Robust explanation supervision for false positive reduction in pulmonary nodule detection.

BACKGROUND: Lung cancer is the deadliest and second most common cancer in the United States due to the lack of symptoms for early diagnosis. Pulmonary nodules are small abnormal regions that can be potentially correlated to the occurrence of lung cancer. Early detection of these nodules is critical because it can significantly improve the patient's survival rates. Thoracic thin-sliced computed tomography (CT) scanning has emerged as a widely used method for diagnosing and prognosis lung abnormalities. PURPOSE: The standard clinical workflow of detecting pulmonary nodules relies on radiologists to analyze CT images to assess the risk factors of cancerous nodules. However, this approach can be error-prone due to the various nodule formation causes, such as pollutants and infections. Deep learning (DL) algorithms have recently demonstrated remarkable success in medical image classification and segmentation. As an ever more important assistant to radiologists in nodule detection, it is imperative ensure the DL algorithm and radiologist to better understand the decisions from each other. This study aims to develop a framework integrating explainable AI methods to achieve accurate pulmonary nodule detection. METHODS: A robust and explainable detection (RXD) framework is proposed, focusing on reducing false positives in pulmonary nodule detection. Its implementation is based on an explanation supervision method, which uses nodule contours of radiologists as supervision signals to force the model to learn nodule morphologies, enabling improved learning ability on small dataset, and enable small dataset learning ability. In addition, two imputation methods are applied to the nodule region annotations to reduce the noise within human annotations and allow the model to have robust attributions that meet human expectations. The 480, 265, and 265 CT image sets from the public Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) dataset are used for training, validation, and testing. RESULTS: Using only 10, 30, 50, and 100 training samples sequentially, our method constantly improves the classification performance and explanation quality of baseline in terms of Area Under the Curve (AUC) and Intersection over Union (IoU). In particular, our framework with a learnable imputation kernel improves IoU from baseline by 24.0% to 80.0%. A pre-defined Gaussian imputation kernel achieves an even greater improvement, from 38.4% to 118.8% from baseline. Compared to the baseline trained on 100 samples, our method shows less drop in AUC when trained on fewer samples. A comprehensive comparison of interpretability shows that our method aligns better with expert opinions. CONCLUSIONS: A pulmonary nodule detection framework was demonstrated using public thoracic CT image datasets. The framework integrates the robust explanation supervision (RES) technique to ensure the performance of nodule classification and morphology. The method can reduce the workload of radiologists and enable them to focus on the diagnosis and prognosis of the potential cancerous pulmonary nodules at the early stage to improve the outcomes for lung cancer patients.

Multifunctional Nanofibrous Scaffolds Capable of Localized Delivery of Theranostic Nanoparticles for Postoperative Cancer Management.

Postoperative recovery of cancer patients can be affected by complications, such as tissue dysfunction or disability caused by tissue resection, and also cancer recurrence resulting from residual cancer cells. Despite impressive progress made for tissue engineering scaffolds that assist tissue regeneration for postoperative cancer patients, the majority of existing tissue engineering scaffolds still lack functions for monitoring and killing residual cancer cells, if there are any, upon their detection. In this study, multifunctional scaffolds that comprise biodegradable nanofibers and core-shell structured microspheres encapsulated with theranostic nanoparticles (NPs) are developed. The multifunctional scaffolds possess an extracellular matrix-like nanofibrous architecture and soft tissue-like mechanical properties, making them excellent tissue engineering patch candidates for assisting in the repair and regeneration of tissues at the cancerous sites after surgery. Furthermore, they are capable of localized delivery of theranostic NPs upon quick degradation of core-shell structured microspheres that contain theranostic NPs. Leveraging on folic acid-mediated ligand-receptor binding, surface-enhanced Raman scattering activity, and near-infrared-responsive photothermal effect of the theranostic gold NPs (AuNPs) delivered locally, the multifunctional scaffolds display excellent active targeting, diagnosis, and photothermal therapy functions for cancer cells, showing great promise for adaptive postoperative cancer management.

The benefits of edible mushroom polysaccharides for health and their influence on gut microbiota: a review.

The gut microbiome is a complex biological community that deeply affects various aspects of human health, including dietary intake, disease progression, drug metabolism, and immune system regulation. Edible mushroom polysaccharides (EMPs) are bioactive fibers derived from mushrooms that possess a range of beneficial properties, including anti-tumor, antioxidant, antiviral, hypoglycemic, and immunomodulatory effects. Studies have demonstrated that EMPs are resistant to human digestive enzymes and serve as a crucial source of energy for the gut microbiome, promoting the growth of beneficial bacteria. EMPs also positively impact human health by modulating the composition of the gut microbiome. This review discusses the extraction and purification processes of EMPs, their potential to improve health conditions by regulating the composition of the gut microbiome, and their application prospects. Furthermore, this paper provides valuable guidance and recommendations for future studies on EMPs consumption in disease management.

Biomanufacturing of biomimetic three-dimensional nanofibrous multicellular constructs for tissue regeneration.

Biomanufacturing of functional tissue analogues is of great importance in regenerative medicine. However, this is still highly challenging due to extreme difficulties in recreating/recapitulating complicated anatomies of body tissues that have both well-defined three-dimensional (3D) multicellular organizations and bioactive nanofibrous extracellular matrix (ECM). In the current investigation, a biomanufacturing approach via concurrent emulsion electrospinning and coaxial cell electrospraying was developed, which could fabricate 3D nanofibrous multicellular constructs that resemble both the multicellular organizations and bioactive nanofibrous microenvironments of body tissues. In the proof-of-concept study, endothelial cells (ECs) and smooth muscle cells (SMCs) were placed in respective layers of multilayer-structured constructs. The two different construct layers consisted of nanofibers providing different topographies (randomly oriented nanofibers or aligned nanofibers) and contained different growth factors (vascular endothelial growth factor or platelet-derived growth factor). The ECs and SMCs in the different construct layers showed high cell densities (> 4 ×105 cells/cm2 after 4-day incubation) and high cell viabilities (> 95%). Owing to the contact guidance/stimulation by different fibrous topographies and sequential release of different growth factors, ECs and SMCs exhibited distinct morphologies (uniformly stretched plaque-shaped or directionally elongated) and displayed enhanced proliferative activities. Our biomanufacturing approach is shown to be effective and efficient in reconstituting/replicating cell-ECM organizations as well as their interactions similar to those in body tissues such as blood vessels, indicating the great promise to produce a range of tissue analogues with biomimetic structures and functions for modeling or regenerating body tissues.

Morphing-to-Adhesion Polysaccharide Hydrogel for Adaptive Biointerfaces.

Reliable functions of medical implants highly depend on biocompatible, conformal, and stable biointerfaces for seamless biointegration with biological tissues. Though flexible biointerfaces based on synthetic hydrogels have shown promise in optimizing implant biointegration via surgical suturing, physical attachment, or manual preshaping, they still suffer from poor adaptability, such as tissue damage by surgical suturing, low bioactivity, and difficulties in conformal contact and stable fixation, especially for specific tissues of large surface curvatures. Here, we report a bilayer hydrogel-based adaptive biointerface (HAB) made of two polysaccharide derivates, N-hydroxysuccinimide (NHS) ester-activated alginate and chitosan, harnessing dual advantages of their different swelling and active groups. Leveraging on the differential swelling between the two hydrogel layers and covalent linkages with active groups at hydrogel interfaces, HABs can be programmed into sealed tubes with tunable diameters via water-induced compliable shape morphing and instant interfacial adhesion. We further demonstrate that the polysaccharide-based morphing-to-adhesion HAB possesses outstanding bioactivity in directing cellular focal adhesion and intercellular junction, versatile geometrical adaptability to diverse tubular tissues with a wide range of surface curvatures (2.8 × 102-1.3 × 103 m-1), and excellent mechanical stability in high load-/shear-bearing physiological environments (blood flow volume: 85 mm·s-1). HABs overcome the limitations of existing biointerfaces in terms of poor bioactivity and difficult biointegration with biological tissues of large surface curvatures, holding promise to open new avenues for adaptive biointerfaces and reliable medical implants.

Nanofibrous bicomponent scaffolds for the dual delivery of NGF and GDNF: controlled release of growth factors and their biological effects.

Electrospun fibrous scaffolds capable of providing dual growth factor delivery in a controlled manner have distinctive advantages for tissue engineering. In this study, we have investigated the formation, structure, and characteristics/properties of fibrous bicomponent scaffolds for the dual delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) for peripheral nerve tissue regeneration. GDNF and NGF were incorporated into core-shell structured poly(lactic-co-glycolic acid) (PLGA) and poly (D,L-lactic acid) (PDLLA) nanofibers, respectively, through emulsion electrospinning. Using dual-source dual-power electrospinning, bicomponent scaffolds composed of GDNF/PLGA fibers and NGF/PDLLA fibers with different fiber component ratios were produced. The structure, properties, and in vitro release behavior of mono- and bicomponent scaffolds were systematically investigated. Concurrent and sustained release of GDNF and NGF from bicomponent scaffolds was achieved and their release profiles could be tuned. In vitro biological investigations were conducted. Rat pheochromocytoma cells were found to attach, spread, and proliferate on all scaffolds. The release of growth factors from scaffolds could induce much improved neurite outgrowth and neural differentiation. GDNF and NGF released from GDNF/PLGA scaffolds and NGF/PDLLA scaffolds, respectively, could induce dose-dependent neural differentiation separately. GDNF and NGF released from bicomponent scaffolds exerted a synergistic effect on promoting neural differentiation.

Three-dimensional endothelial cell incorporation within bioactive nanofibrous scaffolds through concurrent emulsion electrospinning and coaxial cell electrospraying.

Nanofibrous scaffolds hold great promise in tissue engineering owing to their extracellular matrix (ECM)-mimicking architectures. Electrospinning, with its ease for producing nanofibrous scaffolds, has therefore been widely employed for various tissue engineering applications. However, electrospun nanofibrous scaffolds have faced the inherent challenge of three-dimensional (3D) cell distribution due to the small sizes of interconnected pores in these scaffolds when conventional approach of scaffold fabrication with subsequent cell seeding is adopted, which severely limits their applications in repairing/regenerating human body tissues with thick and vascularized structures. In this study, we demonstrate a method to directly place living endothelial cells within bioactive nanofibrous scaffolds in 3D through concurrent emulsion electrospinning and coaxial cell electrospraying. Using this concurrent manufacturing method, endothelial cells are encapsulated in hydrogel microspheres and deposited along with vascular endothelial growth factor (VEGF)-containing nanofibers in the scaffold fabrication process, resulting in nanofibrous scaffolds with 3D embedded cell-encapsulated microspheres. After selective disruption of the hydrogel microspheres, the encapsulated endothelial cells are released, yielding bioactive nanofibrous scaffolds with tissue-like 3D cell-incorporated nanofibrous structures. It is shown that cell viability is well preserved (>98%) during the concurrent manufacturing process and that a deep cell distribution (~100 µm) through the scaffold thickness has been achieved. With combined structural and biochemical cues via the 3D cell-incorporated architectures, endothelial cells can freely stretch, display enhanced intercellular connections, and maintain the phenotype in the bioactive nanofibrous scaffolds. Our investigations offer a promising platform technology for creating bioactive nanofibrous scaffolds with 3D cell incorporation and for overcoming inherent problems of electrospun nanofibrous scaffolds, which should open new avenues for biomanufacturing tissue-mimicking constructs with vascularized structures and complex anatomy. STATEMENT OF SIGNIFICANCE: Electrospun nanofibrous scaffolds face challenges in three-dimensional (3D) cell incorporation and vascularization. Enhancing cell penetration via enlarged interconnected pores is a common strategy to address that. However, there are conflicts between cell penetration and structural integrity for scaffolds formed using such strategy, as deep cell penetration, if possible, can only achieve in highly loose architectures. In this investigation, we demonstrate a concurrent emulsion electrospinning and coaxial cell electrospraying technique, realizing 3D endothelial cell incorporation in electrospun nanofibrous scaffolds independent of cell penetration. Our technology appropriately addresses the conflict between deep 3D cell incorporation and structural integrity. In the scaffolds, the 3D incorporated endothelial cells show well-preserved viability, phenotype and functions, implying improved vascularization potential.

Circular RNA circ_0020123 Promotes Non-Small Cell Lung Cancer Progression Through miR-384/TRIM44 Axis.

BACKGROUND: It was reported that circular RNAs (circRNAs) and microRNAs (miRNAs) were related to non-small cell lung cancer (NSCLC) development. However, the detailed mechanisms of circ_0020123 and miR-384 in NSCLC are elusive. METHODS: QRT-PCR and Western blot assay were performed to detect the transcription and protein levels of genes, respectively. Then, the functional experiments, including MTT assay, flow cytometry, and transwell assay, were employed. Besides, the interaction between miR-384 and circ_0020123 or tripartite motif­containing protein 44 (TRIM44) was predicted by starbase or targetscan, and then verified by the dual-luciferase reporter, RNA pull-down assays and RNA immunoprecipitation assay (RIP). Mouse xenograft assay was performed to evaluate the effect of circ_0020123 on tumor growth in vivo. RESULTS: Levels of circ_0020123 and TRIM44 were enhanced, and the miR-384 level was attenuated in NSCLC tissues and cells. Circ_0020123 depletion attenuated the abilities of NSCLC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT), and induced apoptosis. Besides, circ_0020123 interacted with miR-384, and miR-384 targeted TRIM44. Circ_0020123 regulated cell progression by regulating miR-384 and subsequently mediated TRIM44 expression. Besides, circ_0020123 depletion repressed tumor growth in vivo. CONCLUSION: We demonstrated that circ_0020123 knockdown suppressed NSCLC cell progression by regulating the miR-384/TRIM44 axis, providing the theoretical basis for the therapy of NSCLC.

Shape-adaptable biodevices for wearable and implantable applications.

Emerging wearable and implantable biodevices have been significantly revolutionizing the diagnosis and treatment of disease. However, the geometrical mismatch between tissues and biodevices remains a great challenge for achieving optimal performances and functionalities for biodevices. Shape-adaptable biodevices enabling active compliance with human body tissues offer promising opportunities for addressing the challenge through programming their geometries on demand. This article reviews the design principles and control strategies for shape-adaptable biodevices with programmable shapes and actively compliant capabilities, which have offered innovative diagnostic/therapeutic tools and facilitated a variety of wearable and implantable applications. The state-of-the-art progress in applications of shape-adaptable biodevices in the fields of smart textiles, wound care, healthcare monitoring, drug and cell delivery, tissue repair and regeneration, nerve stimulation and recording, and biopsy and surgery, is highlighted. Despite the remarkable advances already made, shape-adaptable biodevices still confront many challenges on the road toward the clinic, such as enhanced intelligence for actively sensing and operating in response to physiological environments. Next-generation paradigms will shed light on future directions for extending the breadth and performance of shape-adaptable biodevices for wearable and implantable applications.

Advanced reconfigurable scaffolds fabricated by 4D printing for treating critical-size bone defects of irregular shapes.

While scaffold-based tissue engineering has been widely used to treat bone critical-size defects, challenges such as implantation of scaffolds in defects with irregular shapes and implantation of scaffolds through minimally invasive surgery remain in the tissue engineering field. Customized bioactive bone tissue engineering scaffolds with reconfigurable capability for both easy scaffold implantation and perfect shape fitting in irregularly shaped bone defects are therefore needed. Herein, applying 4D printing, photothermal-responsive shape memory bone tissue engineering scaffolds are constructed by incorporating black phosphorus nanosheets and osteogenic peptide into ß-tricalcium phosphate/poly(lactic acid-co-trimethylene carbonate) (TCP/P(DLLA-TMC)) nanocomposite scaffolds. When near-infrared irradiation is applied to customized scaffolds on-demand, scaffold temperature rapidly increases to 45 °C, enabling scaffold shape reconfiguration for easy scaffold implantation and precise fitting in irregular bone defects. Once the implantation is finished, scaffold temperature rapidly decreases to 37 °C and scaffolds display mechanical properties comparable to those of human cancellous bone. The improved osteogenesis in bone defect sites is then initiated through pulsed peptide release from scaffolds. Compact integration of reconfigurable scaffolds in rat cranial bone defects and improved new bone formation are demonstrated through micro-computed tomography and histochemical analyses. This study shows a facile method to clinically treat bone defects of irregular shapes.

Expression of SIRT1 and survivin correlates with poor prognosis in esophageal squamous cell carcinoma.

This study assessed the association of sirtuin type 1 (SIRT1) and survivin expression with the clinicopathological features and survival of esophageal squamous cell carcinoma (ESCC) patients after concurrent chemoradiotherapy.SIRT1 and survivin proteins were immunohistochemically stained in 93 ESCC tissue specimens.SIRT1 was expressed in ESCC (80.6% vs 25.8% in normal mucosae) and survivin was expressed in 67.7% of ESCC vs 19.4% normal tissues (P < .01), and SIRT1 expression was associated with survivin expression (r = 0.39, P < .05). Furthermore, expression of both SIRT1 and survivin was associated with tumor size, depth of tumor invasion, tumor differentiation, lymph node metastasis, advanced clinical stage, and chemoradiotherapy (P < .05) as well as poor progression-free survival (PFS; P < .05) of ESCC patients after concurrent chemoradiotherapy (P < .05). Patient age, chemotherapy, tumor size, clinical stage, lymph node metastasis, and SIRT1 and survivin expression were independent PFS predictors (P < .05).Expression of both SIRT1 and survivin was associated with poor ESCC PFS.

Incorporation and release of dual growth factors for nerve tissue engineering using nanofibrous bicomponent scaffolds.

Electrospun fibrous scaffolds have been extensively used as cell-supporting matrices or delivery vehicles for various biomolecules in tissue engineering. Biodegradable scaffolds with tunable degradation behaviors are favorable for various resorbable tissue replacements. In nerve tissue engineering, delivery of growth factors (GFs) such as nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) from scaffolds can be used to promote peripheral nerve repair. In this study, using the established dual-source dual-power electrospinning technique, bicomponent scaffolds incorporated with NGF and GDNF were designed and demonstrated as a strategy to develop scaffolds providing dual GF delivery. NGF and GDNF were encapsulated in poly(D, L-lactic acid) (PDLLA) and poly(lactic-co-glycolic acid) (PLGA) nanofibers, respectively, via emulsion electrospinning. Bicomponent scaffolds with various mass ratios of GDNF/PLGA fibers to NGF/PDLLA fibers were fabricated. Their morphology, structure, properties, and the in vitro degradation were examined. Both types of core-shell structured fibers were evenly distributed in bicomponent scaffolds. Robust scaffolds with varying component ratios were fabricated with average fiber diameter ranging from 307 ± 100 nm to 688 ± 129 nm. The ultimate tensile stress and elastic modulus could be tuned ranging from 0.23 ± 0.07 MPa to 1.41 ± 0.23 MPa, 11.1 ± 3.0 MPa to 75.9 ± 3.3 MPa, respectively. Adjustable degradation was achieved and the weight loss of scaffolds ranged from 9.2% to 44.0% after 42 day degradation test. GDNF and NGF were incorporated with satisfactory encapsulation efficiency and their bioactivity were well preserved. Sustained release of both types of GFs was also achieved.