Intrauterine botulinum toxin A administration promotes endometrial regeneration mediated by IGFBP3-dependent OPN proteolytic cleavage in thin endometrium.

Adequate endometrial growth is a critical factor for successful embryo implantation and pregnancy maintenance. We previously reported the efficacy of intrauterine administration of botulinum toxin A (BoTA) in improving the endometrial angiogenesis and the rates of embryo implantation. Here, we further evaluated its potent therapeutic effects on the uterine structural and functional repair and elucidated underlying molecular regulatory mechanisms. This study demonstrated that a murine model of thin endometrium was successfully established by displaying dramatically decreased endometrial thickness and the rates of embryo implantation compared to normal endometrium. Interestingly, the expressions of insulin-like growth factor binding protein-3 (IGFBP3) and an active 35 kDa-form of osteopontin (OPN) were significantly reduced in thin endometrium, which were almost fully restored by intrauterine BoTA administration. Neutralization of BoTA-induced IGFBP3 subsequently suppressed proteolytic cleavage of OPN, exhibiting un-recovered endometrial thickness even in the presence of BoTA administration, suggesting that BoTA-induced endometrial regeneration might be mediated by IGFBP3-dependent OPN proteolytic cleavage. Our findings suggest that intrauterine BoTA administration improves the endometrial environment in our murine model with thin endometrium by increasing endometrial receptivity and angiogenesis in a manner dependent on the regulatory effect of IGFBP3 on OPN proteolytic cleavage, proposing BoTA as an efficient therapeutic strategy for the patients with thin endometrium.

Unraveling the link between atopic dermatitis and autoimmune diseases in children: Insights from a large-scale cohort study with 15-year follow-up and shared gene ontology analysis.

BACKGROUND: Atopic dermatitis and autoimmune diseases are highly heritable conditions that may co-occur from an early age. METHODS: The primary study is a national administrative cohort study involving 499,428 children born in 2002, tracked until 2017. Atopic dermatitis was defined as five or more principal diagnoses of atopic dermatitis and two or more topical steroid prescriptions. We estimated the risks for the occurrence of 41 autoimmune diseases, controlling for risk factors. In addition, we sourced a gene library from the National Library of Medicine to conduct a comprehensive gene ontology. We used Gene Weaver to identify gene set similarity and clustering, and used GeneMania to generate a network for shared genes. RESULTS: Exposed and unexposed groups included 39,832 and 159,328 children, respectively. During a mean follow-up of 12 years, the exposed group had an increased risk of autoimmune disease (hazard ratio, 1.27 [95 % confidence interval, 1.23-1.32]) compared to the unexposed group. The hazard ratios of autoimmune illnesses consistently increased with two- and five years lag times and alternative atopic dermatitis definitions. Shared genes between atopic dermatitis and autoimmune diseases were associated with comorbidities such as asthma, bronchiolitis, and specific infections. Genetic interactions of these shared genes revealed clustering in Th1, Th2, Th17, and non-classifiable pathways. CONCLUSIONS: Atopic dermatitis was significantly associated with an increased risk of subsequent autoimmune disease. we identified the genetically associated disease in atopic dermatitis patients comorbid with autoimmune disease and demonstrated a genetic network between atopic dermatitis and autoimmune diseases.

Three-dimensional microengineered vascularised endometrium-on-a-chip.

STUDY QUESTION: Can we reconstitute physiologically relevant 3-dimensional (3D) microengineered endometrium in-vitro model? SUMMARY ANSWER: Our representative microengineered vascularised endometrium on-a-chip closely recapitulates the endometrial microenvironment that consists of three distinct layers including epithelial cells, stromal fibroblasts and endothelial cells in a 3D extracellular matrix in a spatiotemporal manner. WHAT IS KNOWN ALREADY: Organ-on-a-chip, a multi-channel 3D microfluidic cell culture system, is widely used to investigate physiologically relevant responses of organ systems. STUDY DESIGN, SIZE, DURATION: The device consists of five microchannels that are arrayed in parallel and partitioned by array of micropost. Two central channels are for 3D culture and morphogenesis of stromal fibroblast and endothelial cells. In addition, the outermost channel is for the culture of additional endometrial stromal fibroblasts that secrete biochemical cues to induce directional pro-angiogenic responses of endothelial cells. To seed endometrial epithelial cells, on Day 8, Ishikawa cells were introduced to one of the two medium channels to adhere on the gel surface. After that, the microengineered endometrium was cultured for an additional 5-6 days (total ∼ 14 days) for the purpose of each experiment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Microfluidic 3D cultures were maintained in endothelial growth Medium 2 with or without oestradiol and progesterone. Some cultures additionally received exogenous pro-angiogenic factors. For the three distinct layers of microengineered endometrium-on-a-chip, the epithelium, stroma and blood vessel characteristics and drug response of each distinct layer in the microfluidic model were assessed morphologically and biochemically. The quantitative measurement of endometrial drug delivery was evaluated by the permeability coefficients. MAIN RESULTS AND THE ROLE OF CHANCE: We established microengineered vascularised endometrium-on-chip, which consists of three distinct layers: epithelium, stroma and blood vessels. Our endometrium model faithfully recapitulates in-vivo endometrial vasculo-angiogenesis and hormonal responses displaying key features of the proliferative and secretory phases of the menstrual cycle. Furthermore, the effect of the emergency contraception drug levonorgestrel was evaluated in our model demonstrating increased endometrial permeability and blood vessel regression in a dose-dependent manner. We finally provided a proof of concept of the multi-layered endometrium model for embryo implantation, which aids a better understanding of the molecular and cellular mechanisms underlying this process. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This report is largely an in-vitro study and it would be beneficial to validate our findings using human primary endometrial cells. WIDER IMPLICATIONS OF THE FINDINGS: Our 3D microengineered vascularised endometrium-on-a-chip provides a new in-vitro approach to drug screening and drug discovery by mimicking the complicated behaviours of human endometrium. Thus, we suggest our model as a tool for addressing critical challenges and unsolved problems in female diseases, such as endometriosis, uterine cancer and female infertility, in a personalised manner. STUDY FUNDING/COMPETING INTEREST(S): This work is supported by funding from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) to Y.J.K. (No. 2018R1C1B6003), to J.A. (No. 2020R1I1A1A01074136) and to H.S.K. (No. 2020R1C1C100787212). The authors report no conflicts of interest.

Trichloroethylene Hypersensitivity Syndrome: Should Be Considered When Diagnosing DRESS Syndrome.

Trichloroethylene (TCE) is an organic solvent that is used for degreasing and removing impurities from metal parts. However, this solvent's characteristics and hypersensitivity can produce clinical patterns and laboratory data that mimic drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Thus, exposure confirmation is critical to making an accurate diagnosis. This is a case of TCE-induced hypersensitivity syndrome (TCE HS) in a 24-year-old Indonesian man who was working in an electro-plating business. He was admitted to a referral hospital after one month of working, and exhibited a fever with skin symptoms. He was administered immunosuppressive therapy based on an assumed diagnosis of DRESS syndrome, although he subsequently experienced cardiac arrest and did not respond to resuscitation. An investigation into his disease history confirmed that he was prescribed medications one week before he developed the skin disease, and had been periodically exposed to TCE for the previous 4 weeks. Based on these findings, it was believed that his clinical course was caused by TCE HS, rather than DRESS syndrome.

Design and characterization of synthetic fungal-bacterial consortia for direct production of isobutanol from cellulosic biomass.

Synergistic microbial communities are ubiquitous in nature and exhibit appealing features, such as sophisticated metabolic capabilities and robustness. This has inspired fast-growing interest in engineering synthetic microbial consortia for biotechnology development. However, there are relatively few reports of their use in real-world applications, and achieving population stability and regulation has proven to be challenging. In this work, we bridge ecology theory with engineering principles to develop robust synthetic fungal-bacterial consortia for efficient biosynthesis of valuable products from lignocellulosic feedstocks. The required biological functions are divided between two specialists: the fungus Trichoderma reesei, which secretes cellulase enzymes to hydrolyze lignocellulosic biomass into soluble saccharides, and the bacterium Escherichia coli, which metabolizes soluble saccharides into desired products. We developed and experimentally validated a comprehensive mathematical model for T. reesei/E. coli consortia, providing insights on key determinants of the system's performance. To illustrate the bioprocessing potential of this consortium, we demonstrate direct conversion of microcrystalline cellulose and pretreated corn stover to isobutanol. Without costly nutrient supplementation, we achieved titers up to 1.88 g/L and yields up to 62% of theoretical maximum. In addition, we show that cooperator-cheater dynamics within T. reesei/E. coli consortia lead to stable population equilibria and provide a mechanism for tuning composition. Although we offer isobutanol production as a proof-of-concept application, our modular system could be readily adapted for production of many other valuable biochemicals.

The therapeutic effects of vitamin D3 administration on the embryo implantation.

Various adjuvants have been tested clinically for patients with problems with embryo implantation during in vitro fertilization (IVF)-embryo transfer (ET). Vitamin D3, an essential modulator of various physiological processes, has received attention as an important adjuvant for successful pregnancy, as many studies have shown a strong association between vitamin D deficiency and implantation failure and fetal growth restriction. However, vitamin D has been widely utilized in different protocols, resulting in non-reproducible and debatable outcomes. In the present study, we demonstrated that cyclic intrauterine administration of vitamin D3 increased endometrial receptivity and angiogenesis, which could be attributed to increased recruitment of uterus-resident natural killer cells. In particular, cyclic treatment of vitamin D3 promoted stable attachment of the embryo onto endometrial cells in vitro, suggesting its merit during the early stage of embryo implantation to support the initial maternal-fetal interactions. Our findings suggest that women with repeated implantation failure may benefit from the use of vitamin D3 as a risk-free adjuvant prior to IVF-ET procedures to improve the uterine environment, and make it favorable for embryo implantation.

Endometrial organoids: a reservoir of functional mitochondria for uterine repair.

Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility. Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established. Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment. The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium. The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta. To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium. Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice. Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids. Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium. Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS. Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.

Effects of process control agent on the synthesis of AIN-carbon nanotube by ball-milling.

Aluminum and its alloy are of importance due to high specific strength. In particular, aluminum matrix composites have good corrosion resistance and mechanical property at high temperatures. However, enhanced mechanical strength and wear resistance via proper heat treatments are strongly required for many structural applications. For this purpose, we synthesized carbon nanotube (CNT)-reinforced aluminum matrix composites by employing a new method. We employed controlled ball-milling and sintering: the use of some specific process control agents (PCAs) for ball-milling and sintering in a specific atmosphere. The use of our PCAs was beneficial both for homogeneous mixing and for the formation of hard dispersoids. Hardened layers was formed at the surface of the present aluminum-CNT composites as a result of reaction of aluminum with PCAs and nitrogen in the processing atmosphere. The resulting materials after sintering showed interesting mechanical properties, combined with surface hardening. The hardening mainly stems from the formation of Al-N-O phase at the surface of specimens.

3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing.

Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Notably, the hybrid spheroids also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer. STATEMENT OF SIGNIFICANCE: We conducted an integrative study within a vascularized tumor spheroid (VTS) model. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Through RNA sequencing, we elucidated that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behavior such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow.

Properties of high-energy ball-milled Fe-Se based superconductors.

We have synthesized FeSe0.5Te0.5 superconductors by high-energy ball-milling and subsequent annealing. High-energy ball-milling of elemental powder mixtures resulted in the formation of metastable and/or nanocrystalline phases. Both XRD and DSC results show that the ball-milled powers were completely transformed to FeSe0.5Te0.5 with the grain size of a few nanometers during sintering at low temperatures. The resulting materials exhibited superconducting transition at 14 K. The enhancement of critical current density was observed for the high-energy ball-milled powder, compared with the un-milled powders.

Surface hardening of Al alloys through controlled ball-milling and sintering.

One of the drawbacks of aluminum and its alloys is the lack of proper heat-treatment for surface-hardening. In the present work, a new and simple method of hardening the surface of aluminum and its alloys was developed. Low-energy ball-milling using specific process control agents (PCAs) was employed, using subsequent sintering in a controlled atmosphere. The PCAs in the present work were very effective both for milling and the formation of hard nanocrystalline dispersoids during sintering. The residual oxygen in a sintering atmosphere also played an important role in the formation of AIN or Al-O-N dispersoids. Through the proper control of the processing atmosphere and PCAs, the hardness and thickness of the hardened layers could be adjusted. The results of the wear test showed that the present aluminum alloys can be effectively utilized as light-weight components with a good wear resistance. Furthermore, the present method involves a simple forming process of die-compaction and sintering.

Formation of nano-sized Y2O3 dispersoids in mechanically alloyed Ni-(Cr, Y2O3, Y) alloys during heat-treatments.

In the present work, the evolution of nanoparticles during annealing and hot-consolidation in mechanically alloyed Ni-22Cr-1.5Y, Ni-22Cr-1.5Y2O3 and Ni-3% Y2O3 was examined. The high-energy ball-milling of elemental powders resulted in the complete dissolution of the constituent Cr, Y, or Y2O3, forming a Ni-based solid solution. During the subsequent annealing, however, oxide particles precipitated from the solid solution. In the case of mechanically alloyed Ni-22Cr-1.5Y2O3, over-grown Cr2O3 precipitated at a temperature as low as above approximately 500 degrees C and ternary YCrO3 particles precipitated at 1100 degrees C. In the case of mechanically alloyed Ni-22Cr-1.5Y, on the other hand, the binary Y2O3 phase precipitated at 1100 degrees C during spark plasma sintering. The presence of Cr in the alloy composition facilitated the formation of Cr2O3 or YCrO3, and the precipitated oxides were highly prone to grain growth during hot-consolidation, sometimes reaching several micrometers. In Cr-exempt Ni-3%Y or Ni-3% Y2O3, however, the growth of nanodispersoids was restrained even at temperatures as high as 1000 degrees C and the resulting dispersoid was only nano-sized Y2O3.

Formation of nanostructures in Ni-22Cr-11Fe-1X (X = Y2O3, TiO2) alloys by high-energy ball-milling.

Powder mixtures of Ni, Cr, Fe and Y2O3 were high-energy ball-milled and subsequently sintered to fabricate Ni-based oxide-dispersion strengthened (ODS) alloys. Nano-sized Y2O3 and/or TiO2 seem to be dissolved in the Ni matrix forming a metastable solid solution during high-energy ball-milling or mechanical alloying (MA) process. The finely grained MA powders with high dislocation density facilitated the decomposition of oxides. The MA powders were consolidated to near-full density by spark plasma sintering at 1100 degrees C for 5 minutes in an Ar atmosphere. The Cr oxides as well as decomposed Y- and Ti-oxides thermally precipitated as oxide particles of several tens nanometers at this temperature, although sintering was carried out during a short time. The SPSed specimen showed a near full densification with almost pore-free microstructures. Examination of fractured surface showed a typical dimple rupture with fine and homogeneous distribution of dispersoids, indicating non-negligible room temperature ductility combined with high mechanical strength.

Dysfunctional activity of classical DNA end-joining renders acquired resistance to carboplatin in human ovarian cancer cells.

Ovarian cancer is the deadliest gynecological malignancy worldwide. Although chemotherapy is required as the most standard treatment strategy for ovarian cancer, the survival rates are very low, largely because of high incidence of recurrence due to resistance to conventional surgery and genotoxic chemotherapies. Carboplatin-resistant ovarian cancer cells were generated by continuous treatment over six months. Carboplatin-resistance induced morphological alterations and promoted the rates of proliferation and migration of SKOV3 compared to the parental cells. Interestingly, carboplatin-resistant SKOV3 showed the high levels of γH2AX foci formed at the basal level, and the levels of γH2AX foci remained even after the recovery time, suggesting that the DNA damage response and repair machinery were severely attenuated by carboplatin-resistance. Surprisingly, the expression levels of XRCC4, a critical factor in non-homologous end joining (NHEJ) DNA repair, were significantly decreased in carboplatin-resistant SKOV3 compared with those in non-resistant controls. Furthermore, restoration of NHEJ in carboplatin-resistant SKOV3 by suppression of ABCB1 and/or AR re-sensitized carboplatin-resistant cells to genotoxic stress and reduced their proliferation ability. Our findings suggest that attenuation of the NHEJ DNA repair machinery mediated by resistance to genotoxic stress might be a critical cause of chemoresistance in patients with ovarian cancer.

Non-invasive Intrauterine Administration of Botulinum Toxin A Enhances Endometrial Angiogenesis and Improves the Rates of Embryo Implantation.

Endometrial angiogenesis plays crucial roles in determining the endometrial receptivity. Defects in endometrial receptivity often cause repeated implantation failure, which is one of the major unmet needs for infertility and contributes a major barrier to the assisted reproductive technology. Despite the numerous extensive research work, there are currently no effective evidence-based treatments to prevent or cure this condition. As a non-invasive treatment strategy, botulinum toxin A (BoTA) was administered into one side of mouse uterine horns, and saline was infused into the other side of horns for the control. Impact of BoTA was assessed in the endometrium at 3 or 8 days after infusion. We demonstrated that BoTA administration enhances the capacity of endothelial cell tube formation and sprouting. The intrauterine BoTA administration significantly induced endometrial angiogenesis displaying increased numbers of vessel formation and expression levels of related marker genes. Moreover, BoTA intrauterine application promoted the endometrial receptivity, and the rates of embryo implantation were improved with BoTA treatment with no morphologically retarded embryos. Intrauterine BoTA treatment has a beneficial effect on vascular reconstruction of functional endometrium prior to embryo implantation by increasing endometrial blood flow near the uterine cavity suggesting BoTA treatment as a potential therapeutic strategy for patients who are suffering from repeated implantation failure with the problems with endometrial receptivity.

CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. Chemokine CXCL12 derived from pre- and peri-implanting embryos significantly enhances the rates of embryo attachment and promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in C57BL/6 mice improved endometrial receptivity showing increased integrin ß3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Thus, our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a minimally-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.

Development of highly functional bioengineered human liver with perfusable vasculature.

Liver tissue engineering offers a promising strategy for liver failure patients. Since transplantation rejection resulting in vessel thrombosis is regarded as a major hurdle, vascular reconstruction is one of indispensable requirements of whole organ engineering. Here we demonstrated a novel strategy for reconstruction of a vascularized bioengineered human liver (VBHL) using decellularized liver scaffolds in an efficient manner. First we achieved fully functional endothelial coverage of scaffolds by adopting the anti-CD31 aptamer as a potent coating agent for re-endothelialization. Through an ex vivo human blood perfusion that recapitulates the blood coagulation response in humans, we demonstrated significantly reduced platelet aggregation in anti-CD31 aptamer coated scaffolds. We then produced VBHL constructs using liver parenchymal cells and nonparenchymal cells, properly organized into liver-like structures with an aligned vasculature. Interestingly, VBHL constructs displayed prominently enhanced long-term liver-specific functions that are affected by vascular functionality. The VBHL constructs formed perfusable vessel networks in vivo as evidenced by the direct vascular connection between the VBHL constructs and the renal circulation. Furthermore, heterotopic transplantation of VBHL constructs supported liver functions in a rat model of liver fibrosis. Overall, we proposed a new strategy to generate transplantable bioengineered livers characterized by highly functional vascular reconstruction.

Intertube Aggregation-Dependent Convective Heat Transfer in Vertically Aligned Carbon Nanotube Channels.

The heat transfer of carbon nanotube fin geometry has received considerable attention. However, the flow typically occurred over or around the pillars of nanotubes due to the greater flow resistance between the tubes. Here, we investigated the forced convective heat transfer of water through the interstitial space of vertically aligned multiwalled carbon nanotubes (VAMWNTs, intertube distance = 69 nm). The water flow provided significantly a greater Reynolds number (Re) and Nusselt number (Nu) than air flow due to the greater density, heat capacity, and thermal conductivity. However, it resulted in surface tension-induced nanotube aggregation after the flow and drying process, generating random voids in the nanotube channel. This increased permeability (1.27 × 10-11 m2) and Re (2.83 × 10-1) but decreased the heat transfer coefficient (h, 9900 W m-2 K-1) and Nu (53.77), demonstrating a trade-off relationship. The h (25,927 W m-2 K-1) and Nu (153.49) could be further increased, at an equivalent permeability or Re, by increasing nanotube areal density from 2.08 × 1010 to 1.04 × 1011 cm-2. The area-normalized thermal resistance of the densified and aggregated VAMWNTs was smaller than those of the Ni foam, Si microchannel, and carbon nanotube fin array, demonstrating excellent heat transfer characteristics.

Polymeric Nanoparticles Controlled by On-Chip Self-Assembly Enhance Cancer Treatment Effectiveness.

Nanoparticle (NP)-based drug delivery systems or nanomedicines have broadened the horizon of translational research for decades. Conventional bulk mixing synthesis methods have impeded successful clinical translations of nanomedicines due to the limited ability of the controlled, scalable production with high uniformity. Herein, an on-chip preparation of self-assembled, drug-encapsulated polymeric NPs is presented for their improved uniformity and homogeneity that results in enhanced anti-cancer effect in vitro and in vivo. The NPs are formulated through rapid convective mixing of two aqueous solutions of a hydrophilic polymer and an anti-cancer drug, doxorubicin (DOX), in the swirling microvortex reactor (SMR). Compared to conventional bulk-mixed NPs (BMPs), the microvortex-synthesized NPs (MVPs) exhibit narrower size distributions and better size tunability. It is found that the improved uniformity and homogeneity of the MVPs not only enhance cellular uptake and anti-cancer effect with pH-responsive drug release in vitro, but also result in an improved tumor regression and decreased side effects at off-targeted organs in vivo. The findings demonstrate that uniformly designed NPs with more homogeneous properties can induce a significant enhancement of an anti-cancer effect in vivo. The results show the potential of a high-speed on-chip synthesis as a scalable manufacturing platform for reliable clinical translations of nanomedicines.

Validation of urinary 1,2-dichloropropane concentration as a biological exposure index for workers exposed to 1,2-dichloropropane.

BACKGROUND: The International Agency for Research on Cancer classified 1,2-dichloropropane (1,2-DCP) as a human carcinogen in 2016. It is necessary to establish a health monitoring system for workers exposed to 1,2-DCP. We investigated the correlation between 1,2-DCP concentration in air and urine to determine whether it is appropriate to measure 1,2-DCP in urine as a biological exposure index (BEI). METHODS: Twenty-seven workers from 3 manufacturing industries handling 1,2-DCP participated in this study. Airborne 1,2-DCP was collected by personal air. Urine samples were collected at the end of work and analyzed using gas chromatography-mass spectrometry. Correlation analysis and simple regression analysis were performed to investigate the relationship between 1,2-DCP concentration in urine and air. RESULTS: Pearson correlation coefficients between total 1,2-DCP in air and urine (uncorrected, creatinine-corrected) were 0.720 and 0.819, respectively. For urine samples analyzed within 2 weeks, the Spearman's rho of 1,2-DCP concentration in urine (uncorrected and creatinine-corrected) was 0.906 and 0.836, respectively. Simple regression analysis of 1,2-DCP in air and urinary 1,2-DCP concentrations within 2 weeks, which showed the highest correlation, revealed that the coefficient of determination of 1,2-DCP concentration in urine (uncorrected and creatinine-corrected) was 0.801 and 0.784, respectively. CONCLUSIONS: As a BEI for workers exposed to 1,2-DCP, urinary 1,2-DCP without creatinine correction better reflects the exposure levels of 1,2-DCP in air.