Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins, and nucleic acids that contribute to intercellular communication. ENVs have emerged as biomarkers and therapeutic ...targets but they have also been explored as drug delivery vehicles. However, for the latter application, clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes; however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of approximately 10
cells grafted with lipidated ligands can generate cancer cell-targeting ENV and can be prepared in approximately 1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.
A new and rapid method for production of drug-targeting nanovesicles has implications for cancer treatment by chimeric antigen receptor T cells and other therapies.
.
Shape‐morphing hydrogels have emerging applications in biomedical devices, soft robotics, and so on. However, successful applications require a combination of excellent mechanical properties and fast ...responding speed, which are usually a trade‐off in hydrogel‐based devices. Here, a facile approach to fabricate 3D gel constructs by extrusion‐based printing of tough physical hydrogels, which show programmable deformations with high response speed and large output force, is described. Highly viscoelastic poly(acrylic acid‐co‐acrylamide) (P(AAc‐co‐AAm)) and poly(acrylic acid‐co‐N‐isopropyl acrylamide) (P(AAc‐co‐NIPAm)) solutions or their mixtures are printed into 3D constructs by using multiple nozzles, which are then transferred into FeCl3 solution to gel the structures by forming robust carboxyl–Fe3+ coordination complexes. The printed gel fibers containing poly(N‐isopropyl acrylamide) segment exhibit considerable volume contraction in concentrated saline solution, whereas the P(AAc‐co‐AAm) ones do not contract. The mismatch in responsiveness of the gel fibers affords the integrated 3D gel constructs the shape‐morphing ability. Because of the small diameter of gel fibers, the printed gel structures deform and recover with a fast speed. A four‐armed gripper is designed to clamp plastic balls with considerable holding force, as large as 115 times the weight of the gripper. This strategy should be applicable to other tough hydrogels and broaden their applications.
3D constructs of responsive and nonresponsive tough physical hydrogels are fabricated by extrusion‐based multi‐nozzle printing. The mismatch in responsiveness of the gel fibers and the gradient structural cues provide a shape‐morphing ability, which shows programmable deformations with high response speed and large output force. This strategy should be applicable to other hydrogels as soft actuators and biomedical devices.
Circulating tumor cells (CTCs) originate from the primary tumor mass and enter into the peripheral bloodstream. Compared to other “liquid biopsy” portfolios such as exosome, circulating tumor DNA/RNA ...(ctDNA/RNA), CTCs have incomparable advantages in analyses of transcriptomics, proteomics, and signal colocalization. Hence, CTCs hold the key to understanding the biology of metastasis and play a vital role in cancer diagnosis, treatment monitoring, and prognosis. Size-based enrichment features are prominent in CTC isolation. It is a label-free, simple and fast method. Enriched CTCs remain unmodified and viable for a wide range of subsequent analyses. In this review, we comprehensively summarize the differences of size and deformability between CTCs and blood cells, which would facilitate the development of technologies of size-based CTC isolation. Then we review representative size-/deformability-based technologies available for CTC isolation and highlight the recent achievements in molecular analysis of isolated CTCs. To wrap up, we discuss the substantial challenges facing the field, and elaborate on prospects.
Display omitted
Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly ...understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone‐on‐a‐chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co‐culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone‐on‐a‐chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis.
A bone‐on‐a‐chip is reported for spontaneous growth of 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers is naturally formed without the aid of differentiation agents. In co‐culture of metastatic breast cancer cells with osteoblastic tissues, unique hallmarks of breast cancer bone colonization, previously confirmed in vivo, are observed.
Microfluidics has proven to be a powerful tool for probing biology at the single-cell level. However, it is only in the past 5 years that single-cell microfluidics has been used in the field of ...virology. An array of strategies based on microwells, microvalves, and droplets is now available for tracking viral infection dynamics, identifying cell subpopulations with particular phenotypes, as well as high-throughput screening. The insights into the virus–host interactions gained at the single-cell level are unprecedented and usually inaccessible by population-based experiments. Therefore, single-cell microfluidics, which opens new avenues for mechanism elucidation and development of antiviral therapeutics, would be a valuable tool for the study of viral pathogenesis.
Recent developments in single-cell microfluidics are about to unlock a new era of virology by providing additional dimensions to the understanding of virus–host interactions and antiviral therapeutic mechanisms.Microwell- and valve-based technologies have been developed for resolving viral infection dynamics at single-cell resolution. Novel insights and perspectives masked by conventional population-based experiments have been revealed.Transcriptomic analysis of virus–host interactions at the single-cell level has entered the age of mass production along with the commercialization of several valve- and droplet-based microfluidic platforms for single-cell sequencing.Single-cell microfluidic technologies with higher degrees of integration and more comprehensive analytical capability are underway, which might revolutionize the study of viral pathogenesis.
The intracellular delivery of biofunctional enzymes or therapeutic proteins through systemic administration is of great importance in therapeutic intervention of various diseases. However, current ...strategies face substantial challenges owing to various biological barriers, including susceptibility to protein degradation and denaturation, poor cellular uptake, and low transduction efficiency into the cytosol. Here, we developed a biomimetic nanoparticle platform for systemic and intracellular delivery of proteins. Through a biocompatible strategy, guest proteins are caged in the matrix of metal–organic frameworks (MOFs) with high efficiency (up to ∼94%) and high loading content up to ∼50 times those achieved by surface conjunction, and the nanoparticles were further decorated with the extracellular vesicle (EV) membrane with an efficiency as high as ∼97%. In vitro and in vivo study manifests that the EV-like nanoparticles can not only protect proteins against protease digestion and evade the immune system clearance but also selectively target homotypic tumor sites and promote tumor cell uptake and autonomous release of the guest protein after internalization. Assisted by biomimetic nanoparticles, intracellular delivery of the bioactive therapeutic protein gelonin significantly inhibits the tumor growth in vivo and increased 14-fold the therapeutic efficacy. Together, our work not only proposes a new concept to construct a biomimetic nanoplatform but also provides a new solution for systemic and intracellular delivery of protein.
Summary
Context
Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment.
Objective
To ...evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS.
Design
This is a 24‐week open‐label prospective, randomized, clinical study.
Patients and Measurements
This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 μg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks.
Results
After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE‐treated patients was significantly higher than MET‐treated patients (43.60% vs 18.70%, P < .05).
Conclusions
Short‐term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.
Circulating tumor cells (CTCs) are rare cancer cells released from tumors into the bloodstream that are thought to have a key role in cancer metastasis. The presence of CTCs has been associated with ...worse prognosis in several major cancer types, including breast, prostate and colorectal cancer. There is considerable interest in CTC research and technologies for their potential use as cancer biomarkers that may enhance cancer diagnosis and prognosis, facilitate drug development, and improve the treatment of cancer patients. This review provides an update on recent progress in CTC isolation and molecular characterization technologies. Furthermore, the review covers significant advances and limitations in the clinical applications of CTC-based assays for cancer prognosis, response to anti-cancer therapies, and exploratory studies in biomarkers predictive of sensitivity and resistance to cancer therapies.
Metrnl is a newly discovered secreted protein with neurotrophic activity and metabolic effect, while in earlier studies its circulating level in human was not explored. We evaluated two commercial ...enzyme-linked immunosorbent assay kits (DY7867-05, R&D Systems and SK00478-02, Aviscera Bioscience) for the detection of human circulating Metrnl. The DY7867-05 kit showed superiority over the SK00478-02 kit since it generated better curve fitting degree, smaller variation among tests, higher inter-assay reproducibility and better specificity, and could effectively detect human Metrnl in six types of blood samples. Subsequent analysis was performed using the DY7867-05 kit. Sample storage conditions were investigated. No gender difference in circulating Metrnl levels was found, while people with newly diagnosed type 2 diabetes mellitus (T2DM) had significantly lower Metrnl levels compared to the healthy controls.
PDF
