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Recent Advances in Electrospinning Techniques for Precise Medicine.

In the realm of precise medicine, the advancement of manufacturing technologies is vital for enhancing the capabilities of medical devices such as nano/microrobots, wearable/implantable biosensors, and organ-on-chip systems, which serve to accurately acquire and analyze patients' physiopathological information and to perform patient-specific therapy. Electrospinning holds great promise in engineering materials and components for advanced medical devices, due to the demonstrated ability to advance the development of nanomaterial science. Nevertheless, challenges such as limited composition variety, uncontrollable fiber orientation, difficulties in incorporating fragile molecules and cells, and low production effectiveness hindered its further application. To overcome these challenges, advanced electrospinning techniques have been explored to manufacture functional composites, orchestrated structures, living constructs, and scale-up fabrication. This review delves into the recent advances of electrospinning techniques and underscores their potential in revolutionizing the field of precise medicine, upon introducing the fundamental information of conventional electrospinning techniques, as well as discussing the current challenges and future perspectives.

Progress of Ginsenoside Rb1 in neurological disorders.

Ginseng is frequently used in traditional Chinese medicine to treat neurological disorders. The primary active component of ginseng is ginsenoside, which has been classified into more than 110 types based on their chemical structures. Ginsenoside Rb1 (GsRb1)-a protopanaxadiol saponin and a typical ginseng component-exhibits anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-autophagy properties in the nervous system. Neurological disorders remain a leading cause of death and disability globally. GsRb1 effectively treats neurological disorders. To contribute novel insights to the understanding and treatment of neurological disorders, we present a comprehensive review of the pharmacokinetics, actions, mechanisms, and research development of GsRb1 in neurological disorders.

Mechanisms of ferroptosis in hypoxic-ischemic brain damage in neonatal rats.

This study was to explore the mechanism of ferroptosis and hypoxic-ischemic brain damage in neonatal rats. The neonatal rat hypoxic-ischemic brain damage (HIBD) model was established using the Rice-Vannucci method and treated with the ferroptosis inhibitor liproxstatin-1. Cognitive assessment was performed through absentee field experiments to confirm the successful establishment of the model. Brain tissue damage was evaluated by comparing regional cerebral blood flow and quantifying tissue staining. Neuronal cell morphological changes in the rats' cortical and hippocampal regions were observed using HE and Nissl staining. ELISA was performed to determine GPX4, GSH and ROS expression levels in the rats' brain tissues, and Western blotting to assess the expression levels of 4-HNE, GPX4, GSS, ACSL4, SLC7A11, SLC3A2, TFRC, FHC, FLC, HIF-1α, and Nrf2 proteins in rat brain tissues. Compared to the Sham group, the HIBD group exhibited a significant decrease in cerebral blood perfusion, reduced brain nerve cells, and disordered cell arrangement. The use of the ferroptosis inhibitor effectively improved brain tissue damage and preserved the shape and structure of nerve cells. The oxidative stress products ROS and 4-HNE in the brain tissue of the HIBD group increased significantly, while the expression of antioxidant indicators GPX4, GSH, SLC7A11, and GSS decreased significantly. Furthermore, the expression of iron metabolism-related proteins TFRC, FHC, and FLC increased significantly, whereas the expression of the ferroptosis-related transcription factors HIF-1α and Nrf2 decreased significantly. Treatment with liproxstatin-1 exhibited therapeutic effects on HIBD and downregulated tissue ferroptosis levels. This study shows the involvement of ferroptosis in hypoxic-ischemic brain damage in neonatal rats through the System Xc--GSH-GPX4 functional axis and iron metabolism pathway, with the HIF-1α and Nrf2 transcription factors identified as the regulators of ferroptosis involved in the HIBD process in neonatal rats.

3D biofabrication of diseased human skin models in vitro.

Human skin is an organ located in the outermost part of the body; thus, it frequently exhibits visible signs of physiological health. Ethical concerns and genetic differences in conventional animal studies have increased the need for alternative in vitro platforms that mimic the structural and functional hallmarks of natural skin. Despite significant advances in in vitro skin modeling over the past few decades, different reproducible biofabrication strategies are required to reproduce the pathological features of diseased human skin compared to those used for healthy-skin models. To explain human skin modeling with pathological hallmarks, we first summarize the structural and functional characteristics of healthy human skin. We then provide an extensive overview of how to recreate diseased human skin models in vitro, including models for wounded, diabetic, skin-cancer, atopic, and other pathological skin types. We conclude with an outlook on diseased-skin modeling and its technical perspective for the further development of skin engineering.

Engineering of Uniform Epidermal Layers via Sacrificial Gelatin Bioink-Assisted 3D Extrusion Bioprinting of Skin.

To reconstruct an ideal full-thickness skin model, basal keratinocytes must be distributed as a confluent monolayer on the dermis. However, the currently available extrusion bioprinting method for the skin is limited when producing an air-exposed cellular monolayer because the cells are encapsulated within a bioink. This is the first study to use sacrificial gelatin-assisted extrusion bioprinting to reproduce a uniform and stratified epidermal layer. Experimental analyses of the rheological properties, printability, cell viability, and initial keratinocyte adhesion shows that the optimal gelatin bioink concentration is 4 wt.%. The appropriate thickness of the bioprinted gelatin structure for achieving a confluent keratinocyte layer is determined to be 400 µm. The suggested strategy generates a uniform keratinocyte monolayer with tight junctions throughout the central and peripheral regions, whereas manual seeding generates non-uniform cellular aggregates and vacancies. These results influence gene expression, exhibiting a propensity for epidermal differentiation. Finally, the gelatin-assisted keratinocytes are bioprinted onto a dermis composed of gelatin methacryloyl and dermis-derived decellularized extracellular matrix to establish a full-thickness skin model. Thus, this strategy leads to significant improvements in epidermal differentiation/stratification. The findings demonstrate that the gelatin-assisted approach is advantageous for recreating reliable full-thickness skin models with significant consistency for mass production.

Sequentially suspended 3D bioprinting of multiple-layered vascular models with tunable geometries forin vitromodeling of arterial disorders initiation.

As the main precursor of arterial disorders, endothelial dysfunction preferentially occurs in regions of arteries prone to generating turbulent flow, particularly in branched regions of vasculatures. Although various diseased models have been engineered to investigate arterial pathology, producing a multiple-layered vascular model with branched geometries that can recapitulate the critical physiological environments of human arteries, such as intercellular communications and local turbulent flows, remains challenging. This study develops a sequentially suspended three-dimensional bioprinting (SSB) strategy and a visible-light-curable decellularized extracellular matrix bioink (abbreviated as 'VCD bioink') to construct a biomimetic human arterial model with tunable geometries. The engineered multiple-layered arterial models with compartmentalized vascular cells can exhibit physiological functionality and pathological performance under defined physiological flows specified by computational fluid dynamics simulation. Using different configurations of the vascular models, we investigated the independent and synergetic effects of cellular crosstalk and abnormal hemodynamics on the initiation of endothelial dysfunction, a hallmark event of arterial disorder. The results suggest that the arterial model constructed using the SSB strategy and VCD bioinks has promise in establishing diagnostic/analytic platforms for understanding the pathophysiology of human arterial disorders and relevant abnormalities, such as atherosclerosis, aneurysms, and ischemic diseases.

Molecular and clinical features of papillary thyroid cancer in adult patients with a non-classical phenotype.

Purpose: Genotyping is fundamental in papillary thyroid cancer (PTC) and helps to enhance diagnosis and prognosis and determine appropriate treatments. The phenotype-genotype association in PTC was previously studied, with BRAF V600E characterizing classic PTC and tall-cell PTC and RAS mutations characterizing follicular-variant PTC. In clinic, some non-classical histological subtypes of PTC were also identified, however, their genotype remains unclear. In this study, we collected samples of these non-classical PTC after the exclusion of classic phenotypes and examined their phenotypes, genotype and the relationship between phenotype and genotype. Methods: We screened out non-classical PTC by excluding classical PTC from 1,059 different thyroid samples, and a total of 24 cases was obtained and described from the morphological features, which is rare in differentiated PTC. DNA/RNA sequencing was performed using 18 available samples to describe the genetic features. Results: PTC with the non-classical phenotype were characterized cuboidal to low columnar tumor cells with subtle nuclear features of PTC and without discernible nuclear elongation, concurrently with dense microfollicles, delicate papillae or solid nodules with delicate fibrovascular cores. They were associated with lymphatic vessel invasion (P<0.001) but not with a worse prognosis (P=0.791). Gene fusions were identified in 14 of 18 (77.8%) cases, including eight fusions of NTRK and six fusions of RET. The high percentage of fusions in this papillary thyroid cancer subgroup suggested a correlation of gene fusions with the phenotype that does not belong to the BRAF V600E-mutant or RAS-mutant group. Conclusions: Our study retrospectively screened a large cohort of different thyroid tissue samples, and presented the histopathological and genetic features of a non-classical phenotype of PTC from 24 patients. It may contribute to diagnose in PTC, and patients of these non-classical phenotype may benefit from targeted therapy, compared to a natural patient cohort without selection.

Three-dimensional printing of smart constructs using stimuli-responsive biomaterials: A future direction of precision medicine.

Three-dimensional (3D) printing, which is a valuable technique for the fabrication of tissue-engineered constructs and biomedical devices with complex architectures, has brought about considerable progress in regenerative medicine, drug delivery, and diagnosis of diseases. However, because of the static and inanimate properties of conventional 3D-printed structures, it is difficult to use them in therapies for active and precise medicine, such as improved tissue regeneration, targeted or controlled drug delivery, and advanced pathophysiological monitoring. The integration of stimuli-responsive biomaterials into 3D printing provides a potential strategy for designing and building smart constructs that exhibit programmed functions and controllable changes in properties in response to exogenous and autogenous stimuli. These features make 3D-printed smart constructs the next generation of tissue-engineered products. In this review, we introduce the prevalent 3D printing techniques (with an emphasis on the differences between 3D printing and bioprinting, and biomaterials and bioink), the working principle of each technique, and the advantages of using 3D printing for the fabrication of smart constructs. Stimuli-responsive biomaterials that are widely used for 3D printing of smart constructs are categorized, followed by a summary of their applications in tissue regeneration, drug delivery, and biosensors. Finally, the challenges and future perspectives of 3D-printed smart constructs are discussed.

Clinical characteristics and prognostic analysis of acute necrotizing encephalopathy of childhood: a retrospective study at a single center in China over 3 years.

Objective: Acute Necrotizing Encephalopathy of Childhood (ANEC) is a rare, fulminant neurological disease in children with unknown mechanisms and etiology. This study summarized the clinical characteristics, treatment, and prognosis of ANEC through a retrospective analysis, providing insights into the ANEC early diagnosis and prognosis assessment. Methods: Clinical data of children diagnosed with ANEC at the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from July 1, 2020, to June 30, 2023, were retrospectively analyzed. Results: There were 25 cases, 14 males and 11 females, with a median age of 3 years. Hospital admissions were mainly in the winter (14/25, 56%) and spring (9/25, 36%). All patients presented with varying degrees of fever and altered consciousness, with 92% (23/25) experiencing high body temperatures (>39.1°C) and 88% (22/25) having a Glasgow coma scale (GCS) score of ≤8. Seizures were observed in 88% (22/25) of patients. Laboratory findings indicated 100% B lymphocyte activation (14/14), and 78% (14/18) of patients showed cytokine storm (interleukin (IL)-6, IL-8, IL-10, interferon (IFN)-α). Neuroimaging showed symmetrical thalamus involvement, commonly involving basal ganglia and brainstem regions. Viral infection (23/24, 96%) was the predominant etiological finding, with 42% (10/24) of cases due to SARS-CoV-2 infection and 42% (10/24) to influenza A virus infection. Multi-organ dysfunction occurred in 68% (17/25) of patients, and 52% (13/25) died. Correlation analysis revealed the death group exhibited higher proportion of male, lower GCS scores, higher IL-6 level and a greater likelihood of associated brainstem impairment (p < 0.05). Conclusion: ANEC is more prevalent in the winter and spring, and its etiology may be associated with B lymphocyte activation and cytokine storm following viral infections. Clinical manifestations lack specific features, with fever, consciousness disturbances, and seizures being the main presentations, particularly in cases of high fever and hyperpyrexia. ANEC progresses rapidly and has a high mortality rate. The child's gender, GCS score, IL-6 levels, and the presence of brainstem involvement can serve as important risk factors for assessing the risk of mortality.

Tislelizumab-related enteritis successfully treated with adalimumab: A case report.

BACKGROUND: With programmed death-1 (PD-1) inhibitors becoming the standard treatment for lung cancer, PD-1-related adverse reactions and treatment have gradually become prominent. CASE SUMMARY: First reported case of tislelizumab-related enteritis successfully treated with adalimumab 40mg every 2 wk for 3 times in an advanced lung cancer patient who received first-line tislelizumab/pemetrexed/carboplatin for 4 cycles. The patient continued receiving the treatment of pemetrexed/carboplatin after symptoms, abdominal computed tomography and colonoscopy improved, significant diarrhea was not occurred. CONCLUSION: Adalimumab can be an effective treatment option for patients with PD-1 antibody related enteritis if they do not respond well to glucocorticoid treatment.

Genome-Wide DNA Methylation and Gene Expression Profiling Characterizes Molecular Subtypes of Esophagus Squamous Cell Carcinoma for Predicting Patient Survival and Immunotherapy Efficacy.

BACKGROUND: Immunotherapy is recently being used to treat esophageal squamous cell carcinoma (ESCC); however, response and survival benefits are limited to a subset of patients. A better understanding of the molecular heterogeneity and tumor immune microenvironment in ESCC is needed for improving disease management. METHODS: Based on the DNA methylation and gene expression profiles of ESCC patients, we identify molecular subtypes of patients and construct a predictive model for subtype classification. The clinical value of molecular subtypes for the prediction of immunotherapy efficacy is assessed in an independent validation cohort of Chinese ESCC patients who receive immunotherapy. RESULTS: We identify two molecular subtypes of ESCC (S1 and S2) that are associated with distinct immune-related pathways, tumor microenvironment and clinical outcomes. Accordingly, S2 subtype patients had a poorer prognosis. A 15-gene expression signature is developed to classify molecular subtypes with an overall accuracy of 94.7% (89/94, 95% CI: 0.880-0.983). The response rate of immunotherapy is significantly higher in the S1 subtype than in the S2 subtype patients (68.75% vs. 25%, p = 0.028). Finally, potential target drugs, including mitoxantrone, are identified for treating patients of the S2 subtype. CONCLUSIONS: Our findings demonstrated that the identified molecular subtypes constitute a promising prognostic and predictive biomarker to guide the clinical care of ESCC patients.

Allergic Bronchopulmonary Mycosis Caused by Mucor Overlapping With Invasive Pulmonary Mucormycosis: A Case Report.

Mucormycosis is a rare and invasive fungal infection with high mortality. Cases of invasive pulmonary mucormycosis that involve allergic reactions such as allergic bronchopulmonary mycosis are rarely reported. Herein, we describe a case of invasive pulmonary mucormycosis overlapping with allergic diseases in a patient who presented with eosinophilia and high total plasma immunoglobulin E (IgE). The patient was successfully treated with systemic corticosteroids (initial dose of prednisolone approximately 0.5 mg/kg per day, total duration less than 3 months) combined with posaconazole antifungal therapy. The treatment resulted in recovery of peripheral-blood eosinophil count and total plasma IgE, and significant reduction in lung lesions. A subsequent lobectomy was performed. The findings in this case indicate that systemic corticosteroid therapy may contribute to the treatment of pulmonary mucormycosis combined with allergic factors.

The Biofabrication of Diseased Artery In Vitro Models.

As the leading causes of global death, cardiovascular diseases are generally initiated by artery-related disorders such as atherosclerosis, thrombosis, and aneurysm. Although clinical treatments have been developed to rescue patients suffering from artery-related disorders, the underlying pathologies of these arterial abnormalities are not fully understood. Biofabrication techniques pave the way to constructing diseased artery in vitro models using human vascular cells, biomaterials, and biomolecules, which are capable of recapitulating arterial pathophysiology with superior performance compared with conventional planar cell culture and experimental animal models. This review discusses the critical elements in the arterial microenvironment which are important considerations for recreating biomimetic human arteries with the desired disorders in vitro. Afterward, conventionally biofabricated platforms for the investigation of arterial diseases are summarized, along with their merits and shortcomings, followed by a comprehensive review of advanced biofabrication techniques and the progress of their applications in establishing diseased artery models.

Advanced Strategies for 3D Bioprinting of Tissue and Organ Analogs Using Alginate Hydrogel Bioinks.

Alginate is a natural polysaccharide that typically originates from various species of algae. Due to its low cost, good biocompatibility, and rapid ionic gelation, the alginate hydrogel has become a good option of bioink source for 3D bioprinting. However, the lack of cell adhesive moieties, erratic biodegradability, and poor printability are the critical limitations of alginate hydrogel bioink. This review discusses the pivotal properties of alginate hydrogel as a bioink for 3D bioprinting technologies. Afterward, a variety of advanced material formulations and biofabrication strategies that have recently been developed to overcome the drawbacks of alginate hydrogel bioink will be focused on. In addition, the applications of these advanced solutions for 3D bioprinting of tissue/organ mimicries such as regenerative implants and in vitro tissue models using alginate-based bioink will be systematically summarized.

Peripheral Lung Squamous Carcinoma With ROS1 Rearrangement Sensitive to Crizotinib: A Case Report.

ROS1 rearrangements have been identified as driver mutations, accounting for 1-2% of lung adenocarcinoma, but are extremely rare in case of lung squamous cell carcinoma. In this work, we report a lung squamous cell carcinoma in a patient with peripheral lung cancer radiological manifestation, harboring ROS1 rearrangement, with high sensitivity to crizotinib. Our findings suggest that clinicians should pay more attention toward the occurrence of ROS1 rearrangements and the application of crizotinib for lung squamous cell carcinoma treatment.

Case Report: Transformation From Non-Small Cell Lung Cancer to Small Cell Lung Cancer During Anti-PD-1 Therapy: A Report of Two Cases.

BACKGROUND: Histological transformation of lung cancer to small cell lung cancer (SCLC) is uncommon. It is a small subset of the possible resistance mechanisms, even in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Reports on programmed cell death-1 (PD-1) inhibitors are rare. We report two cases of lung squamous carcinomas that transformed to SCLC during anti-PD-1 therapy, and present a detailed description of histological examination of the pre-and post-transformation tissues, hitherto absent from reports on the topic. CASE PRESENTATION: Case 1: A 69-year-old man was diagnosed with stage IVa squamous cell carcinoma of the lung. He had a programmed cell death-ligand 1 tumor proportion score ≥50%. He achieved partial response after four cycles of sintilimab as first-line treatment. However, sintilimab was discontinued because of severe decrease in hemoglobin levels and platelet counts. Moreover, the occurrence of pleural effusion favored disease progression. Interestingly, bone marrow puncture and biopsy showed transformation to SCLC. Case 2: A 71-year-old man diagnosed with stage IIIa lung squamous cell carcinoma received neoadjuvant chemotherapy, underwent radical surgery, and finally received adjuvant chemotherapy. Five months later, he presented with tumor recurrence. He was treated with nivolumab, though disease progression was observed after four cycles. Notably, a subsequent computed tomography-guided biopsy showed SCLC. CONCLUSION: Phenotypic transformation to SCLC is a potential mechanism of resistance to immunotherapy in squamous cell carcinomas of the lung. Disease progression should prompt re-biopsy to diagnose potential histological changes to assess the requirement for change in treatment.

Eosinophils may serve as CEA-secreting cells for allergic bronchopulmonary aspergillosis (ABPA) patients.

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by an exaggerated response of the immune system to the fungus Aspergillus. This study aimed to assess the relationship between carcinoembryonic antigen (CEA) and eosinophils in ABPA patients. We describes a case of a 50-year-old patient who was diagnosed with ABPA presenting with high level of CEA and eosinophils. Besides,we used immunohistochemistry and immunofluorescence to identify eosinophils and CEA in sections which were obtained by Endobronchial ultrasound-guided transbronchial lung biopsy aspiration (EBUS-TBLB). The sections were then visualized using confocal microscopy. We also retrospectively analyzed a cohort of 37 ABPA patients between January 2013 and December 2019 in our hospital. We found the patient whose serum CEA levels were consistent with eosinophils during the follow-up (r = 0.929, P = 0.022). The positive expression of CEA and abnormal expression of eosinophils was higher in the ABPA tissue compared to the normal lung tissue. The co-localization was represented as pixels containing both red and green color in the image (with various shades of orange and yellow) which signified that eosinophils were immunohistochemically positive for CEA. Patients with higher levels of eosinophils had higher levels of CEA in the serum (P < 0.001). The results of Pearson correlation analysis showed that the levels of eosinophils were positively correlated with serum CEA levels (r = 0.459 and r = 0.506, P = 0.004 and P = 0.001). Serum CEA level is elevated in ABPA patients. The elevated serum CEA level was shown to be normalized after treatment. Increased CEA levels in ABPA patients may be positively correlated with eosinophil levels, and eosinophils may be served as CEA-secreting cells in patients with ABPA.