton assemblages that were dominated by Microcystis at a highly eutrophic Dianchi Lake, China. The results showed that Microcystis was more sensitive to H2O2 than other eukaryotic algae. More interestingly, application of H2O2 changed the community structure of bacterioplankton, evidenced by the emergence of Firmicutes as the dominant species in place of Bacteroidetes and Proteobacteria. The H2O2 treatment resulted in the community of bacterioplankton that was primarily dominated by Exiguobacterium and Planomicrobium. Our results show that the abundance changed and the bacterioplankton diversity did not recover even after the concentration of H2O2 reached to the background level. Thus, the response of bacterioplankton must be considered when assessing the ecological risks of using H2O2 to control Microcystis blooms, because bacterioplankton is the key player that forms the basis of food web of aquatic environment.

Aim: To evaluate the diagnostic accuracy of real-time elastography as a method for detecting prostate cancer.Material and methods: Relevant studies applying real-time elastography as the diagnostic modality and biopsy as the reference standard, published by March 1, 2018 were retrieved from PubMed, EMBASE, Web of Science and Cochrane Library databases. Two independent reviewers inspected all these articles to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. Randomized effect method, meta-regression and subgroup analysis were performed.Results: Twenty-four studies out of 1156 identified articles met the inclusion criteria. Three groups were set: analysisby patient (Group 1), by core (Group 2), and by image (Group 3) and subgroups set in Group 1. The pooled estimate ofreal-time elastography sensitivity/ specificity/ DOR calculated with the identical P-value 0.00. Within subgroups “Asia” and“PSA>=10 ng/ml”, the pooled sensitivity, specificity and DOR were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) and 20.2, 8.67 (p=0.09, I2=54.2%; p=0.20, I2=35.5%), respectively. In these three groups, the areas under the SROC curve were 0.7417, 0.9246, and 0.6213 independently.Conclusions: Real-time elastography is a promising, reliable modality for the non-invasive diagnosis of patients with prostate cancer. The diagnostic accuracy of real-time elastography correlates tightly to the presence of higher PSA level and may help avoid unnecessary biopsy. It seems to be a useful tool in systemic biopsy.

The distribution of metals in cyanobloom-forming lakes, and potential risks of these metals during irrigation with water derived from the bloom were evaluated in this study. Seven metals were monitored throughout a cyanobacterial bloom season in Lake Taihu. Cyanobloom bio-dilution of the targeted metals could be explained by the negative relationships between total phytoplankton metal contents (Cu, Fe, Zn, Pb and Cr) and Chl a concentrations (p0.05). Meanwhile, the ratios of extracellular bound to total cellular bound metals (Cu, Zn, Pb, Cr and Cd) were positively correlated with the ratios of cyanophyta to total phytoplankton (p0.01), indicating the enhanced extracellular bound of these metals during cyanobloom period. Secondly, Cd, Pb and Cr were detected in several local vegetables. In comparison to reference vegetables, vegetables (e.g., radish, soybean, and cowpea), which were irrigated with cyanobloom broth collected from Lake Taihu, presented high health risk index (HRI) and were not safe for human consumption. Collectively, the frequent dominant colonial Microcystis blooms which performed high metal affinity might mediate the distribution of heavy metals in lake and potentially transferred these pollutants into terrestrial system.

Capture and detection of circulating tumor cells (CTCs) is of great significance in the early diagnosis, prognosis evaluation and personalized therapy of cancer. Herein, we report a unique microfluidic platform integrated with zwitterion-modified aligned polyethyleneimine/polyvinyl alcohol nanofibers for efficient capture and rapid release of CTCs. We show that zwitterions of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) can be immobilized onto the aligned nanofibers via an atomic transfer radical polymerization approach. The combined strategy of using aligned nanofibers instead of random nanofibers and PMPC immobilization endows the nanofibers with excellent antifouling properties against protein adsorption and blood cell attachment, thereby significantly improving the capture purity of cancer cells. Meanwhile, the targeting ligand folic acid (FA) can be modified onto the surface of nanofibers via a redox-sensitive disulfide bond to specifically and efficiently capture cancer cells overexpressing FA receptors and to rapidly release the cancer cells in a non-destructive manner through tris(2-carboxyethyl)phosphine treatment. The dynamic capture assay using the fiber-integrated microfluidic platform demonstrates that FA receptor-expressing cancer cells can be isolated with a high capture efficiency (92.7%) and considerable purity (43.4%) in a time period of 30 min and can be rapidly detached from the nanofibrous substrates within 5 min with a release efficiency up to 98.9%. These results as well as the isolation and detection of CTCs from the blood of cancer patients suggest that the developed microfluidic chip may be potentially used for clinical cancer diagnosis applications.

Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i). Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume. Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm2 to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors. Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments.

Gas-assisted therapy and diagnosis of tumors have attracted extensive interest due to their low toxicity and convenience, but are severely limited by the uncontrollable gas release. In this work, we proposed a kind of ammonia borane (AB) and doxorubicin (DOX) co-loaded and PEGylated Hollow Mesoporous Polydopamine (AB/DOX@HMPDA-PEG) nanoparticles for acid-sensitive hydrogen (H2)-assisted ultrasonic (US) imaging and chemotherapy of drug-resistant tumors. The in vitro experiment showed that as a high H2-storage molecule, AB can controllably release massive H2 in an acidic environment. For one thing, the H2 release in the acidic tumor environment and lysosomes of tumor cells in vivo helped to improve the US imaging performance; for another, it facilitated the lysosomal escape of nanoparticles, DOX release from nanoparticles, and blockage of mitochondrial respiratory chain. Furtherly, the blockage of mitochondrial respiratory chain reduced the production of triphosadenine (ATP), thereby decreasing the expression of heat shock protein 90 (HSP90) and promoting the therapeutic effect of DOX on drug-resistant tumors. Therefore, the nanoparticles provided an effective platform for controllable H2-assisted chemotherapy and US imaging of the drug-resistant tumors.

SonoVue microbubbles could serve as artificial nuclei for ultrasound-triggered stable and inertial cavitation, resulting in beneficial biological effects for future therapeutic applications. To optimize and control the use of the cavitation of SonoVue bubbles in therapy while ensuring safety, it is important to comprehensively understand the relationship between the acoustic parameters and the cavitation behavior of the SonoVue bubbles. An agarose-gel tissue phantom was fabricated to hold the SonoVue bubble suspension. 1-MHz transmitting transducer calibrated by a hydrophone was used to trigger the cavitation of SonoVue bubbles under different ultrasonic parameters (i.e., peak rarefactional pressure (PRP), pulse repetition frequency (PRF), and pulse duration (PD)). Another 7.5-MHz focused transducer was employed to passively receive acoustic signals from the exposed bubbles. The ultraharmonics and broadband intensities in the acoustic emission spectra were measured to quantify the extent of stable and inertial cavitation of SonoVue bubbles, respectively. We found that the onset of both stable and inertial cavitation exhibited a strong dependence on the PRP and PD and a relatively weak dependence on the PRF. Approximate 0.25MPa PRP with more than 20μs PD was considered to be necessary for ultraharmonics emission of SonoVue bubbles, and obvious broadband signals started to appear when the PRP exceeded 0.40MPa. Moreover, the doses of stable and inertial cavitation varied with the PRP. The stable cavitation dose initially increased with increasing PRP, and then decreased rapidly after 0.5MPa. By contrast, the inertial cavitation dose continuously increased with increasing PRP. Finally, the doses of both stable and inertial cavitation were positively correlated with PRF and PD. These results could provide instructive information for optimizing future therapeutic applications of SonoVue bubbles.

In the present study, we determined whether ultrasound-targeted microbubble destruction (UTMD) combined with dual targeting of transforming growth factor (TGF)-β1 and tissue inhibitors of metalloproteinase (TIMP) 1 recombinant adeno-associated virus (rAAV) can stabilize atherosclerotic vulnerable plaques. First, we used rabbit model to detect the TGF-β1/TIMP1 virus therapy result. H&E staining was used to evaluate the tissues. The protein levels of TGF-β1 and TIMP1 were detected in rabbit models. The THP-1 cells were induced into macrophages, and transfected with TGF-β1 and TIMP1 rAAV under optimized UTMD. The expression of TGF-β1 and TIMP1 was measured by RT-PCR and western blotting. We found that the apoptotic rates were induced when compared to the control group. The rAAV virus group showed a significant decrease in the p-ERT and p-AKT expression. These data support the hypothesis that TGF-β1 and TIMP1 are crucial in the regulation of atherosclerotic plaques.

// Yang Liu 1, * , Fan Li 1, * , Feng Gao 1 , Lingxi Xing 1 , Peng Qin 2 , Xingxin Liang 1 , Jiajie Zhang 1 , Xiaohui Qiao 1 , Lizhou Lin 1 , Qian Zhao 3 and Lianfang Du 1 1 Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, China 2 Department of Instrument Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China 3 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis and National Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China * These authors contributed equally to this work Correspondence to: Lianfang Du, email: lianfang_du@126.com Qian Zhao, email: qzhao@shsmu.edu.cn Keywords: periostin, pancreatic cancer, microenvironment, pancreatic stellate cells, EGFR Received: March 17, 2016 Accepted: July 09, 2016 Published: August 23, 2016 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic reaction. Pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Aberrant up-regulation of periostin expression has been reported in activated PSCs. In this study, we investigated the role of periostin and the mechanisms underlying its aberrant upregulation in PDAC. We used lentiviral shRNA and human recombinant periostin protein to down and up regulate periostin expression in vitro . Specific oncogenic signaling pathways such as EGFR-Akt and EGFR-Erk-c-Myc were assessed in vitro and in vivo . Tissue microarray immunohistochemical assays including 80 pancreatic cancer tissues and paired normal tissues were used to understand the function relationship between periostin expression and PDAC pathologic stage and overall survival. We found that periostin was strongly expressed in PSCs and the stroma of PDAC tumors. We also observed a significant decrease in proliferation, metastasis, and clonality of pancreatic cancer cells when co-cultured with supernatant of periostin shRNA-transfected PSCs. Specifically, the biological behavior of periostin correlated with EGFR-Akt and EGER-Erk-c-Myc signaling pathways. Moreover, increased periostin expression significantly associated with advanced disease stage and decreased survival rate in PDAC patients. Together, our findings provide novel insights into the role of microenvironmental periostin in pancreatic cancer progression, and periostin may serve as a prognostic biomarker for PDAC.

Constructing nanosystems that synergistically combine therapeutic and diagnostic features is of great interest to the nanomedicine community but also remains a tremendous challenge. Methods: In this work, we report novel catalytic nanoparticles composed of the enzyme catalase, encapsulated in a polymer shell and surface decorated with pH-sensitive poly(ethylene glycol) (PEGylated nCAT). These nanoparticles were used as a promoter for ultrasound (US)-guided focused ultrasound (FUS) ablation and hypoxia alleviation for application in Doxorubicin-based chemotherapy. Results: The PEGylated nCAT produced highly effectively O2 from endogenous H2O2 to ameliorate the hypoxic and therefore poor-acoustic tumor environment. The generated O2 was utilized as 1) a contrast agent for US imaging; 2) strengthening agent for FUS ablation and 3) normoxia inducer to enhance chemotherapeutic efficacy. The PEGylated nCAT exhibited favorable enzyme activity after long-term storage, and after exposure to proteolytic conditions and elevated temperatures. The pH-responsive PEGylation contributed on the one hand to an extended in vivo circulation time over 48 h and on the other hand enabled PEG cleavage in the vicinity of cancer cells to facilitate cellular uptake. Conclusion: The developed PEGylated nCAT can therefore effectively combine US-guided FUS and chemotherapy and can be regarded as a highly promising theranostic platform.

Aim: To develop a multifunctional nanofibrous mat-embedded microfluidic chip system for specific capture and intact release of circulating tumor cells. Materials & methods: Electrospun polyethylenimine/polyvinyl alcohol nanofibers were functionalized with zwitterions to reduce the nonspecific adhesion of blood cells, followed by modification with arginine-glycine-aspartic acid peptide via an acid-sensitive benzoic imine bond. Results: The nanofiber-embedded microchip can be applied for capturing various types of cancer cells and circulating tumor cells with high efficiency and considerable purity. The captured cancer cells can be released from the nanofibrous substrates within 30 min. Conclusion: The developed multifunctional nanofiber-embedded microfluidic chip may have a great potential for clinical applications.

International audience; Design of simple-component theranostic agents with enhanced tumor accumulation represents a novel strategy in the area of precision nanomedicine for effective tumor theranostics. Herein, we report an innovative theranostic strategy based on ultrasound-enhanced tumor accumulation of a theranostic agent of phosphorus dendrimer-copper(II) complexes (1G3-Cu). The employed 1G3-Cu complexes represent a drug-free nanotheranostic agent with a simple composition possessing an r1 relaxivity of 0.7024 mM−1 s−1 for T1-weighted magnetic resonance (MR) imaging and an IC50 of 1.24 μM to inhibit the growth of a pancreatic cancer cell line. We show that cancer cells can be inhibited by the 1G3-Cu complexes through the activation of the apoptotic process with the upregulation of Bax, P53 and PTEN, downregulation of Bcl-2, and decrease of intracellular ATP. With the assistance of ultrasound targeted microbubble destruction (UTMD) technology that can increase cell membrane permeability temporarily via sonoporation effect, the 1G3-Cu complexes enable enhanced tumor MR imaging and chemotherapy due to their improved tumor accumulation. With the proven minimal toxicity to normal tissues at imaging and therapeutic doses, the prepared 1G3-Cu complexes may be potentially employed for UTMD-enhanced theranostics of different types of cancer.

Pancreatic cancer (PaC) consists of a bulk of stroma cells which contribute to tumor progression by releasing angiogenic factors. Recent studies have found that periostin (POSTN) is closely associate with the metastatic potential and prognosis of PaC. The purpose of this study is to determine the role of POSTN in tumor angiogenesis and explore the precise mechanisms. In this study, we used lentiviral shRNA and human recombinant POSTN protein (rPOSTN) to negatively and positively regulate POSTN expression in vitro. We found that increased POSTN expression promoted the tubule formation dependent on human umbilical vein endothelial cells (HUVECs). Moreover, knockdown of POSTN in PaC cells reduced tumor growth and VEGF expression in vivo. In accordance with these observations, we found that Erk phosphorylation and its downstream VEGF expression were upregulated achieved in rPOSTN-treated groups, opposing results were obversed in POSTN-slienced group. Meanwhile, Erk inhibitor SCH772984 significantly decreased VEGF expression as well as tubule formation of HUVECs in rPOSTN-treated PaC cells. Taken together, these findings suggest that POSTN promotes tumor angiogenesis via Erk/VEGF signaling in PaC and POSTN may be a new target for cancer anti-vascular treatment.

Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for early-stage cancer diagnosis, estimation of cancer development, and individualized cancer therapy. Herein, we report the development of hyaluronic acid (HA)-functionalized electrospun chitosan nanofiber (CNF)-integrated microfludic platform for highly specific capture and nondestructive release of CTCs. First, electrospun CNFs were formed and modified with zwitterion of carboxyl betaine acrylamide (CBAA) via Michael addition reaction and then targeting ligand HA through a disulfide bond. We show that the formed nanofibers still maintain the smooth fibrous morphology after sequential surface modifications, have a good hemocompatibility, and exhibit an excellent antifouling property due to the CBAA modification. After being embedded within a microfluidic chip, the fibrous mat can capture cancer cells (A549, a human lung cancer cell line) with an efficiency of 91% at a flow rate of 1.0 mL/h. Additionally, intact release of cancer cells is able to be achieved after treatment with glutathione for 40 min to have a release efficiency of 90%. Clinical applications show that 9 of 10 nonsmall-cell lung cancer patients and 5 of 5 breast cancer patients are diagnosed to have CTCs (1 to 18 CTCs per mL of blood). Our results suggest that the developed microfluidic system integrated with functionalized CNF mats may be employed for effective CTCs capture for clinical diagnosis of cancer.

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths. The nucleoside analog gemcitabine has been the cornerstone of adjuvant chemotherapy in PDAC for decades. However, gemcitabine resistance develops within weeks of chemotherapy initiation, which might be intrinsic to cancer cells and influenced by tumor microenvironment. Recently, pancreatic stellate cells (PSCs) have greatly increased our attention on tumor microenvironment-mediated drug resistance. Periostin is exclusively overexpressed in PSCs and the stroma of PDAC creating a tumor-supportive microenvironment in the pancreas. However, whether periostin contributed to chemoresistance in PDAC remains unknown. Therefore, we focused on the role of periostin in PDAC by observing the effects of silencing this gene on gemcitabine resistance in vitro and in vivo aiming to explore the possible molecular mechanism. In this study, the pancreatic cancer cell (PCC) proliferation and apoptosis were assayed to investigate the sensitivity to gemcitabine after silencing periostin. We provide the evidence that periostin not only drives the carcinogenic process itself but also significantly associated with gemcitabine-induced apoptosis. These findings collectively indicated that periostin increases the chemoresistance to gemcitabine. Thus, targeting periostin might offer a new opportunity to overcome the gemcitabine resistance of PDAC.