Effects of intensive blood pressure control on left ventricular hypertrophy in aortic valve disease.

BACKGROUND: Hypertension adds to the pressure overload on the left ventricle (LV) in combination with aortic valve (AV) disease, but the optimal blood pressure (BP) targets for patients with AV disease remain unclear. We tried to investigate whether intensive BP control reduces LV hypertrophy in asymptomatic patients with aortic stenosis (AS) or aortic regurgitation (AR). METHODS: A total of 128 hypertensive patients with mild to moderate AS (n = 93) or AR (n = 35) were randomly assigned to intensive therapy, targeting a systolic BP <130 mm Hg, or standard therapy, targeting a systolic BP <140 mm Hg. The primary end point was the change in LV mass from baseline to the 24-month follow-up. Secondary end points included changes in severity of AV disease, LV volumes, ejection fraction and global longitudinal strain (GLS). RESULTS: The treatment groups were generally well balanced regarding the baseline characteristics. The mean (±SD) age of the patients was 68 ± 8 years and 48% were men. The mean BP was 145 ± 12/81 ± 10 mm Hg at baseline. Medication at baseline was similar between the 2 groups. The 2 treatment strategies resulted in a rapid and sustained difference in systolic BP (P < .05). At 24-month, the mean systolic BP was 129 ± 12 mm Hg in the intensive therapy group and 135 ± 14 mm Hg in the standard therapy group. No patient died or underwent AV surgery during follow-up in either of the groups. LV mass was changed from 189.5 ± 41.3 to 185.6 ± 41.5 g in the intensive therapy group (P = .19) and from 183.8 ± 38.3 to 194.0 ± 46.4 g in the standard therapy group (P < .01). The primary end point of change in LV mass was significantly different between the intensive therapy and the standard therapy group (-3.9 ± 20.2 g vs 10.3 ± 20.4 g; P = .0007). The increase in LV mass index was also significantly greater in the standard therapy group (P = .01). No significant differences in secondary end points (changes in severity of AV disease, LV volumes, ejection fraction and GLS) were observed between the treatment groups. CONCLUSIONS: Among hypertensive patients with AV disease, intensive hypertensive therapy resulted in a significant reduction in LV hypertrophy, although progression of AV disease was similar between the treatment groups. CLINICAL TRIAL REGISTRATION: http://ClinicalTrials.gov (Number NCT03666351).

Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy.

Tumour-derived exosomes (T-EXOs) impede immune checkpoint blockade therapies, motivating pharmacological efforts to inhibit them. Inspired by how antiviral curvature-sensing peptides disrupt membrane-enveloped virus particles in the exosome size range, we devised a broadly useful strategy that repurposes an engineered antiviral peptide to disrupt membrane-enveloped T-EXOs for synergistic cancer immunotherapy. The membrane-targeting peptide inhibits T-EXOs from various cancer types and exhibits pH-enhanced membrane disruption relevant to the tumour microenvironment. The combination of T-EXO-disrupting peptide and programmed cell death protein-1 antibody-based immune checkpoint blockade therapy improves treatment outcomes in tumour-bearing mice. Peptide-mediated disruption of T-EXOs not only reduces levels of circulating exosomal programmed death-ligand 1, but also restores CD8+ T cell effector function, prevents premetastatic niche formation and reshapes the tumour microenvironment in vivo. Our findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.

Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia.

BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.

Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination.

BACKGROUND: Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge. METHODS: We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival. RESULTS: We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell-matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth. CONCLUSION: We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.

O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity.

The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.

Role of Nasal Fibroblasts in Airway Remodeling of Chronic Rhinosinusitis: The Modulating Functions Reexamined.

Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nose and sinuses that affects more than 10% of the adult population worldwide. Currently, CRS is classified into endotypes according to the inflammatory response (Th1, Th2, and Th17) or the distribution of immune cells in the mucosa (eosinophilic and non-eosinophilic). CRS induces mucosal tissue remodeling. Extracellular matrix (ECM) accumulation, fibrin deposition, edema, immune cell infiltration, and angiogenesis are observed in the stromal region. Conversely, epithelial-to-mesenchymal transition (EMT), goblet cell hyperplasia, and increased epithelial permeability, hyperplasia, and metaplasia are found in the epithelium. Fibroblasts synthesize collagen and ECM, which create a structural skeleton of tissue and play an important role in the wound-healing process. This review discusses recent knowledge regarding the modulation of tissue remodeling by nasal fibroblasts in CRS.

The EphA1 and EphA2 Signaling Modulates the Epithelial Permeability in Human Sinonasal Epithelial Cells and the Rhinovirus Infection Induces Epithelial Barrier Dysfunction via EphA2 Receptor Signaling.

Deficiencies in epithelial barrier integrity are involved in the pathogenesis of chronic rhinosinusitis (CRS). This study aimed to investigate the role of ephrinA1/ephA2 signaling on sinonasal epithelial permeability and rhinovirus-induced epithelial permeability. This role in the process of epithelial permeability was evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to rhinovirus infection. EphrinA1 treatment increased epithelial permeability, which was associated with decreased expression of ZO-1, ZO-2, and occludin. These effects of ephrinA1 were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. Furthermore, rhinovirus infection upregulated the expression levels of ephrinA1 and ephA2, increasing epithelial permeability, which was suppressed in ephA2-deficient cells. These results suggest a novel role of ephrinA1/ephA2 signaling in epithelial barrier integrity in the sinonasal epithelium, suggesting their participation in rhinovirus-induced epithelial dysfunction.

Use of the Self- and Family Management Framework in quantitative studies.

BACKGROUND: The Self- and Family Management Framework (SFMF) identifies factors and outcomes of patient and family management of chronic illness. In a previous citation analysis, we reported the frequency and nature of use of the SFMF. PURPOSE: We conducted a sub-analysis of quantitative articles in the citation analysis to examine testing of relationships depicted in the SFMF. METHODS: We analyzed study purposes, independent and dependent variables, study implications, and text that referred to the SFMF in 40 articles. FINDINGS: The SFMF has been used largely to explore factors affecting SFM behaviors, focusing on patient versus family self-management. Independent variables included all categories of facilitators/barriers specified in the SFMF. Dependent variables included all SFMF components (Facilitators/Barriers, Processes, Proximal and Distal Outcomes). Racial/ethnic diversity was limited among study participants. Study implications pertained mostly to psychosocial outcomes. Most studies referred to the SFMF generally. DISCUSSION: Findings will contribute to revision of the SFMF.

Blending Low-Frequency Vibrations and Push-Pull Effects Affords Superior Photoacoustic Imaging Agents.

Photoacoustic imaging (PAI), a state-of-the-art noninvasive in vivo imaging technique, has been widely used in clinical disease diagnosis. However, the design of high-performance PAI agents with three key characteristics, i.e., near-infrared (NIR) absorption (λabs >800 nm), intense PA signals, and excellent photostability, remains a challenging goal. Herein, we present a facile but effective approach for engineering PAI agents by amplifying intramolecular low-frequency vibrations and enhancing the push-pull effect. As a demonstration of this blended approach, we constructed a PAI agent (BDP1-NEt2 ) based on the boron-dipyrromethene (BODIPY) scaffold. Compared with indocyanine green (ICG, an FDA-approved organic dye widely utilized in PAI studies; λabs =788 nm), BDP1-NEt2 exhibited a UV/Vis-NIR spectrum peaked at 825 nm, superior in vivo PA signal intensity and outstanding stability to offer improved tumor diagnostics. We believe this work provides a promising strategy to develop the next generation of PAI agents.

Functional Extracellular Vesicles for Regenerative Medicine.

The unique biological characteristics and promising clinical potential of extracellular vesicles (EVs) have galvanized EV applications for regenerative medicine. Recognized as important mediators of intercellular communication, naturally secreted EVs have the potential, as innate biotherapeutics, to promote tissue regeneration. Although EVs have emerged as novel therapeutic agents, challenges related to the clinical transition have led to further functionalization. In recent years, various engineering approaches such as preconditioning, drug loading, and surface modification have been developed to potentiate the therapeutic outcomes of EVs. Also, limitations of natural EVs have been addressed by the development of artificial EVs that offer advantages in terms of production yield and isolation methodologies. In this review, an updated overview of current techniques is provided for the functionalization of natural EVs and recent advances in artificial EVs, particularly in the scope of regenerative medicine.

Chemical vapour deposition of Fe-N-C oxygen reduction catalysts with full utilization of dense Fe-N4 sites.

Replacing scarce and expensive platinum (Pt) with metal-nitrogen-carbon (M-N-C) catalysts for the oxygen reduction reaction in proton exchange membrane fuel cells has largely been impeded by the low oxygen reduction reaction activity of M-N-C due to low active site density and site utilization. Herein, we overcome these limits by implementing chemical vapour deposition to synthesize Fe-N-C by flowing iron chloride vapour over a Zn-N-C substrate at 750 °C, leading to high-temperature trans-metalation of Zn-N4 sites into Fe-N4 sites. Characterization by multiple techniques shows that all Fe-N4 sites formed via this approach are gas-phase and electrochemically accessible. As a result, the Fe-N-C catalyst has an active site density of 1.92 × 1020 sites per gram with 100% site utilization. This catalyst delivers an unprecedented oxygen reduction reaction activity of 33 mA cm-2 at 0.90 V (iR-corrected; i, current; R, resistance) in a H2-O2 proton exchange membrane fuel cell at 1.0 bar and 80 °C.

Raspberry Pi Platform Wireless Sensor Node for Low-Frequency Impedance Responses of PZT Interface.

A wireless impedance monitoring system, called SSeL-Pi, is designed to have cheap, mobile, and handy practical features as compared to wired commercial impedance analyzers. A Raspberry Pi platform impedance sensor node is designed to measure signals at a low-frequency range of up to 100 kHz. The low-frequency impedance measurement via the proposed node has been combined with a new PZT interface technique for measuring local responses sensitive to structural damage. The new PZT interface can work as a surface-mounted or embedded sensor, and its local dynamic characteristics are numerically analyzed to pre-determine an effective impedance resonant frequency range of less than 100 kHz. Next, a software scheme was designed to visualize the input/output parameters of the proposed SSeL-Pi system (i.e., Raspberry Pi platform and PZT interface) and automate signal acquisition procedures of the impedance sensor node. The calibration for impedance signals obtained from the proposed system was performed by a series of procedures, from acquiring real and imaginary impedance to adjusting them with respect to a commercial impedance analyzer (HIOKI-3532). The feasibility of the wireless impedance monitoring system was experimentally evaluated for PZT interfaces that were subjected to various compressive loadings. The consistent results analyzed from signals measured by the SSeL-Pi and HIOKI 3532 systems were observed. Additionally, the strong relationships between impedance features (frequency shift and RMSD index) and compressive stresses of the PZT interfaces showed the potential for axial force/stress variation monitoring in real structures using the Raspberry Pi platform impedance sensor node and developed PZT interface.

Barriers and engagement in breast cancer survivorship wellness activities.

PURPOSE: Breast cancer survivors may be at risk for increased rates of emotional distress and poorer quality of life. Survivorship care plans (SCPs) promoting wellness activities may support well-being; however, survivors may not receive or engage in their SCPs. This study aimed to assess receipt and participation in SCP activities as well as barriers to engagement amongst breast cancer survivors. METHODS: Breast cancer survivors (n = 187; 99% female, Mean age = 57.7) consented and completed self-reported assessments of SCP recommendations, engagement and interest in wellness activities, and potential barriers to engagement. RESULTS: A minority of participants recalled receiving an SCP (21%). The most physician recommended (62%) and completed (53%) activity was exercise. Interest in adding other wellness activities to the SCP was high, with reported interest levels of approximately 50% for several activities (e.g., mind body, nutrition, psychotherapy interventions). Fully half reported that having a physician-designed plan would influence participation in activities. The most common reported barriers to SCP activity engagement were lack of time (82%), work/school (65%), and lack of information (65%). CONCLUSION: Few survivors recalled receiving a formal SCP, and lack of information about wellness activities was a commonly reported barrier to participation. Interest in wellness activities was generally high and may indicate the need for more formal prescription or motivation enhancement techniques to promote SCP engagement. There may be a clinical need to emphasize SCP recommendations to enhance recall and increase engagement in wellness activities that may reduce psychological distress and improve quality of life.

Nanomedicines for Reactive Oxygen Species Mediated Approach: An Emerging Paradigm for Cancer Treatment.

Growth in the knowledge of cancer biology has led to the emergence and evolution of cancer nanomedicines by providing the rationale for leveraging nanotechnology to develop better treatment options. The discovery of nanometer-sized intercellular openings in the defective angiogenic tumor vasculature contributed to the development of an idea for the well-known cancer passive targeting regime, enhanced permeability and retention (EPR) effect, of the nanomedicines. Recently, reactive oxygen species (ROS) have been highlighted as one of the key players that underlie the acquisition of the various hallmarks of cancer. As ROS are associated with all stages of cancer, their applications in cancer treatment based on the following concentration-dependent implications have attracted much attention: (1) low to moderate levels of ROS as key signaling molecules, (2) elevated levels of ROS in cancer cells as one of the unique characteristics of cancer, and (3) excessive levels of ROS as cytotoxic agents. Considering ROS from a different point of view, various cancer nanomedicines have been designed to achieve spatiotemporal control of therapeutic action, the main research focus in this area. This Account includes our efforts and preclinical achievements in development of nanomedicines for a range of ROS-mediated cancer therapies. It begins with general background regarding cancer nanomedicines, the significance of ROS in cancer, and a brief overview of ROS-mediated approaches for cancer therapy. Then, this Account highlights the two key roles of ROS that define therapeutic purposes of cancer nanomedicines: (1) ROS as drug delivery enhancers and (2) ROS as cell death inducers. The former inspired us to develop nitric oxide-generating nanoparticles for improved EPR effect, endogenous ROS-responsive polymeric micelles for enhanced intracellular drug delivery, and exogenous ROS-activated micelles for subcellular localization via photochemical internalization. While refining conventional chemotherapy, recent researches also have focused on the latter, the cytotoxic ROS, to advance alternative treatment modalities such as oxidation therapy, photodynamic therapy (PDT), and sonodynamic therapy (SDT). In particular, we have been motivated to develop polymeric nanoreactors containing enzymes to produce H2O2 for oxidation therapy, photosensitizer-loaded gold-nanoclustered polymeric nanoassemblies for photothermally activated PDT overcoming the oxygen dependency of PDT, and hydrophilized TiO2 nanoparticles and Au-TiO2 nanocomposites as novel sonosensitizers for improved SDT efficiency. The integration of nanomedicine and ROS-mediated therapy has emerged as the new paradigm in the treatment of cancer, based on promising proof-of-concept demonstrations in preclinical studies. Further efforts to ensure clinical translation along with more sophisticated cancer nanomedicines to address relevant challenges are expected to be made in the coming years.

Effect of Dispersion Medium Composition and Ionomer Concentration on the Microstructure and Rheology of Fe-N-C Platinum Group Metal-free Catalyst Inks for Polymer Electrolyte Membrane Fuel Cells.

We present an investigation of the microstructure and rheological behavior of catalyst inks consisting of Fe-N-C platinum group metal-free catalysts and a perfluorosulfonic acid ionomer in a dispersion medium (DM) of water and 1-propanol (nPA). The effects of the ionomer-to-catalyst (I/C) ratio and weight percentage of water (H2O %) in the DM on the ink microstructure were studied. Steady-shear and dynamic-oscillatory-shear rheology, in combination with synchrotron X-ray scattering, was utilized to understand interparticle interactions and the level of agglomeration of the inks. In the absence of the ionomer, the inks were significantly agglomerated, approaching a gel-like microstructure for catalyst concentrations as low as 2 wt %. The effect of H2O % in the DM on particle agglomeration was found to vary with particle concentration. In concentrated inks (≥2 wt % catalyst), increasing H2O % was found to increase agglomeration because of the hydrophobic nature of the catalysts. In dilute inks (<1 wt % catalyst), the trend was reversed with increasing H2O %, suggesting that electrostatic interactions are dominating the behavior. In inks with 5 wt % catalyst, the addition of an ionomer was found to significantly stabilize the catalyst against agglomeration. Maximum stability was observed at 0.35 I/C for all DM H2O % studied. At high ionomer concentrations (I/C > 0.35), interesting differences were observed between nPA-rich inks (H2O % ≤ 50%) and H2O-rich (82% H2O) inks. The nPA-rich inks remained predominantly stable-ink viscosity only weakly increased with I/C and the Newtonian behavior was maintained for I/C up to 0.9. In contrast, the H2O-rich inks exhibited a significant increase in viscoelasticity with increasing I/C, suggesting flocculation of the catalyst by the ionomer. These differences suggest that the nature of the interactions between the ionomer and catalyst is highly dependent on the H2O % in the DM.

Melatonin ameliorates SGLT2 inhibitor-induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective hypoglycemic agents that can induce glycosuria. However, there are increasing concerns that they might induce diabetic ketoacidosis. This study investigated the effect of melatonin on SGTL2i-induced ketoacidosis in insulin-deficient type 2 diabetic (T2D) mice. The SGLT2i dapagliflozin reduced blood glucose level and plasma insulin concentrations in T2D mice, but induced increases in the concentrations of plasma ß-hydroxybutyrate, acetoacetate, and free fatty acid and a decrease in the concentration of plasma bicarbonate, resulting in ketoacidosis. Melatonin inhibited dapagliflozin-induced ketoacidosis without inducing any change in blood glucose level or plasma insulin concentration. In white adipose tissue, melatonin inhibited lipolysis and downregulated phosphorylation of PKA, HSL, and perilipin-1. In liver tissue, melatonin suppressed cellular cyclic AMP levels and downregulated phosphorylation of PKA, AMPK, and acetyl-CoA carboxylase (ACC). In addition, melatonin increased hepatic ACC activity, but decreased hepatic CPT1a activity and acetyl-CoA content. These effects of melatonin on lipolysis and hepatic ketogenesis were blocked by pretreatment with melatonin receptor antagonist or PKA activator. Collectively, these results suggest that melatonin can ameliorate SGLT2i-induced ketoacidosis by inhibiting lipolysis and hepatic ketogenesis though cyclic AMP/PKA signaling pathways in T2D mice. Thus, melatonin treatment may offer protection against SGLT2i-induced ketoacidosis.

Correction to: Sweet taste receptors as a tool for an amplifying pathway of glucose-stimulated insulin secretion in pancreatic ß cells.

The publisher would like to apologize for the failed cross-linking of the following Commentary by Jae-Hyung Park and Dae-Kyu Song.

A Comparative Study on Albumin-Binding Molecules for Targeted Tumor Delivery through Covalent and Noncovalent Approach.

Various types of albumin-binding molecules have been conjugated to anticancer drugs, and these modified prodrugs could be effective in cancer treatments compared to free anticancer drugs. However, the tumor targeting of albumin-binding prodrugs has not been clearly investigated. Herein, we examined the in vitro and in vivo tumor-targeting efficiency of three different albumin-binding molecules including albumin-binding peptide (DICLPRWGCLW: PEP), fatty acid (palmitic acid: PA), and maleimide (MI), respectively. In order to characterize the different targeting efficiency of albumin-binding molecules, PEP, PA, or MI was chemically labeled with near-infrared fluorescence (NIRF) dye, Cy5.5, in resulting PEP-Cy5.5, PA-Cy5.5, and MI-Cy5.5. These NIRF dye-labeled albumin-binding molecules were physically or chemically bound to albumin via gentle incubation in aqueous conditions in vitro. Notably, PA-Cy5.5 with reversible and multivalent binding affinities formed stable albumin complexes, compared to PEP-Cy5.5 and MI-Cy5.5, confirmed via surface plasmon resonance measurement, gel electrophoresis assay, and albumin-bound column-binding test. In tumor-bearing mice model, the different albumin-binding affinities of PA-Cy5.5, PEP-Cy5.5, and MI-Cy5.5 greatly contributed to their tumor-targeting ability. Even though the binding affinity of PEP-Cy5.5 and MI-Cy5.5 to albumin is higher than that of PA-Cy5.5 in vitro, intravenous PA-Cy5.5 showed a higher tumor-targeting efficiency in tumor-bearing mice compared to that of PEP-Cy5.5 and MI-Cy5.5. The reversible and multivalent affinities of albumin-binding molecules to native serum albumin greatly increased the pharmacokinetics and tumor-targeting efficiency in vivo.

Overcoming Tamoxifen Resistance by Regulation of Del-1 in Breast Cancer.

BACKGROUND: Hormone receptor-positive breast cancer accounts for nearly two-thirds of breast cancer cases; it ultimately acquires resistance during endocrine treatment and becomes more aggressive. This study evaluated the role of developmental endothelial locus (Del)-1 in tamoxifen-resistant (TAM-R) breast cancer. METHODS: Del-1 expression in recurrent TAM-R breast cancer tissue was evaluated and compared to that in the original tumor tissue from the same patients. Del-1 expression was also evaluated in TAM-R cells by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assay. The effects of Del-1 knockdown on the proliferation, migration, and invasion of TAM-R cells was assessed with wound-healing and Matrigel transwell assays. RESULTS: Del-1 was more highly expressed in recurrent breast cancer as compared to the original tumor tissues before initiation of endocrine treatment. Del-1 mRNA was upregulated in TAM-R and small interfering RNA-mediated knockdown of Del-1 suppressed the migration and proliferation of TAM-R cells while partly restoring TAM sensitivity. And the TAM resistance was recovered by knockdown of Del-1. CONCLUSIONS: TAM-R breast cancer is characterized by Del-1 overexpression and tumor progression can be inhibited by Del-1 depletion, which restores TAM sensitivity. Thus, therapeutic strategies that target Del-1 may be effective for the treatment of hormone-resistant breast cancer.

Measurement of a solid-state triple point at the metal-insulator transition in VO2.

First-order phase transitions in solids are notoriously challenging to study. The combination of change in unit cell shape, long range of elastic distortion and flow of latent heat leads to large energy barriers resulting in domain structure, hysteresis and cracking. The situation is worse near a triple point, where more than two phases are involved. The well-known metal-insulator transition in vanadium dioxide, a popular candidate for ultrafast optical and electrical switching applications, is a case in point. Even though VO2 is one of the simplest strongly correlated materials, experimental difficulties posed by the first-order nature of the metal-insulator transition as well as the involvement of at least two competing insulating phases have led to persistent controversy about its nature. Here we show that studying single-crystal VO2 nanobeams in a purpose-built nanomechanical strain apparatus allows investigation of this prototypical phase transition with unprecedented control and precision. Our results include the striking finding that the triple point of the metallic phase and two insulating phases is at the transition temperature, Ttr = Tc, which we determine to be 65.0 ± 0.1 °C. The findings have profound implications for the mechanism of the metal-insulator transition in VO2, but they also demonstrate the importance of this approach for mastering phase transitions in many other strongly correlated materials, such as manganites and iron-based superconductors.