Extracellular vesicles (EVs), including exosomes and microvesicles, are present in a variety of bodily fluids, and the concentration of these sub-cellular vesicles and their associated biomarkers ...(proteins, nucleic acids, and lipids) can be used to aid clinical diagnosis. Although ultracentrifugation is commonly used for isolation of EVs, it is highly time-consuming, labor-intensive and instrument-dependent for both research laboratories and clinical settings. Here, we developed an integrated double-filtration microfluidic device that isolated and enriched EVs with a size range of 30-200 nm from urine, and subsequently quantified the EVs via a microchip ELISA. Our results showed that the concentration of urinary EVs was significantly elevated in bladder cancer patients (n = 16) compared to healthy controls (n = 8). Receiver operating characteristic (ROC) analysis demonstrated that this integrated EV double-filtration device had a sensitivity of 81.3% at a specificity of 90% (16 bladder cancer patients and 8 healthy controls). Thus, this integrated device has great potential to be used in conjunction with urine cytology and cystoscopy to improve clinical diagnosis of bladder cancer in clinics and at point-of-care (POC) settings.
Aggregation‐induced emission (AIE) and aggregation‐caused quenching (ACQ) are two classes of opposite luminescence phenomena. It is almost impossible to show both AIE and ACQ effect simultaneously by ...the same molecule. However, here we report that a simple TPE derivative TAP‐TPE grows into both AIE crystals and ACQ ones. It is found that equatorial, contact distance‐longer and weak ArH‐π interactions exist in AIE crystals while vertical, contact distance‐shorter and strong ArH‐π interactions appear in ACQ crystals. Theoretical calculation of electron density on the interaction atoms unveils that ACQ crystals have much larger change in electron density than AIE ones, suggesting that the intermolecular electron transfer aroused by the strong ArH‐π hydrogen bonds leads to ACQ phenomenon. This result provides a new insight into the emission mechanism in aggregation state. Interestingly, due to the ArH‐pi interactions difference, only one of five kinds of crystals shows rapid photochromism, and can act as multimode anti‐counterfeiting materials. Very exceptionally, for the first time we find that the photochromic micrometric rod‐like crystal even makes forward rolling movement as it repeatedly bends and straightens by responding to on and off of the ultraviolet light irradiation, displaying potential for photo‐actuator and light‐driven micro‐vehicle.
New TPE derivatives bearing p‐AP groups: Among 5 kinds of crystals of TPE derivative, it is found for the first time that strong intermolecular ArH‐pi interactions cause ACQ effect while weak ArH‐pi interactions induce AIE phenomenon. The interactions also arouse photochromism, photodeformation and even the first forward rolling movement of crystal by UV light irradiation, providing promising materials in multimode anti‐counterfeiting, photo‐actuator and light‐driven micro‐vehicle.
Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular ...biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and ...II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.
Tumor-specific CD8
T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called "exhaustion." Though functioning to limit damage caused by immune response, T ...cell exhaustion leads to attenuated effector function whereby cytotoxic CD8
T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to "progenitor exhaustion" through to "terminally exhaustion" with distinct properties. With the rapid development of immunotherapy
enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8
T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.
Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an ...essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe
efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small ...lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently.
: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice.
: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin α
β
(LFA-1) and α
β
(VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy.
, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis).
: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.
A novel dodecanuclear Zr oxo cluster Zr6O4(OH)4 (HSCH2CH2COO)122 (ZrO‐SH‐10) has been constructed under the room temperature, followed by oxidation of the sulfhydryl group with H2O2 to achieve a ...bifunctional catalyst with Lewis acid and Brönsted acid sites. The characterization of catalysts indicated that {Zr6O4} cluster core can be stabilized with a shell of carboxylate ligands, and the resulting ZrO‐SO3H was formed as a discrete molecular catalyst, exhibiting superior activity and recyclability for the cascade conversion of furfural to alkyl levulinate by the integration of transfer hydrogenation and alcoholysis in n‐butanol. The yield of n‐butyl levulinate can achieve as high as 91 % under the optimum conditions. Meanwhile, no leaching of the active species was found, which confirmed the structure of the Zr oxo cluster was air and moisture‐stable. On the basis of the studies on the reaction kinetics and isotope tracking, the reaction mechanism was proposed accordingly.
Zr oxo cluster bifunctional catalyst: The Zr oxo cluster Zr6O4(OH)4 (HSCH2CH2COO)122 has been developed, and then the molecular catalyst with Lewis acid and Brönsted acid sites were attained by the oxidation of the sulfhydryl group of the Zr oxo cluster with H2O2. The resulting bifunctional catalyst showed a superior catalytic activity for alcoholysis of furfural to alkyl levulinates.
Metal-halide perovskite thin monocrystals featuring efficient carrier collection and transport capabilities are well suited for radiation detectors, yet their growth in a generic, well-controlled ...manner remains challenging. Here, we reveal that mass transfer is one major limiting factor during solution growth of perovskite thin monocrystals. A general approach is developed to overcome synthetic limitation by using a high solute flux system, in which mass diffusion coefficient is improved from 1.7×10
to 5.4×10
m
s
by suppressing monomer aggregation. The generality of this approach is validated by the synthesis of 29 types of perovskite thin monocrystals at 40-90 °C with the growth velocity up to 27.2 μm min
. The as-grown perovskite monocrystals deliver a high X-ray sensitivity of 1.74×10
µC Gy
cm
without applied bias. The findings regarding limited mass transfer and high-flux crystallization are crucial towards advancing the preparation and application of perovskite thin monocrystals.
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