Bioengineering & Translational Medicine最新文献

The tumor immune microenvironment has manifested a crucial correlation with tumor occurrence, development, recurrence, and metastasis. To explore the mechanisms intrinsic to osteosarcoma (OS) initiation and progression, this study synthesizes multiple single-cell RNA sequencing data sets, constructing a comprehensive landscape of the OS microenvironment. Integrating single-cell RNA sequencing with bulk RNA sequencing data has enabled the identification of a significant correlation between heightened expression of the fatty acid metabolism-associated gene (C1QBP) and patient survival in OS. C1QBP not only amplifies the proliferation, migration, invasion, and anti-apoptotic properties of OS but also instigates cisplatin resistance. Subsequent investigations suggest that C1QBP potentially promotes macrophage polarization from monocytes/macrophages toward M2 and M3 phenotypes. Consequently, C1QBP may emerge as a novel target for modulating OS progression and resistance therapy.

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha-synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune-specific response against alpha-synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha-synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha-synuclein and its amyloid form. The prion domain of the fungal HET-s protein was selected as a scaffold to introduce select epitopes from the surface of alpha-synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in-register beta-sheet structure seen in alpha-synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha-synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha-synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha-synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha-synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha-synuclein, provides a promising avenue toward developing effective vaccines against alpha-synuclein fibrils.

Nanoparticles (NP) play a crucial role in nanomedicine, serving as carriers for localized therapeutics to allow for precise drug delivery to specific disease sites and conditions. When injected systemically, NP can directly interact with various blood cell types, most critically with circulating platelets. Hence, the potential activation/inhibition of platelets following NP exposure must be evaluated a priori due to possible debilitating outcomes. In recent years, various studies have helped resolve the physicochemical parameters that influence platelet-NP interactions, and either emphasize nanoparticles' therapeutic role such as to augment hemostasis or to inhibit thrombus formation, or conversely map their potential undesired side effects upon injection. In the present review, we discuss some of the main effects of several key NP types including polymeric, ceramic, silica, dendrimers and metallic NPs on platelets, with a focus on the physicochemical parameters that can dictate these effects and modulate the therapeutic potential of the NP. Despite the scientific and clinical significance of understanding Platelet-NP interactions, there is a significant knowledge gap in the field and a critical need for further investigation. Moreover, improved guidelines and research methodologies need to be developed and implemented. Our outlook includes the use of biomimetic in vitro models to investigate these complex interactions under both healthy physiological and disease conditions.

Glioma is one of the most common primary malignant brain tumors. Despite progress in therapeutic approaches, the median survival of patients with glioma remains less than 2 years, generating the need for new therapeutic approaches. Ultrasound (US) is widely used in medical fields and is used as a therapeutic tool mainly for improving the performance of therapeutic entities. In this study, we examined a novel approach using low frequency US (20 kHz) (LFUS) as an independent treatment tool for malignant glioma, since primary studies showed that cancer cells are more susceptible to LFUS than healthy cells. LFUS safety and efficacy were examined in a 9L gliosarcoma-bearing female Fischer 344 rats. Two LFUS protocols were examined: a one-time treatment (US1X), and two treatments 24 h apart (US2X). For safety evaluation, rats were monitored for weight change and pain measurements. For efficacy, tumor volume was measured as a function of time and the tumor structural chances were examined histopathologically. LFUS treatment showed rapid inhibition of tumor growth, seen as soon as 12 h after US application. In addition, LFUS was found to affect the tumor structure, which was more extensive (>60% of tumor area) in smaller tumors. In US2X, the tumor tissue was completely destroyed, and an extensive immune response was observed. Importantly, the treatment was highly selective, keeping the healthy tissue surrounding the tumor unharmed. We developed a highly efficient and selective therapeutic protocol for treating malignant glioma with minimal side effects based solely on LFUS.

Neuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation-two glucose-dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti-epileptic drug, valproic acid (GD2–VPA), for efficacy studies in the pilocarpine-mouse model of seizure. When delivered intranasally, GD2–VPA significantly decreased the seizure-severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron-specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection.

The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid-lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte-like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three-dimensional (3D) approach using Biomimesys®, a hyaluronic acid-based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28-day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low-density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC-derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

Electroporation, or the use of electric pulses to facilitate the intracellular delivery of DNA, RNA, and other molecules, is a well-established technique, that has been demonstrated to significantly augment the immunogenicity of DNA/mRNA vaccines and therapeutics. However, the clinical translation of traditional electroporators has been limited due to high costs, large size, complex user operation, and poor tolerability in humans due to nerve stimulation. In prior work, we introduced ePatch: an ultra-low-cost, handheld, battery-free electroporator employing a piezoelectric pulser coupled with a microneedle electrode array that showed enhanced immunogenic responses to an intradermal SARS-CoV-2 DNA vaccine in mice. The current study shifts focus from efficacy to tolerability, hypothesizing that ePatch's microneedle array, which localizes the electric field to the superficial skin strata, will minimize nerve stimulation and improve patient comfort. We tested this hypothesis in 14 healthy adults, monitoring pain and other potential adverse effects associated with electroporation. Compared to the insertion of a traditional hypodermic needle, the ePatch was less painful. Adverse effects such as pain, tenderness, erythema and swelling at the application sites were minimal, transient, and statistically indistinguishable between the experimental and placebo ePatch application, suggesting excellent tolerability towards electroporation. In summary, ePatch has a favorable tolerability profile in humans and offers the potential for the safe use of electroporation in a variety of clinical settings, including DNA and mRNA vaccination.

Cervical cancer is a significant public health concern, particularly in low- and middle-income countries where resources for prevention and treatment are limited. Routine screening, such as the Papanicolaou test (Pap smears) and human papillomavirus (HPV) testing, plays a crucial role in the early detection and prevention of cervical cancer. However, the participation rate in cervical cancer screening programs remains below optimal levels due to various factors. This study aimed to evaluate the reliability and acceptability of the HygeiaTouch Self Sampling Kit for Women in collecting vaginal samples for HPV typing, comparing the results with samples collected by physicians. The study included 1210 women aged 21–65 from three medical centers in Taiwan. The findings indicated that the self-sampling kit was as effective as physician-collected specimens in terms of obtaining valid samples and identifying HPV. The agreement between the two methods was 88%, with a κ value of 0.75. Furthermore, the study assessed the mechanical characteristics of the self-sampling applicator through tensile, bending, and torque tests, and determined that it was safe for intravaginal use. Additionally, the study evaluated the safety and satisfaction of self-sampling and found a low rate of adverse events (0.7%) and high levels of satisfaction (over 90%) among participants. Overall, we demonstrated that the HygeiaTouch Self Sampling Kit for Women is a reliable and acceptable device for HPV testing and cervical screening, providing a convenient, safe, and effective alternative for women.

Determining the precise course of bacterial infection requires abundant in vivo real-time data. Synchronous monitoring of the bacterial load, temperature, and immune response can satisfy the shortage of real-time in vivo data. Here, we conducted a study in the joint-infected mouse model to synchronously monitor the bacterial load, temperature, and immune response using the second near-infrared (NIR-II) fluorescence imaging, infrared thermography, and immune response analysis for 2 weeks. Staphylococcus aureus (S. aureus) was proved successfully labeled with glucose-conjugated quantum dots in vitro and in subcutaneous-infected model. The bacterial load indicated by NIR-II fluorescence imaging underwent a sharp drop at 1 day postinfection. At the same time, the temperature gap detected through infrared thermography synchronously brought by infection reached lowest value. Meanwhile, the flow cytometry analysis demonstrated that immune response including macrophage, neutrophil, B lymphocyte, and T lymphocyte increased to the peak at 1 day postinfection. Moreover, both M1 macrophage and M2 macrophage in the blood have an obvious change at ~ 1 day postinfection, and the change was opposite. In summary, this study not only obtained real-time and long-time in vivo data on the bacterial load, temperature gap, and immune response in the mice model of S. aureus infection, but also found that 1 day postinfection was the key time point during immune response against S. aureus infection. Our study will contribute to synchronously and precisely studying the complicated complex dynamic relationship after bacterial infection at the animal level.