Fluorescent Phenotyping of Blood Cells Using a Differential Sensing Strategy: Differentiating Physiological Aging Stages and Neuro-Degenerative Disease Drugs.

Blood continually contributes to the maintenance of homeostasis of the body and contains information regarding the health state of an individual. However, current hematological analyses predominantly rely on a limited number of CD markers and morphological analysis. In this work, differentially sensitive fluorescent compounds based on TCF scaffolds are introduced that are designed for fluorescent phenotyping of blood. Depending on their structures, TCF compounds displayed varied responses to reactive oxygen species, biothiols, redox-related biomolecules, and hemoglobin, which are the primary influential factors within blood. Contrary to conventional CD marker-based analysis, this unbiased fluorescent phenotyping method produces diverse fingerprints of the health state. Precise discrimination of blood samples from 37 mice was demonstrated based on their developmental stages, ranging from 10 to 19 weeks of age. Additionally, this fluorescent phenotyping method enabled the differentiation between drugs with distinct targets, serving as a simple yet potent tool for pharmacological analysis to understand the mode of action of various drugs.

Clinical infection of Brucella canis in a companion dog with discospondylitis in the Republic of Korea.

A 2-year-old, spayed female, Bichon Frise dog was presented with reluctance to exercise, back pain, and frequent sitting down. Multiple osteolysis, periosteal proliferation, and sclerosis of the vertebral endplates of T11-13 were observed in the radiography, computed tomography, and magnetic resonance imaging. The bacterial culture of the urine specimen, the polymerase chain reaction (PCR) of the blood, and the antibody tests were positive for Brucella canis. Accordingly, discospondylitis caused by B. canis was diagnosed and doxycycline was administered. The clinical signs resolved and the culture and PCR results were negative afterwards. Doxycycline was discontinued after 6 months. The clinical signs recurred 2 weeks later, and the combination treatment of doxycycline and enrofloxacin was initiated. Though no clinical signs were observed after 9 months and the bacterial cultures and PCR were negative, the antibody titre remained at 1 : 200 or more. The dog will continue taking antibiotics until the antibody titre drops. To the best of our knowledge, this is the first case report of a clinical infection of B. canis associated with canine discospondylitis in the Republic of Korea. Although the clinical signs of brucellosis might improve with antibiotic treatment, the disease cannot be cured due to Brucella's various strategies to evade host immune systems. Specifically, it can proliferate and replicate within the host cells, resulting in an environment that makes treatment less effective. Furthermore, owing to its zoonotic potential, owners and veterinarians should consider lifelong management or euthanasia.

Multifunction-Harnessed Afterglow Nanosensor for Molecular Imaging of Acute Kidney Injury In Vivo.

Afterglow is superior to other optical modalities for biomedical applications in that it can exclude the autofluorescence background. Nevertheless, afterglow has rarely been applied to the high-contrast "off-to-on" activatable sensing scheme because the complicated afterglow systems hamper the additional inclusion of sensory functions while preserving the afterglow luminescence. Herein, a simple formulation of a multifunctional components-incorporated afterglow nanosensor (MANS) is developed for the superoxide-responsive activatable afterglow imaging of cisplatin-induced kidney injury. A multifunctional iridium complex (Ir-OTf) is designed to recover its photoactivities (phosphorescence and the ability of singlet oxygen-generating afterglow initiator) upon exposure to superoxide. To construct the nanoscopic afterglow detection system (MANS), Ir-OTf is incorporated with another multifunctional molecule (rubrene) in the polymeric micellar nanoparticle, where rubrene also plays dual roles as an afterglow substrate and a luminophore. The multiple functions covered by Ir-OTf and rubrene renders the composition of MANS quite simple, which exhibits superoxide-responsive "off-to-on" activatable afterglow luminescence for periods longer than 11 min after the termination of pre-excitation. Finally, MANS is successfully applied to the molecular imaging of cisplatin-induced kidney injury with activatable afterglow signals responsive to pathologically overproduced superoxide in a mouse model without autofluorescence background.

Intramedullary parasite eggs, latent for three decades, mimicking acute transverse myelitis.

BACKGROUND: Intramedullary parasitic infection is extremely uncommon, and clinical presentation of Brown-Sequard syndrome is even rarer. CASE PRESENTATION: The authors report a case involving a 57-year-old woman with Brown-Sequard syndrome, in whom magnetic resonance imaging and clinical and epidemiological features were similar to those of acute transverse myelitis. Myelotomy suggested inflammation caused by latent parasite eggs in the spinal cord. Antiparasitic and steroid therapies were administered postoperatively. To the author's knowledge, this is the first report to describe a surgical experience for Taenia solium eggs in the spinal cord. CONCLUSION: Intramedullary parasitic infection is a diagnostic challenge that requires careful discrimination from other diseases. If parasite infection is suspected in a progressively deteriorating patient, myelotomy should be considered for rapid and accurate treatment.

Red-Emitting Latex Nanoparticles by Stepwise Entrapment of ß-Diketonate Europium Complexes.

The core-shell structure of poly(St-co-MAA) nanoparticles containing ß-diketonate Eu3+ complexes were synthesized by a step-wise process. The ß-diketonate Eu3+ complexes of Eu (TFTB)2(MAA)P(Oct)3 [europium (III); 4,4,4-Trifluoro-1-(2-thienyl)-1,3-butanedione = TFTB; trioctylphosphine = (P(Oct)3); methacrylic acid = MAA] were incorporated to poly(St-co-MAA). The poly(St-co-MAA) has highly monodispersed with a size of 300 nm, and surface charges of the poly(St-co-MAA) are near to neutral. The narrow particle size distribution was due to the constant ionic strength of the polymerization medium. The activated carboxylic acid of poly(St-co-MAA) further chelated with europium complex and polymerize between acrylic groups of poly(St-co-MAA) and Eu(TFTB)2(MAA)P(Oct)3. The Em spectra of europium complexes consist of multiple bands of Em at 585, 597, 612 and 650 nm, which are assigned to 5D0→7FJ (J = 0-3) transitions of Eu3+, respectively. The maximum Em peak is at 621 nm, which indicates a strong red Em characteristic associated with the electric dipole 5D0→7F2 transition of Eu3+ complexes. The cell-specific fluorescence of Eu(TFTB)2(MAA)P(Oct)3@poly(St-co-MAA) indicated endocytosis of Eu(TFTB)2(MAA)P(Oct)3@poly(St-co-MAA). There are fewer early apoptotic, late apoptotic and necrotic cells in each sample compared with live cells, regardless of the culture period. Eu(TFTB)2(MAA)P(Oct)3@poly(St-co-MAA) synthesized in this work can be excited in the full UV range with a maximum Em at 619 nm. Moreover, these particles can substitute red luminescent organic dyes for intracellular trafficking and cellular imaging agents.

Th2 cytokines-DUOX2-ROS-HMGB1 translocation axis is important in the pathogenesis of allergic rhinitis.

The function of high-mobility group box 1 (HMGB1) varies according to its location. However, the translocation mechanism behind HMGB1 remains unclear. We hypothesize that type 2 helper T cell (Th2) cytokines are involved in the translocation of HMGB1 in the upper airway epithelium. We investigated the mechanism behind HMGB1 translocation using Th2 cytokine stimulation and examined the clinical significance of HMGB1 translocation in allergic rhinitis (AR). Cytoplasmic and extracellular HMGB1 were increased in AR. Inhibiting HMGB1 translocation with glycyrrhizic acid (GA) decreased the level of antigen-specific immunoglobulin E (IgE), the degree of Periodic Acid-Schiff (PAS), and Sirius Red staining in the murine model. The in vivo reactive oxygen species (ROS) level in the nasal mucosa was higher in the mice with AR than in the controls. Th2 cytokine-induced up-regulation of the ROS and translocation of HMGB1 by Th2 cytokines was dependent on the generated ROS. The ROS level also increased in the murine model. We suggest that the Th2 cytokine-dual oxidase (DUOX)2-ROS-HMGB1 translocation axis is important in AR pathogenesis.

Superoxide-responsive fluorogenic molecular probes for optical bioimaging of neurodegenerative events in Alzheimer's disease.

Since oxidative stress has been recognized as a major factor contributing to the progression of several neurodegenerative disorders, reactive oxygen species (ROS) including superoxide have received great attention as a representative molecular marker for the diagnosis of Alzheimer's disease (AD). Here, superoxide-sensitive fluorogenic molecular probes, benzenesulfonylated resorufin derivatives (BSRs), were newly devised for optical bioimaging of oxidative events in neurodegenerative processes. BSRs, fluorescence-quenched benzenesulfonylated derivatives of resorufin, were designed to recover their fluorescence upon exposure to superoxide through a selective nucleophilic uncaging reaction of the benzenesulfonyl cage. Among BSRs, BSR6 presented the best sensitivity and selectivity to superoxide likely due to the optimal reactivity matching between the nucleophilicity of superoxide and its electrophilicity ascribed to the highly electron-withdrawing pentafluoro-substitution on the benzenesulfonyl cage. Fluorescence imaging of inflammatory cells and animal models presented the potential of BSR6 for optical sensing of superoxide in vitro and in vivo. Furthermore, microglial cell (Bv2) imaging with BSR6 enabled the optical monitoring of intracellular oxidative events upon treatment with an oxidative stimulus (amyloid beta, Aß) or the byproduct of oxidative stress (4-hydroxynonenal, HNE).

Color Doppler ultrasonography for predicting the patency of anastomosis after superficial temporal to middle cerebral artery bypass surgery.

BACKGROUND: Color Doppler ultrasonography (CDUS) is used to evaluate the surgical success and postoperative hemodynamic changes of patients who receive superficial temporal to middle cerebral artery (STA-MCA) bypass surgery. Previous studies enrolled small populations, and difficulties interpreting the results have limited their use in clinical settings. OBJECTIVE: We attempted to determine the feasibility of using CDUS to evaluate STA hemodynamics and identify the most reliable parameter as a new clinical implication for determining bypass patency. METHOD: Twenty-six patients who underwent STA-MCA bypass surgery were prospectively enrolled. Four times CDUS and two times digital subtraction angiography (DSA) were performed. The CDUS parameters were compensated using the ratio of the operated to the non-operated sides (R1) and compared before and after surgery (R2). The CDUS parameters are then compared with the patency on DSA by statistical analyses. RESULTS: Increased CDUS parameters of the mean flow rate (MFR) and cross-sectional diameter (CSD) showed significant correlations with good patency on DSA. The R2 at 1 month was identified as the most reliable parameter for predicting the patency in both MFR and CSD. Their cutoff values were 1.475 and 1.15, respectively. CONCLUSION: CDUS can be utilized for predicting the patency after STA-MCA bypass surgery; if the postoperative (compensated and compared) CDUS parameters increased by more than 47.5% in the MFR or 15% in the CSD, the patency of the anastomosis on DSA would be good.

Same same but different: A Web-based deep learning application revealed classifying features for the histopathologic distinction of cortical malformations.

OBJECTIVE: The microscopic review of hematoxylin-eosin-stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine. METHODS: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities. RESULTS: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance. SIGNIFICANCE: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning-aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.

Paraspinal muscle changes after single-level posterior lumbar fusion: volumetric analyses and literature review.

BACKGROUND: Posterior lumbar fusion is a widely accepted surgical technique; however, it has been related to the possibility of paraspinal muscle atrophy after surgery. We investigated 1-year postoperative changes in paraspinal muscle volume using a simple formula applicable to magnetic resonance imaging (MRI) or computed tomography (CT) images. METHODS: Patients with degenerative lumbar spinal stenosis who underwent posterior interbody fusion (PLIF) at the L4/5 level in the period from May 2010 to June 2017 were enrolled in this study. Radiologic parameters were measured using MRI or CT images which were taken before surgery and at 1 year after surgery. The volume of the paraspinal muscles was calculated using a simple formula which was derived from the formula for calculating the volume of truncated elliptic cones. RESULTS: A total of 40 patients were included; 24 were analyzed using MRI and 16 were analyzed using CT. The mean age of the patients was 59.6 ± 12.1 years and 32 (80.5%) were female. When comparing the preoperative and 1-year-postoperative images, multifidus muscle (MF) reduction was consistently observed in the MRI and CT groups, right and left (p = 0.003, p < 0.001, p = 0.005 and p < 0.001, respectively). In the erector spinae (ES) group, decrease in muscle volume was observed in the right-sided muscles of the CT group (p < 0.001), but no significant change was observed in the MRI group. The psoas muscle showed no significant change after 1 year. Conversely, regression analysis showed a negative correlation between MF muscle volume loss and age in the MRI group (right and left, p = 0.002 and p = 0.015, respectively), that is, the younger the age, the greater loss of muscle mass. CONCLUSION: After the posterior lumbar fusion, the volume of the MF muscles was markedly decreased, and the degree of decrease was apparent in the MRI. The volume of the ES muscles, which are located relatively laterally, also tended to decrease at 1 year after surgery.

A Sequential Framework for Improving Identifiability of FE Model Updating using Static and Dynamic Data.

By virtue of the advances in sensing techniques, finite element (FE) model updating (FEMU) using static and dynamic data has been recently employed to improve identification on updating parameters. Using heterogeneous data can provide useful information to improve parameter identifiability in FEMU. It is worth noting that the useful information from the heterogeneous data may be diluted in the conventional FEM framework. The conventional FEMU framework in previous studies have used heterogeneous data at once to compute residuals in the objective function, and they are condensed to be a scalar. In this implementation, it should be careful to formulate the objective function with proper weighting factors to consider the scale of measurement and relative significances. Otherwise, the information from heterogeneous data cannot be efficiently utilized. For FEMU of the bridge, parameter compensation may exist due to mutual dependence among updating parameters. This aggravates the parameter identifiability to make the results of the FEMU worse. To address the limitation of the conventional FEMU method, this study proposes a sequential framework for the FEMU of existing bridges. The proposed FEMU method uses two steps to utilize static and dynamic data in a sequential manner. By using them separately, the influence of the parameter compensation can be suppressed. The proposed FEMU method is verified through numerical and experimental study. Through these verifications, the limitation of the conventional FEMU method is investigated in terms of parameter identifiability and predictive performance. The proposed FEMU method shows much smaller variabilities in the updating parameters than the conventional one by providing the better predictions than those of the conventional one in calibration and validation data. Based on numerical and experimental study, the proposed FEMU method can improve the parameter identifiability using the heterogeneous data and it seems to be promising and efficient framework for FEMU of the existing bridge.

In-Situ Data-Driven Buffeting Response Analysis of a Cable-Stayed Bridge.

To analytically evaluate buffeting responses, the analysis of wind characteristics such as turbulence intensity, turbulence length, gust, and roughness coefficient must be a priority. The analytical buffeting response is affected by the static aerodynamic force coefficient, flutter coefficient, structural damping ratio, aerodynamic damping ratio, and natural frequencies of the bridge. The cable-stayed bridge of interest in this study has been used for 32 years. In that time, the terrain conditions around the bridge have markedly changed from the conditions when the bridge was built. Further, the wind environments have varied considerably due to climate change. For these reasons, the turbulence intensity, length, spectrum coefficient, and roughness coefficient of the bridge site must be evaluated from full-scale measurements using a structural health monitoring system. Although the bridge is located on a coastal area, the evaluation results indicated that the wind characteristics of bridge site were analogous to those of open terrain. The buffeting response of the bridge was analyzed using the damping ratios, static aerodynamic force coefficients, and natural frequencies obtained from measured data. The analysis was performed for four cases. Two case analyses were performed by applying the variables obtained from measured data, while two other case analyses were performed based on the Korean Society of Civil Engineers (KSCE) Design Guidelines for Steel Cable Supported Bridges. The calculated responses of each analysis case were compared with the buffeting response measured at wind speeds of less than 25 m/s. The responses obtained by numerical analysis using estimated variables based on full-scale measurements agreed well with the measured buffeting responses measured at wind speeds of less than 25 m/s. Moreover, an extreme wind speed of 44 m/s, corresponding to a recurrence interval of 200 years, was derived from the Gumbel distribution. Therefore, the buffeting responses at wind speeds of 45 m/s were also determined by applying the estimated variables. From these results, management criteria based on measurement data for in-service bridge are determined and each level of management is proposed.

Proton Transfer Hydrogels: Versatility and Applications.

Proton transfer polymerization between thiol and epoxide groups is shown to be an adaptable and utilitarian method for the synthesis of hydrogels. For instance, the polymerization catalyst can be organic or inorganic, and the polymerization medium can be pure water, buffer solutions, or organic solvents. The gelation mechanism can be triggered at ambient conditions, at a physiological temperature of 37 °C, or through using light as an external stimulus. The ambient and photochemical methods both allow for nanoimprint lithography to produce freestanding patterned thick films. The required thiol- and epoxide-carrying precursors can be chosen from a long list of commercially available small molecular as well as polymeric materials. The water uptake, mechanical, and biodegradation properties of the gels can, therefore, be tuned through the choice of appropriate gelation precursors and polymerization conditions. Finally, the thio-ether groups of the cross-linked networks can be functionalized through a postgelation modification reaction to access sulfonium-based cationic structures. Such structural changes endow antibacterial properties to the networks. In their pristine form, however, the gels are biocompatible and nonadhesive, allowing cancer cells to grow in a cluster formation.

Conversion of glioma cells to glioma stem-like cells by angiocrine factors.

Glioma stem-like cells (GSCs) contribute to tumor initiation, progression, and therapeutic resistance, but their cellular origin remains largely unknown. Here, using a stem/progenitor cell-fate tracking reporter system in which eGFP is expressed by promoter of OCT4 that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both in vitro cultures and in vivo xenografts. These eGFP-positive-GCs exhibited GSC features and primarily localized to the perivascular region in tumor xenografts, similar to the existence of OCT4-expressing GCs in the perivascular region of human glioblastoma specimens. Angiocrine factors, including nitric oxide (NO), converted eGFP-negative-GCs into eGFP-positive-GCs. Mechanistically, NO signaling conferred GSC features to GCs by increasing OCT4 and NOTCH signaling via ID4. NO signaling blockade and a suicide gene induction prevented tumorigenicity with a decrease in eGFP-positive-GCs in the perivascular region. Taken together, our results reveal the molecular mechanism underlying GSCs generation by cancer cell dedifferentiation.

Fluorescent Molecular Rotors for Viscosity Sensors.

Fluorescent molecular rotors (FMRs) can act as viscosity sensors in various media including subcellular organelles and microfluidic channels. In FMRs, the rotation of rotators connected to a fluorescent π-conjugated bridge is suppressed by increasing environmental viscosity, resulting in increasing fluorescence (FL) intensity. In this minireview, we describe recently developed FMRs including push-pull type π-conjugated chromophores, meso-phenyl (borondipyrromethene) (BODIPY) derivatives, dioxaborine derivatives, cyanine derivatives, and porphyrin derivatives whose FL mechanism is viscosity-responsive. In addition, FMR design strategies for addressing various issues (e.g., obtaining high FL contrast, internal FL references, and FL intensity-contrast trade-off) and their biological and microfluidic applications are also discussed.

Molecular Viscosity Sensors with Two Rotators for Optimizing the Fluorescence Intensity-Contrast Trade-Off.

A series of fluorescent molecular rotors obtained by introducing two rotational groups ("rotators"), which exhibit different rotational and electron-donating abilities, are discussed. Whereas the control molecular rotor, PH, includes a single rotator (the widely used phenyl group), the PO molecular rotors consist of two rotators (a phenyl group and an alkoxy group), which exhibit simultaneous strongly electron-donating and easy rotational abilities. Compared with the control rotor PH, PO molecular rotors exhibited one order of magnitude higher quantum yield (fluorescence intensity) and simultaneously exhibited significantly higher fluorescence contrast. These properties are directly related to the strong electron-donating ability and low energy barrier of rotation of the alkoxy group, as confirmed by dynamic fluorescence experiments and quantum chemical calculations. The PO molecular rotors exhibited two fluorescence relaxation pathways, whereas the PH molecular rotor exhibited a single fluorescence relaxation pathway. Cellular fluorescence imaging with PO molecular rotors for mapping cellular viscosity was successfully demonstrated.

Simultaneous Delivery of Electrostatically Complexed Multiple Gene-Targeting siRNAs and an Anticancer Drug for Synergistically Enhanced Treatment of Prostate Cancer.

Simultaneous silencing of multiple apoptosis-related genes is an attractive approach to treat cancer. In this article, we present a multiple gene-targeting siRNA/drug delivery system for prostate cancer treatment with a high efficiency. Bcl-2, survivin, and androgen receptor genes involved in the cell apoptosis pathways were chosen as silencing targets with three different siRNAs. The colloidal nanocomplex delivery system (<10 nm in size) was formulated electrostatically between anionic siRNAs and a cationic drug (BZT), followed by encapsulation with the Pluronic F-68 polymer. The formulated nanocomplex system exhibited sufficient stability against nuclease-induced degradation, leading to successful intracellular delivery for the desired therapeutic performance. Silencing of targeted genes and apoptosis induction were evaluated in vitro on human prostate LNCaP-LN3 cancer cells by using various biological analysis tools (e.g., real-time PCR, MTT cell viability test, and flow cytometry). It was demonstrated that when the total loaded siRNA amounts were kept the same in the nanocomplexes, the simultaneous silencing of triple genes with co-loaded siRNAs (i.e., Bcl-2, survivin, and AR-targeting siRNAs) enhanced BZT-induced apoptosis of cancer cells more efficiently than the silencing of each single gene alone, offering a novel way of improving the efficacy of gene therapeutics including anticancer drug.

Looking into the labyrinth of gender inequality: women physicians in academic medicine.

CONTEXT: Gender inequality remains prevalent worldwide in academic medicine. A closer look into women physicians' gendered experiences through the lens of culture is necessary to advance understanding of gender inequality in this context. Relatively few studies, however, have investigated how social and cultural practices implicitly yet significantly affect gender inequality throughout women physicians' careers. OBJECTIVES: This study aimed to investigate the lived experiences of South Korean women physicians working in academic medicine and to focus on social and cultural influences on the gendered process of their career journeys. The study will extend our understanding of gender inequality in academic medicine through an in-depth analysis of social and cultural practices that affect the phenomenon. METHODS: We conducted a qualitative study utilising a grounded theory approach. Twenty-one women physicians participated in semi-structured interviews. Data were recorded, transcribed and analysed through a process of constant comparison using grounded theory to extract themes. RESULTS: Junior women physicians were more vulnerable to gender discrimination and channelled to 'ghettos' through the seniority-based, patriarchal, collectivist and business hospital culture in South Korea. Under pressure to excel at work, they had no work-family balance and experienced identity crises as competent doctors and mothers. They felt themselves to be 'othered' in multiple cultural contexts, including school ties, rankism and a culture of after-work gatherings. Minimal levels of leadership aspiration created a vicious cycle of a lack of social networking and mentoring. Pursuing individual excellence, they attributed their struggles to personal choices and rarely sought organisational support. CONCLUSIONS: The dynamics of cultural and social practices constantly and implicitly recreate mechanisms to maintain gender inequality in academic medicine in South Korea. Planned culture changes at individual, organisational and national levels are imperative to discontinue the vicious cycle that exists in the labyrinth of women physicians' career development in academic medicine.

How Can Doxorubicin Loading Orchestrate in Vitro Degradation Behaviors of Mesoporous Silica Nanoparticles under a Physiological Condition?

In the field of drug-delivery research, mesoporous silica nanoparticles (MSNs) have received a great deal of attention because of their capability to load and release drug molecules through the internal mesopores. To maximize the biomedical applicability of MSN-based drug carriers, it is important to ensure their degradability in a physiological environment as well as to obtain MSNs with desirable physicochemical properties. We present in vitro degradability of drug-loaded MSNs (DMSNs) that contain an anticancer drug (doxorubicin) in the pores and are suspended in physiological media (i.e., PBS at 37 °C). To obtain comprehensive understanding of the degradation process of DMSNs, cargo-free MSNs and nonporous solid silica nanoparticles (SSNs) were studied comparatively. Degradation of each particle was studied by using ICP, TEM, and gas sorption measurement and analyzed in terms of structural parameters, external particle surface dissolution, and acidity of the PBS. It is demonstrated for the first time that drug loading into the pores leads to better degradability of MSNs by combining each distinct advantage of bare MSNs and SSNs to make DMSNs simultaneously possess an initial degradation rate as fast as drug-unloaded MSNs and a total degradation quantity as high as SSNs. The presented data not only demonstrate a high biodegradability of MSN-based drug carriers but also provide new insights into their unique in vitro degradation pattern.

ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, -31 to -21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.