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• An oxidation induced phase transition layer were observed at subsurface. • Clarify the relationship between oxidation failure and the detachment of Al 2 O 3 particles. • Explained why the failure mode after oxidation shifts from toughness fracture to brittle fracture. This study investigated the impact of surface degradation caused by oxygen (O) and nitrogen (N) elements in the environmental atmosphere on the service failure of nearly lamellar TNM alloy. The results show that oxidation-induced phase transformations at the surface and subsurface regions strongly affect the alloy's tensile properties at high temperatures. The precipitation of Al 2 O 3 , which disrupts the integrity of the Ti 2 AlN layer, has a weaker deformation resistance capacity compared to the Z-phase. Under stress conditions, numerous dislocations concentrate at the Al 2 O 3 phase, causing Al 2 O 3 particles to easily detach and initiating crack nucleation at the Z-phase/Al 2 O 3 interface. This is the origin of oxidation failure. Cracks nucleate at the Al 2 O 3 detachment region, propagate, and connect with surface microcracks induced by the rough and loose outer oxide layer structure. This leads to the rapid propagation of cracks into the subsurface. The consumption of β-stabilizing elements at the surface, along with the internal diffusion of O and N elements into the subsurface region, results in the formation of the hard brittle Z-phase at the subsurface lamellar structure and a transition from β 0 to α 2 at the lamellar colony boundaries. The precipitation of α 2 and Z-phase also accelerates crack propagation. In summary, the failure mode shifts from toughness fracture to brittle fracture. [Display omitted] [ABSTRACT FROM AUTHOR]

There is no report on the (anti)aromaticity of metallacyclopentatrienes, one kind of common and important five-membered metallacycles. This work presents the novel synthesis of osmium cis-biscarbene complexes and their oxidation to osmacyclopentatrienes. The osmacyclopentatriene unit is antiaromatic, as revealed by experimental and theoretical studies. This finding provides new insight into the discovery of antiaromatic species.

• Lamellar fragmentation during thermal compression is investigated by quasi-in-situ experiment. • Complete fragmentation of the lamellar colonies is mainly attributed to α recrystallization. • Lamellar colony characteristics are the main factor affecting α recrystallization. • The dissolution mechanism of the recrystallized γ grains during thermal compression is proposed. The coarse as-cast lamellar microstructure in TiAl alloys is difficult to be broken completely by thermomechanical processing. Some remnant lamellar colonies in the deformed microstructure seriously affect the microstructural homogeneity and deteriorate the properties. In this study, it is found that by isothermal compression at 1230 °C and 1250 °C, the lamellar colonies of Ti-43.5Al-4Nb-1Mo-0.1B (TNM) alloys can be completely broken. This is attributed to the weakened anisotropic deformation behavior of the lamellar colonies due to the isothermal holding treatment before deformation. The deformation behavior at 1230 °C was investigated by quasi-in-situ experiments. It is observed that the regions near lamellar colony boundaries first undergo dynamic recrystallization at small strain, while the lamellar colonies gradually break down with increasing strain. The adequate fragmentation of lamellar colonies mainly depends on the recrystallization of α lamellae (α L). The isothermal holding at 1230 °C leads to an increase in the content and thickness of α L , which allows it to assume more deformation and promotes its recrystallization by reaching critical strain. The interrupted γ lamellae (γ L) formed by decomposition during isothermal holding facilitates the occurrence of α recrystallization within the lamellar colonies by hindering dislocation movement. In addition, recrystallized γ grains (γ R) are gradually dissolved by the formation of α precipitates inside them through the γ → α phase transformation and the subsequent consumption of α precipitates by the recrystallized α grains. [Display omitted] [ABSTRACT FROM AUTHOR]

The rectangular billet of TNM alloy with oriented lamellar microstructure was obtained by extrusion above its α transus temperature. The as-extruded TNM alloy exhibits a nearly lamellar microstructure with an average colony size of approximately 60 μm, and the proportion of lamellar colonies with an angle between the interface and the extrusion direction less than 30° exceeds 70 %. EBSD results show that strong basal texture of α phase with basal planes parallel to the extrusion direction was formed during the extrusion process in the (α+β) two-phase field. During the subsequent cooling process, the γ lamellae precipitates along the (0001) plane of α phase according to the Blackburn orientation relationship, allowing the lamellar structure to inherit the orientation of the parent phase. Tensile test results indicate that the strength and fracture elongation of the as-extruded TNM alloy along the extrusion direction (ED) increased simultaneously, which were 1100 MPa and 1.26 %, respectively. The hindrance effect of interfaces on dislocations and stacking faults in lamellar colonies parallel to the extrusion direction helps to improve strength, while the activation of the prismatic slip and pyramidal slip systems in the α2lamellae is beneficial to the plasticity. This study shows that it is feasible to control the lamellar orientation and improve the mechanical properties of TNM alloy by extrusion above its α transus temperature.

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The present study explores the clinical efficacy of probiotics in the treatment of patients with NAFLD by conducting a systematic search of relevant databases. The RevMan 5.4 software was used to evaluate the effects of probiotics on liver function (i.e. alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], lipid metabolism, blood glucose, inflammatory factors [e.g. tumor necrosis factor-α, TNF-α] and body mass index [BMI]) in patients with NAFLD. A total of 18 high-quality studies were included in the final meta-analysis. The results of the meta-analysis showed that the use of probiotics in the adjuvant treatment of patients with NAFLD improved liver function and reduced ALT levels (mean difference [MD]: −0.07; 95% confidence interval [CI]: −12.95, −7.19), AST levels (MD: −11.90; 95% CI: −16.55, −7.25) and GGT levels (MD: −8.61; 95% CI: −14.74, −2.48); additionally, the treatment effect was more obvious when the treatment time exceeded 12 weeks. Probiotic therapy reduced patients’ triglyceride levels (MD: −9.71; 95% CI: −18.39, −1.03) and total cholesterol levels (MD: −22.31; 95% CI: −25.41, −19.21). Probiotic treatment improved patients’ levels of fasting blood (MD: −8.22; 95% CI: −12.25, −4.20), insulin (MD: −2.68; 95% CI: −4.94, −0.41) and insulin resistance (MD: −0.72; 95% CI: −1.21, −0.24). Probiotic adjuvant therapy for patients with NAFLD reduced their BMI by approximately 1.67 (95% CI: −2.93, −0.41) and TNF-α levels. The adjuvant treatment of NAFLD with probiotics has a positive clinical effect, which is influenced by treatment time.

Efficient bifunctional OER/ORR catalysts are crucial for the further development of zinc-air battery. From a sustainable point of view, it is important that electrocatalysts are efficient, low cost, and composed of abundant resources instead of scarce metals. Due to their good conductivity, low cost, and strong durability, carbon-based materials are considered a promising alternative in the field of commercial zinc-air battery catalysts. Herein, we briefly introduce the zinc-air battery and then summarize recent progress in the development of carbon-based bifunctional catalysts by defect engineering, heteroatom doping and metal doping. Finally, we discuss the main challenges and prospects for the future development of carbon-based bifunctional oxygen catalysts.

A visible-light-driven iron-catalyzed C(sp3)–H amination of diphenylmethane derivatives with 1,2,3,4-tetrazoles under mild conditions has been developed. The reaction proceeds with photosensitizer-free conditions and features satisfactory to good yields. Mechanistic studies revealed that the reaction proceeded via an iron–nitrene intermediate, and H atom abstraction was the rate-determining step. Computational studies showed that the denitrogenation of 1,2,3,4-tetrazole depends on the conversion of the sextet ground state of 1,2,3,4-tetrazole-bounding iron species to the quartet spin state under visible-light irradiation.

Tumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-β-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation.

Stable, high-resolution intravital imaging of the lung has become possible through the utilization of vacuum-stabilized imaging windows. However, this technique is extremely invasive and limited to only hours in duration. Here we describe a minimally invasive, permanently implantable window for high-resolution intravital imaging of the murine lung that allows the mouse to survive surgery, recover from anesthesia, and breathe independently. Compared to vacuum-stabilized windows, this window produces the same high-quality images without vacuum-induced artifacts; it is also less invasive, which allows imaging of the same lung tissue over a period of weeks. We further adapt the technique of microcartography for reliable relocalization of the same cells longitudinally. Using commonly employed experimental, as well as more clinically relevant, spontaneous metastasis models, we visualize all stages of metastatic seeding, including: tumor cell arrival; extravasation; growth and progression to micrometastases; as well as tumor microenvironment of metastasis function, the hallmark of hematogenous dissemination of tumor cells.

Hypoxia is a poor-prognosis microenvironmental hallmark of solid tumours, but it is unclear how it influences the fate of disseminated tumour cells (DTCs) in target organs. Here we report that hypoxic HNSCC and breast primary tumour microenvironments displayed upregulation of key dormancy (NR2F1, DEC2, p27) and hypoxia (GLUT1, HIF1α) genes. Analysis of solitary DTCs in PDX and transgenic mice revealed that post-hypoxic DTCs were frequently NR2F1hi/DEC2hi/p27hi/TGFβ2hiand dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hiexpression. Post-hypoxic DTCs evaded chemotherapy and, unlike ER−breast cancer cells, post-hypoxic ER+breast cancer cells were more prone to enter NR2F1-dependent dormancy. We propose that primary tumour hypoxic microenvironments give rise to a subpopulation of dormant DTCs that evade therapy. These post-hypoxic dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.

The nucleus accumbens (NAc) is a key part of the neural circuitry that creates reward, pleasure and motivation that facilitates human feeding, sexual and smoking behaviors. In the brain reward system, the NAc is a crucial component responsible for natural and drug-induced reinforcement behaviors. Yet it is unclear whether NAc is indispensible for all reward behaviors in human beings. The present study aimed to investigate the long-term effects of NAc ablation on sexual function, appetite, and nicotine dependence level in chronic heroin users. Eighteen former heroin-dependent patients (male) with bilateral NAc ablation via stereotactic radiofrequency surgery for alleviating drug psychological dependence were recruited. Their postoperative time ranged from 12 to 103 months. All subjects received MRI scans for assessing the accuracy of the lesion site. Evaluation of appetite, sexual function, and nicotine dependence were measured using the Simplified Nutrition Appetite Questionnaire, the Brief Sexual Function Inventory, and the Fagerström Test for Nicotine Dependence, respectively. After precluding the potential confounding variables, such as drug use (dosage and duration), post-operation duration, age, body-weight, marital status and education level, ANOVA with repeated measures revealed that the NAc ablation improved the patients’ appetite, sexual drive and sexual satisfaction. Yet there was no change in male erectile function, ejaculatory function, or nicotine dependence levels compared to the preoperative. These may suggest that although NAc is a key part of the neural circuitry, the NAc surgical lesions left the fundamental aspects of natural and drug-induced reinforcement and motivation almost intact.

Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8+ tumor cells. The proinflammatory mediators TNF, IL-1β, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1–CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.

Relative deficiency in production of glycoprotein hormone erythropoietin (Epo) is a major cause of renal anemia. This study planned to investigate whether the hypoxia-regulated system of Epo expression, constructed by fusing Epo gene to the chimeric phosphoglycerate kinase (PGK) hypoxia response elements (HRE) in combination with cytomegalovirus immediate-early (CMV IE) basal gene promoter and delivered by plasmid intramuscular injection, might provide a long-term physiologically regulated Epo secretion expression to correct the anemia in adenine-induced uremic rats. Plasmid vectors (pHRE-Epo) were synthesized by fusing human Epo cDNA to the HRE/CMV promoter. Hypoxia-inducible activity of this promoter was evaluated first in vitro and then in vivo in healthy and uremic rats (n = 30 per group). The vectors (pCMV-Epo) in which Epo expression was directed by a constitutive CMV gene promoter served as control. ANOVA and Student's t-test were used to analyze between-group differences. A high-level expression of Epo was induced by hypoxia in vitro and in vivo. Though both pHRE-Epo and pCMV-Epo corrected anemia, the hematocrit of the pCMV-Epo-treated rats exceeded the normal (P < 0.05), but that of the pHRE-Epo-treated rats didn't. Hypoxia-regulated system of Epo gene expression constructed by fusing Epo to the HRE/CMV promoter and delivered by plasmid intramuscular injection may provide a long-term and stable Epo expression and secretion in vivo to correct the anemia in adenine-induced uremic rats.

Thirsty battery: We introduce a Li–liquid cathode battery which employs an inexpensive aqueous solution of the Fe3+/Fe2+redox couple as both cathode and electrolyte. The liquid cathode can be recovered through electric or chemical “charging” after discharge of the battery and, depending on the targeted utilization, can be switched to be operated in either a static or a flow mode.

The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development. To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivoinvasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice. Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivoinvasion, in vivomotility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching. Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM–treated mice demonstrated a CD4 T cell–mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node–like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.

Mesoporous carbon nanofibers have been prepared by a confined self-assembly of triblock copolymers with soluble low molecular weight phenolic resol within the channels of anodic alumina membranes. SEM and TEM observations showed that hexagonally arranged mesoporous channels were coiled concentrically around the longitudinal axis of the carbon nanofibers. These carbon nanofibers with BET surface area over 1424 m2g−1have been used as electrode materials for electrochemical capacitors tested in KOH and EC/DEC electrolyte solutions. Compared to mesoporous carbon prepared from the same precursor sol, these one-dimensional nanofibers could provide a shortened diffusion distance for electrolyte ions. The better performance of these mesoporous nanofibers greatly benefited from their high specific surface area, shortened diffusion distance, mesoporous openings on the outer surface, and well-controlled pore size. These mesoporous carbon nanofibers have been proved to be promising electrode materials for electrochemical supercapacitors in high-rate charge/discharge operations.

No Abstract

Truly long‐life: A LiFePO4/carbon composite containing a highly crystalline LiFePO4core with a size of about 20–40 nm and a semi‐graphitic carbon shell with a thickness of about 1–2 nm provides both high power and very long cycling life (see picture). The synthetic method can be extended to the preparation of other materials, such as Li4Ti5O12/carbon and Mn3O4/carbon composites.

Abstract: Doped ceria (CeO2) compounds are fluorite type oxides that show oxygen ionic conductivity higher than yttria stabilized zirconia, in oxidizing atmosphere. In order to improve the conductivity, the effective index was suggested to maximize the oxygen ionic conductivity in doped CeO2 based oxides. In addition, the true microstructure of doped CeO2 was observed at atomic scale for conclusion of conduction mechanism. Doped CeO2 had small domains (10-50 nm) with ordered structure in a grain. It is found that the electrolytic properties strongly depended on the nano-structural feature at atomic scale in doped CeO2 electrolyte.

Multimodal electronic skin devices capable of detecting multimodal signals provide the possibility for health monitoring. Sensing and memory for temperature and deformation by human skin are of great significance for the perception and monitoring of physiological changes of the human body. Electronic skin is highly expected to have similar functions as human skin. Here, by implementing intrinsically stretchable neuromorphic transistors with mechanoreceptors and thermoreceptors in an array, we have realized stretchable temperature-responsive multimodal neuromorphic electronic skin (STRM-NES) with both sensory and memory functions, in which synaptic plasticity can be modulated by multiple modalities, in situtemperature variations, and stretching deformations. Temperature-responsive functions, spontaneous recovery, and temperature-dependent multitrial learning are proposed. Furthermore, a stretchable temperature neuromorphic array composed of multiple fully functional subcells is demonstrated to identify temperature distributions and variations at different regions and conditions after various strains of skin. The STRM-NES has temperature- and strain-responsive neuromorphic functions, excellent self-healing, and reusable capability, showing similar abilities as human skin to sense, transmit, memory, and recovery from external stimuli. It is expected to facilitate the development of wearable electronics, intelligent robotics, and prosthetic applications.

Type VI secretion system (T6SS) is widely distributed in Gram-negative bacteria and functions as a versatile protein export machinery that translocates effectors into eukaryotic or prokaryotic target cells. Growing evidence indicates that T6SS can deliver several effectors to promote bacterial survival in harmful environments through metal ion acquisition. Here, we report that the Pseudomonas aeruginosaH2-T6SS mediates molybdate (MoO42−) acquisition by secretion of a molybdate-binding protein, ModA. The expression of H2-T6SS genes is activated by the master regulator Anr and anaerobiosis. We also identified a ModA-binding protein, IcmP, an insulin-cleaving metalloproteinase outer membrane protein. The T6SS-ModA-IcmP system provides P. aeruginosawith a growth advantage in bacterial competition under anaerobic conditions and plays an important role in bacterial virulence. Overall, this study clarifies the role of T6SS in secretion of an anion-binding protein, emphasizing the fundamental importance of this bacterium using T6SS-mediated molybdate uptake to adapt to complex environmental conditions.

Chemotherapy induces prometastatic changes in breast cancer, reversible by TIE2 or MENA inhibition.

ABSTRACTTumor hypoxia is linked to tumor progression, metastasis, and therapy resistance. However, the underlying mechanisms behind this linkage are not fully understood. Here we present a novel fluorescent mCherry hypoxia-responsive marker that can be used in real time imaging to specifically and sensitively identify hypoxic cells in vivo at single cell resolution. Tumors derived from triple negative tumor cells expressing the hypoxia marker reveal that the hypoxic tumor cells congregate near flowing blood vessels. Using multiphoton microscopy, hypoxic MDA-MB-231 cells were directly visualized and showed a more persistent slow migration phenotype as compared to normoxic cells in the same field in vivo. Hypoxic tumor cells are enriched in the cell population that migrates toward human epithelial growth factor gradients in vivo, and has increased collagen degradation and intravasation activity, characteristics of dissemination and metastasis competent tumor cells. The hypoxia probe introduced in this study provides a specific reporter of hypoxic cell phenotypes in vivo which reveals new insights into the mechanisms by which hypoxia is linked to metastasis.

ABSTRACTThe tumor microenvironment is recognized as playing a significant role in the behavior of tumor cells and their progression to metastasis. However, tools to manipulate the tumor microenvironment directly, and image the consequences of this manipulation with single cell resolution in real time in vivo, are lacking. We describe here a method for the direct, local manipulation of microenvironmental parameters through the use of an implantable Induction Nano Intravital Device (iNANIVID) and simultaneous in vivovisualization of the results at single-cell resolution. As a proof of concept, we deliver both a sustained dose of EGF to tumor cells while intravital imaging their chemotactic response as well as locally induce hypoxia in defined microenvironments in solid tumors.

Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor.

The Nano Intravital Device, or NANIVID, is under development as an optically transparent, implantable tool to study the tumor microenvironment. Two etched glass substrates are sealed using a thin polymer membrane to create a reservoir with a single outlet. This reservoir is loaded with a hydrogel blend that contains growth factors or other chemicals to be delivered to the tumor microenvironment. When the device is implanted in the tumor, the hydrogel will swell and release these entrapped molecules, forming a gradient. Validation of the device has been performed in vitro using epidermal growth factor (EGF) and MenaINV, a highly invasive, rat mammary adenocarcinoma cell line. In both 2-D and 3-D environments, cells migrated toward the gradient of EGF released from the device. The chorioallantoic membrane (CAM) of White Leghorn chicken eggs is being utilized to grow xenograft tumors that will be used for ex vivo cell collection. Device optimization is being performed for in vivo use as a tool to collect the invasive cell population. Preliminary cell collection experiments in vivo were performed using a mouse model of breast cancer. As a second application, the device is being explored as a delivery vehicle for chemicals that induce controlled changes in the tumor microenvironment. H2O2was loaded in the device and generated intracellular reactive oxygen species (ROS) in cells near the device outlet. In the future, other induction targets will be explored, including hypoglycemia and the manipulation of extracellular matrix stiffness.

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