Breast Cancer Molecular Subtype Prediction on Pathological Images with Discriminative Patch Selection and Multi-Instance Learning.

Molecular subtypes of breast cancer are important references to personalized clinical treatment. For cost and labor savings, only one of the patient's paraffin blocks is usually selected for subsequent immunohistochemistry (IHC) to obtain molecular subtypes. Inevitable block sampling error is risky due to the tumor heterogeneity and could result in a delay in treatment. Molecular subtype prediction from conventional H&E pathological whole slide images (WSI) using the AI method is useful and critical to assist pathologists to pre-screen proper paraffin block for IHC. It is a challenging task since only WSI-level labels of molecular subtypes from IHC can be obtained without detailed local region information. Gigapixel WSIs are divided into a huge amount of patches to be computationally feasible for deep learning, while with coarse slide-level labels, patch-based methods may suffer from abundant noise patches, such as folds, overstained regions, or non-tumor tissues. A weakly supervised learning framework based on discriminative patch selection and multi-instance learning was proposed for breast cancer molecular subtype prediction from H&E WSIs. Firstly, co-teaching strategy using two networks was adopted to learn molecular subtype representations and filter out some noise patches. Then, a balanced sampling strategy was used to handle the imbalance in subtypes in the dataset. In addition, a noise patch filtering algorithm that used local outlier factor based on cluster centers was proposed to further select discriminative patches. Finally, a loss function integrating local patch with global slide constraint information was used to fine-tune MIL framework on obtained discriminative patches and further improve the prediction performance of molecular subtyping. The experimental results confirmed the effectiveness of the proposed AI method and our models outperformed even senior pathologists, which has the potential to assist pathologists to pre-screen paraffin blocks for IHC in clinic.

Fabrication of multi-functional carbon dots based on "one stone, three birds" strategy and their applications for the dual-mode Fe3+ detection, effective promotion on cell proliferation and treatment on ferric toxicosis in vitro.

The ingenious design of multi-functional materials to simultaneously achieve the accurate detection of targets and effective treatment of target-related diseases is of great significance for both practical and clinical applications. Accordingly, based on their advantages of facile synthesis and function designability, functional nanomaterials have become promising candidates for integrating multi-functionality into one platform, especially carbon dot (CD)-based materials. Herein, deferoxamine (DFO)-inspired CDs with integrated "sense and treatment" potential were elaborately designed and fabricated via a one-pot hydrothermal synthesis by employing l-aspartic acid (Asp) and 2,5-diaminobenzenesulfonic acid (DABSA) as the reactants. A series of characterization results distinctly confirmed that the synthesized CDs possessed a unique chemical composition, uniform spherical morphology (diameter of around 5 nm) and good dispersibility in aqueous solution, exhibiting excellent fluorescence stability under different conditions. Owing to the complexation interaction between Fe3+ and the functional groups of CDs, the selective and sensitive detection of Fe3+ could be successfully realized through fluorescent and colorimetric dual-mode detection based on the statistic quenching in the initial stage, and subsequently the FRET process. Furthermore, these CDs could be utilized for cellular imaging and effective Fe3+ detection due to their outstanding biocompatibility and cytoplasmatic distribution. More significantly, these DFO-inspired CDs could remarkably promote the proliferation of various mammalian cells. Particularly, the results in this work obviously indicated that this type of CDs could weaken the damage of Fe3+ towards the physiological behaviors of cells, helping the cells to regain their capability of differentiation after ferric toxicosis. Therefore, this work presents an original approach for the design and fabrication of multi-functional materials according to the "one stone, three birds" strategy, which may be an optional solution to develop various multi-functional platforms for disease diagnosis and corresponding clinical treatment.

Fabrication of fluorescent hybrid nanomaterials based on carbon dots and its applications for improving the selective detection of Fe (III) in different matrices and cellular imaging.

Considering that detection on cations or ions still meets some challenges in achieving the effectivity and selectivity just by employing one platform, the ingenious fabrication of nanomaterials exhibits an increasing research interests for the preponderance in improving or integrating the performance of single platform. Herein, a fluorescent hybrid nanomaterials based on an organic dye 4-methylumbelliferone (4-MU) as modifier and D-arginine as carbon cores has been developed via a facile one-step hydrothermal synthesis, forming carbon dots (CDs)/4-MU hybrid nanomaterials (CDs-4-MU). This kind of nanomaterials can improve the sensitive and selective detection of single CDs towards Fe3+ ions in different matrices. The detection mechanism of CDs-4-MU towards Fe3+ can be attributed to an electron transfer process between CDs-4-MU and Fe3+, leading to the fluorescence quenching. The limit of detection (LOD) and corresponding linear range in tris-HCl buffer solution are 0.68 µM and 2.29-200 µM, respectively. Furthermore, this nanomaterial can also achieve a detection of Fe3+ ions in real samples such as tap water, culture medium and fetal bovine serum. In particular, CDs-4-MU exhibits a good biocompatibility and can be uptaken by MC3T3 cells, thus can be applied for Fe3+ ions detection in cellular level and cellular imaging. Therefore, this work provides a versatile strategy for the synthesis of CDs-based hybrid nanomaterials and opens a new pathway for improving the ion detection in real samples, which is of significance in practical applications.

Biomimetic synthesis of chondroitin sulfate-analogue hydrogels for regulating osteogenic and chondrogenic differentiation of bone marrow mesenchymal stem cells.

As a typical representative of crucial glycosaminoglycans (GAGs), chondroitin sulfate (CS) with sulfonated polysaccharide in structures extensively exists in the extracellular matrix (ECM) and exhibits peculiar bioactivity on the regulation of cells behaviors and fates (e.g. proliferation and differentiation) in organisms. Nevertheless, some intrinsic disadvantages of natural CS mainly ascribe to the intricate structure and inhomogeneous composition (especially the uncontrollable sulfonate degrees), resulting in overt restrictions on its physiological functions and applications. Although recent bionic synthesis of artificial GAGs analogues at the molecular level have already provides an efficient strategy to reconstruct GAG for regulating the cellular behaviors and fates, it still remains great challenges to rationally design and synthesize GAGs analogues with special composition and structure for precisely mimicking ECM. Simultaneously, the relevant regulation process of GAG analogues on cell fate needs to be further studied as well. Herein, chondroitin sulfate-analogue (CS-analogue) hydrogels with diverse contents of saccharide and sulfonate units in the networks were fabricated through photo-polymerization and then characterized by Fourier transform infrared (FT-IR) spectroscopy, zeta potential and scanning electron microscope (SEM). Additionally, CS-analogue hydrogels with proper mechanical properties exhibited favorable swelling, degradation performance and prominent cytocompatibility. According to cell cultivation results, CS-analogue hydrogel with a certain proportion of saccharide and sulfonate units presented preferable promotion on the adhesion, spreading, proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs), shedding light on the significance of saccharide and sulfonate units in regulating cell behaviors. Furthermore, BMSCs cultivated with CS-analogue hydrogels under different culture conditions were also systematically investigated, revealing that with the help of cultivation environment CS-analogue hydrogels owned the remarkable capacity of directing either chondrogenic or osteogenic differentiation of BMSCs. Therefore, it is envisioned that versatile CS-analogue hydrogels would have promising application prospects in the biomedical and clinical fields.

Correlation of Myopia with Physical Exercise and Sleep Habits among Suburban Adolescents.

PURPOSE: To analyse the correlation of myopia with physical exercise and sleep habits to explore the possible risk or protective factors of juvenile myopia. METHODS: This study was a retrospective cross-sectional study. A total of 1831 students aged 11-18 years from five schools in Qingpu completed questionnaires from 2018 to 2019; the students were divided into the nonmyopia group and the myopia group, with students in the myopia group having myopia in at least one eye. Based on the chi-square test, the variables with statistical significance were selected for the logistic regression analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were determined. RESULTS: Myopia was positively associated with older age (OR = 2.216, 95% CI: 1.720-2.855), having a parent with myopia (father: OR = 2.463, 95% CI: 1.900-3.193; mother: OR = 2.853, 95% CI: 2.232-3.646), and a late bedtime during holidays (before 10 pm: p = 0.002; 10 pm-11 pm: OR = 1.516, 95% CI: 1.095-2.100; 11 pm-12 am: OR = 1.966, 95% CI: 1.383-2.795), but negatively correlated with male gender (OR = 0.693, 95% CI: 0.549-0.876), a late daily wake time (OR = 0.782, 95% CI: 0.621-0.985), and having more days per week of outdoor activities during the semester (OR = 0.764, 95% CI: 0.597-0.978). After adjustment for demographic characteristics, myopia was positively associated with a late bedtime during holidays (before 10 pm: p = 0.003; 10 pm-11 pm: OR = 1.570, 95% CI: 1.076-2.289; 11 pm-12 am: OR = 2.173, 95% CI: 1.451-3.253; after 12 am: OR = 1.786, 95% CI: 1.093-2.919), but negatively correlated with a late daily wake time during the semester (OR = 0.761, 95% CI: 0.581-0.997). CONCLUSION: The association of outdoor exercise with myopia among Chinese suburban adolescents does not seem to be as strong as that of sleep habits. Future research could seek to provide consistent evidence for a potential association between myopia and sleep habits.

Hyaluronic acid bioinspired polymers for the regulation of cell chondrogenic and osteogenic differentiation.

As the simplest glycosaminoglycan (GAG) in extracellular matrix, hyaluronic acid (HA) takes part in several important biological processes, such as regulating cell proliferation, differentiation, and migration. In this work, a series of HA-inspired polymers with different saccharide and carboxylate units (HA-analogue polymers) are synthesized by free radical polymerization, and characterized using Fourier transform infrared spectroscopy (FT-IR), gel permeation chromatography (GPC) and nuclear magnetic resonance spectrometer (NMR), Moreover, cell experiments demonstrate that HA-analogue polymers with a certain proportion of saccharide and carboxylate (PM1G1) units shows a positive effect on the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). Furthermore, HA-analogue polymers have prominent cartilage inductive capacity in chondrogenic induction medium (CIM) and brilliant bone inductive capacity in osteogenic induction medium (OIM) toward BMSCs. Therefore, it is confirmed that the HA-analogue polymers can effectively mimic the functions of HA and have broad potential application prospects in the biomedical and clinical fields.

Sulfonated glycosaminoglycan bioinspired carbon dots for effective cellular labelling and promotion of the differentiation of mesenchymal stem cells.

Although carbon dots (CDs) have been synthesized and applied in a variety of biological fields, such as disease diagnosis and gene/drug delivery, the exploration of facile bioinspired synthesis and applications of CDs is still of great significance. Particularly, recent increasing research has clearly confirmed that nanomaterials can affect a series of physiological behaviors and functions of mesenchymal stem cells (MSCs) (e.g., differentiation and pluripotency). Therefore, it is very important to develop multifunctional nanomaterials to simultaneously realize the cellular labelling and regulation of MSC behaviors in practical applications. Herein, sulfonated glycosaminoglycan-bioinspired CDs as bi-functional nanomaterials were ingeniously designed for cellular imaging and promoting the differentiation of rat bone MSCs (rBMSCs) in different culture media, which simultaneously met the two fundamental requirements in the field of MSC-based treatments (e.g., precisely directing the differentiation of MSCs and effective cellular labeling). These bifunctional CDs were successfully prepared via one-pot hydrothermal synthesis by using d-glucosamine hydrochloride (GA·HCl) and sodium p-styrenesulfonate (NaSS) as the reactants. The synthesized CDs with a uniform particle size (around 4 nm) dispersed well in aqueous solutions and exhibited remarkable fluorescence stability under different conditions. Additionally, cell viability and proliferation results demonstrated that the CDs possessed good biocompatibility, having negligible effects on the self-renewal potential of rBMSCs. The as-prepared CDs presented a cytoplasmatic distribution after being ingested by rBMSCs; thus, they are particularly suitable for cellular imaging. More importantly, the addition of CDs to osteogenic and chondrogenic induction media (OIM and CIM), respectively, was capable of effectively promoting the osteogenic and chondrogenic differentiation of rBMSCs due to the generation of reactive oxygen species (ROS) while having no influence on their pluripotency. In brief, this study not only implements a cellular labeling method based on CDs that were synthesized by a biomimicking strategy, but also paves a new way to regulate the differentiation of MSCs by designing multifunctional nanomaterials; this will enable the extensive development of facile synthesis methods and new applications of CDs and will also provide some research foundations for MSC-based fields.

Fabrication of a multifunctional hydrogel with a robust interface bioinspired by the structure of the dentogingival junction.

The dentogingival junction with a perforating fiber structure is an anatomical and functional interface between the gingiva and tooth structure. Inspired by this structure, this study involves the development of a handy method to fabricate a multifunctional hydrogel with a robust interface, which is also universal for preparing diverse materials that require a Janus structure.

Self-Assembled Upconversion Nanoparticle Clusters for NIR-controlled Drug Release and Synergistic Therapy after Conjugation with Gold Nanoparticles.

Fabricated three-dimensional (3D) upconversion nanoclusters (abbreviated as EBSUCNPs) are obtained via an emulsion-based bottom-up self-assembly of NaGdF4:Yb/Er@NaGdF4 nanoparticles (abbreviated as UCNPs), which comprise a NaGdF4:Yb/Er core and a NaGdF4 shell. The EBSUCNPs were then coated with a thin mesoporous amino-functionalized SiO2 shell (resulting in EBSUCNPs@SiO2 precursor) and further conjugated with gold nanoparticles to give the novel EBSUCNPs@SiO2@Au material. Finally, EBSUCNPs@SiO2@Au was applied as a biocompatible and efficient drug carrier for doxorubicin (DOX), thus giving rise to a multifunctional EBSUCNPs@SiO2-DOX@Au nanocomposite. This final material, EBSUCNPs@SiO2-DOX@Au, and the precursor nanoparticles, EBSUCNPs@SiO2@Au, were both fully characterized and their luminescence was investigated in detail. In addition, the drug release properties and photothermal effects of EBSUCNPs@SiO2-DOX@Au were also discussed. Interestingly, when under NIR irradiation, an increasing DOX release was achieved owing to the thermal effect of the Au NPs after absorbing the green light from the upconversion nanoclusters based on the fluorescence resonance energy transfer (FRET) effect. Thus, a near-infrared (NIR)-controlled "on-off" pattern of drug release behavior can be achieved. Moreover, compared with a single therapy method, the assembled nanocomposites exhibit a good synergistic therapy against cancer cells that combines chemotherapy with photothermal therapy. In addition, the in vitro fluorescence microscopy images of EBSUCNPs@SiO2-DOX@Au show a higher enhancement in the red region due to the loading of DOX molecules with respect to EBSUCNPs@SiO2@Au. Therefore, this novel multifunctional 3D cluster architecture can be used in the biomedical field after modification and may pave a new way in other application areas of UCNPs clusters.

A Stimuli-Responsive Smart Lanthanide Nanocomposite for Multidimensional Optical Recording and Encryption.

A stimuli-responsive lanthanide-based smart nanocomposite has been fabricated by supramolecular assembly and applied as an active material in multidimensional memory materials. Conjugation of the lanthanide complexes with carbon dots provides a stimuli response that is based on the modulation of the energy level of the ligand and affords microsecond-to-nanosecond fluorescence lifetimes, giving rise to intriguing memory performance in the spatial and temporal dimension. The present study points to a new direction for the future development of multidimensional memory materials based on inorganic-organic hybrid nanosystems.

A core-shell metal-organic-framework (MOF)-based smart nanocomposite for efficient NIR/H2O2-responsive photodynamic therapy against hypoxic tumor cells.

Core-shell MOF-based smart nanocomposite UCNPs/MB@ZIF-8@catalase (UCNPs = upconversion nanoparticles; MB = methylene blue; ZIF = zeolitic imidazolate framework) has been constructed for bio-imaging and efficient NIR/H2O2-responsive photodynamic therapy against hypoxic tumor cells. The nanoporous MOF shell can prevent aggregation of photosensitizers and serve as an efficient self-sufficient oxygen gas acceptor.

A multifunctional nanocomposite for luminescence resonance energy transfer-guided synergistic monitoring and therapy under single near infrared light.

By utilizing a drug coordinated to Eu(3+) as a blocker of luminescence resonance energy transfer from the Eu(3+) complex to gold nanotriangles, we successfully implemented multiple functions into one nanocomposite; it operates under single near infrared light and is efficient for the temperature/luminescence monitoring of drug release and synergistic turning-on of photothermal chemotherapy.

Two-photon sensitized hollow Gd2O3:Eu(3+) nanocomposites for real-time dual-mode imaging and monitoring of anticancer drug release.

New two-photon sensitized multifunctional nanocomposites were designed for dual-mode imaging and real-time drug release monitoring by photoluminescence (PL) and magnetic resonance imaging (MRI). By drug loading based on coordination effect, PL signals of Eu(3+) and MRI signals of Gd(3+) can be stabilized and enhanced, respectively, which then display excellent linear decreases on drug release.

Absolute measurement of optical flat surface shape based on the conjugate differential method.

In this paper the conjugate differential method is proposed to measure the absolute surface shape of the flat mirror using a phase-shifting interferometer. The conjugate differential method is derived from the differential method, which extracts absolute phase differences by introducing the slight transverse shifts of the optic. It employs the measurement schemes making transverse shifts on the orthogonally bilateral symmetry positions. So the measurement procedures have been changed into four-step tests to get the phase difference map instead of three-step tests for the differential method. The precision of the slope approximation is enhanced by reducing couplings between multi-step tests, and the reliability of the measurements can be improved. Several differential wavefront reconstruction methods, such as Fourier transform, Zernike polynomial fitting and Hudgin model method, can be applied to reconstruct the absolute surface shape from the differencing phase maps in four different simulation environment. They were also used to reconstruct the absolute surface shape with the conjugate differential method in the experiment. Our method accords with the classical three-flat test better than the traditional differential method, where the deviation of RMS value between the conjugate differential method and the three-flat test is less than 0.3 nm.