Cervical Cell/Clumps Detection in Cytology Images Using Transfer Learning.

Cervical cancer is one of the most common and deadliest cancers among women and poses a serious health risk. Automated screening and diagnosis of cervical cancer will help improve the accuracy of cervical cell screening. In recent years, there have been many studies conducted using deep learning methods for automatic cervical cancer screening and diagnosis. Deep-learning-based Convolutional Neural Network (CNN) models require large amounts of data for training, but large cervical cell datasets with annotations are difficult to obtain. Some studies have used transfer learning approaches to handle this problem. However, such studies used the same transfer learning method that is the backbone network initialization by the ImageNet pre-trained model in two different types of tasks, the detection and classification of cervical cell/clumps. Considering the differences between detection and classification tasks, this study proposes the use of COCO pre-trained models when using deep learning methods for cervical cell/clumps detection tasks to better handle limited data set problem at training time. To further improve the model detection performance, based on transfer learning, we conducted multi-scale training according to the actual situation of the dataset. Considering the effect of bounding box loss on the precision of cervical cell/clumps detection, we analyzed the effects of different bounding box losses on the detection performance of the model and demonstrated that using a loss function consistent with the type of pre-trained model can help improve the model performance. We analyzed the effect of mean and std of different datasets on the performance of the model. It was demonstrated that the detection performance was optimal when using the mean and std of the cervical cell dataset used in the current study. Ultimately, based on backbone Resnet50, the mean Average Precision (mAP) of the network model is 61.6% and Average Recall (AR) is 87.7%. Compared to the current values of 48.8% and 64.0% in the used dataset, the model detection performance is significantly improved by 12.8% and 23.7%, respectively.

Redox-Activated Contrast-Enhanced T1-Weighted Imaging Visualizes Glutathione-Mediated Biotransformation Dynamics in the Liver.

GSH-mediated liver biotransformation is a crucial physiological process demanding efficient research tools. Here, we report a type of amorphous FexMnyO nanoparticles (AFMO-ZDS NPs) as redox-activated probes for in vivo visualization of the dynamics of GSH-mediated biotransformation in liver with T1-weighted magnetic resonance imaging (MRI). This imaging technique reveals the periodic variations in GSH concentration during the degradation of AFMO-ZDS NPs due to the limited transportation capacity of GSH carriers in the course of GSH efflux from hepatocytes to perisinusoidal space, providing direct imaging evidence for this important carrier-mediated process during GSH-mediated biotransformation. Therefore, this technique offers an effective method for in-depth investigations of GSH-related biological processes in liver under various conditions as well as a feasible means for the real-time assessment of liver functions, which is highly desirable for early diagnosis of liver diseases and prompt a toxicity evaluation of pharmaceuticals.

Reversible redox-responsive 1H/19F MRI molecular probes.

Herein we report a pair of redox-responsive manganese complexes Mn(iii)/(ii)-N,N'-bis(2-hydroxy-4-trifluoromethylbenzyl)ethylenediamine-N,N'-diacetate (HTFBED, L1), which are water soluble and biologically interconvertible, as reversible redox-responsive probes in 1H/19F MRI for detecting and imaging biological redox species, offering a means to access valuable redox information associated with various diseases.

Directional assembly of a stapled α-helical peptide.

The de novo design of stapled peptide-based self-assemblies attracts vast interest, yet still remains challenging. The development of an oxidation trigger for peptide stapling and subsequent self-assembly is described here. A self-assembling sequence, Fmoc-R(RCEX)2-NH2, transformed from a random coil to an α-helical structure upon disulphide bonding of the flanking cysteine residues positioning at the i/i + 4 locations. The stapling form of this peptide enforces a conformational restraint that affords the driving force for self-assembly into nanorod/nanovesicle structures. Moreover, these assembled materials can transport siRNA into cancer cells and immediately release the cargo in a reductive environment.

A gadolinium-complex-based theranostic prodrug for in vivo tumour-targeted magnetic resonance imaging and therapy.

Here we report a target-specific theranostic prodrug (1a) containing Gd-DOTA, biotin, and camptothecin (CPT) along with a disulfide self-immolative linker. This prodrug exhibits selective targeting towards tumour cells and tissues, stimuli-responsive controlled release, enhanced anticancer efficacy, and accurate diagnosis and real-time monitoring via contrast-enhanced magnetic resonance imaging (MRI).

Erratum: In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell: Erratum.

[This corrects the article DOI: 10.7150/thno.19840.].

Iron-oxide-based twin nanoplates with strong T2 relaxation shortening for contrast-enhanced magnetic resonance imaging.

Iron oxide nanomaterials have been intensively investigated over the past few decades as magnetic resonance imaging (MRI) contrast agents (CAs) due to their favorable magnetism and excellent biocompatibility. However, commercial iron-oxide-nanoparticle-based CAs suffer from low T2 relaxivity, which significantly limits their applications in the biomedical field. Herein, we report a new type of iron oxide nanoplate (IOP) with an interesting twinning plane, which is fabricated via seed growth. Compared with the conventional iron oxide (IO) spherical nanoparticles, iron oxide twin nanoplates (IOP-13) have a larger effective radius, higher saturation magnetization, and greater anisotropy, resulting in their superior T2 relaxivity of 571.21 mM-1 s-1 at 0.5 T, which is about six times higher than that of commercial IO nanoparticles. In vivo MR imaging demonstrated that IOP-13 could be used for liver imaging and liver tumor diagnosis with high sensitivity and accuracy, revealing the great potential of IOP-13 as a next-generation CA. This work provides a novel strategy of structure tuning to devise high-performance T2 contrast agents, which expands the applications of iron oxide nanoparticles in biology and materials.

Facile Chemoselective Modification of Thio-Ethers Generates Chiral Center-Induced Helical Peptides.

A precisely positioned sulfimide chiral center on-tether of a thio-ether tethered peptide determines the peptide secondary structure by chemoselective oxaziridine modification. This method provides a facile way to tune peptides' secondary structures and biophysical properties.

A Self-Assembled Biocompatible Nanoplatform for Multimodal MR/Fluorescence Imaging Assisted Photothermal Therapy and Prognosis Analysis.

The need for better imaging assisted cancer therapy calls for new biocompatible agents with excellent imaging and therapeutic capabilities. This study successfully fabricates albumin-cooperated human serum albumin (HSA)-GGD-ICG nanoparticles (NPs), which are comprised of a magnetic resonance (MR) contrast agent, glycyrrhetinic-acid-modified gadolinium (III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GGD), and a fluorescence (FL) dye, indocyanine green (ICG), for multimodal MR/FL imaging assisted cancer therapy. These HSA-GGD-ICG NPs with excellent biocompatibility are stable under physiological conditions, and exhibit enhanced T1 contrast capability and improved fluorescence imaging capacity. In vitro experiments reveal an apparent effect of the NPs in killing tumor cells under low laser irradiation, due to the enhanced photothermal conversion efficiency (≈85.1%). Importantly, multimodal MR/FL imaging clearly shows the in vivo behaviors and the efficiency of tumor accumulation of HSA-GGD-ICG NPs, as confirmed by a pharmacokinetic study. With the guidance of multimodal imaging, photothermal therapy is subsequently conducted, which demonstrates again high photothermal conversion capability for eliminating tumors without relapse. Notably, real-time monitoring of tumor ablation for prognosis and therapy evaluation is also achieved by MR imaging. This strategy of constructing nanoplatforms through albumin-mediated methods is both convenient and efficient, which would enlighten the design of multimodal imaging assisted cancer therapy for potential clinical translation.

In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell.

Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy.

Development of a high quantum yield dye for tumour imaging.

A fluorescent dye, FEB, with high fluorescence quantum yield for tumour imaging is reported. FEB dyes can be efficiently synthesized in three steps and then easily modified with either PEG or PEG-iRGD to yield FEB-2000 or FEB-2000-iRGD, respectively. Both modified dyes showed negligible toxicity and were thus able to be adopted for in vivo tumour imaging. PEG modification endowed the dye FEB-2000 with both long circulating times and good tumour targeting properties in a MDA-MB-231 xenograft model. Further conjugation with iRGD to generate FEB-2000-iRGD showed minimal targeting enhancement. These results provide a template for the efficient preparation of FEB dyes for use in tumour imaging, thus providing a foundation for future modifications.

Reversible and Versatile On-Tether Modification of Chiral-Center-Induced Helical Peptides.

Modification of the cross-linker of constrained peptides has recently received considerable attention. Here, we present a versatile approach to modifing the cross-linking tether of chiral-center-induced helical (CIH) peptides via the S-alkylation reaction. The alkylation process displayed high conversion efficiency, selectivity, and substrate tolerance. Notably, although on-tether S-alkylation could lead to a pair of peptide epimers, the major alkylated product retained the helical structure of its helical precursor peptide. This S-alkylation was readily reversible under reductive conditions, which provides a simple method for traceless modification. In addition to expanding the chemical space of CIH peptides, this strategy is the first on-tether modification platform with known retention of the peptides' original helicity.

Geometrical confinement directed albumin-based nanoprobes as enhanced T1 contrast agents for tumor imaging.

There is an urgent demand for the development of new magnetic resonance imaging (MRI) contrast agents (CAs) with high T1 contrast ability and good biocompatibility. Herein, we report a novel albumin-based nanoprobe loaded with ibuprofen-modified gadolinium chelates, named Ibu-Gd-BSA nanoparticles (NPs). The interfacial pore structure among the albumin molecules endows the Ibu-Gd-BSA NPs with geometrical confinement, which could prolong the rotational correlation time (τR) of CAs and the diffusion correlation time (τD) of water molecules trapped within the pores. As a result, the Ibu-Gd-BSA NPs exhibited an extremely high relaxivity of 48.9 mM-1 s-1, which is about 9 times higher than that of the clinical contrast agent Gd-DOTA (Dotarem®). In addition, the Ibu-Gd-BSA NPs showed good biocompatibility in vitro and in vivo due to the intrinsically biocompatible property of each component. Moreover, the Ibu-Gd-BSA NPs showed much longer blood circulation half-life and higher accumulation in tumors due to the enhanced permeability and retention effect compared to small molecular CAs. In vivo T1-weighted MR imaging confirmed that Ibu-Gd-BSA NPs could serve as an optimal candidate for sensitive tumor imaging. This study provides a facile strategy to assemble geometrically confined albumin-based nanoparticles as T1 CAs with high biocompatibility and enhanced contrast ability, which have great potential for diverse uses in biomedical imaging and disease detection.

Investigation of Cellular Uptakes of the In-Tether Chiral-Center-Induced Helical Pentapeptides.

We recently reported that a precisely positioned in-tether chiral center can modulate backbone peptides' secondary structures, which provides an unbiased platform to evaluate peptides' biophysical properties solely imposed by secondary structure differences. In this work, we studied the cellular uptake efficiency and mechanism of epimer pairs of a panel of chirality-induced helical peptides (CIH peptides). Although the peptides' cellular uptake is a synergetic result of various factors, our results unambiguously indicate that helical content is an important factor for the cellular uptake of CIH peptides.

An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide.

The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X-ray diffraction analysis suggests that the absolute configuration of the in-tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation.

A Protein-Corona-Free T(1)-T(2) Dual-Modal Contrast Agent for Accurate Imaging of Lymphatic Tumor Metastasis.

Precise nodal staging is particularly important to guide the treatments and determine the prognosis for cancer patients. However, it is still challenging to noninvasively and precisely detect in-depth tumor metastasis in lymph nodes (LNs) because of the small size and high potential of obtaining pseudopositive results. Herein, we report the rational design of a T1-T2 dual-modal MRI contrast agent for accurate imaging of tumor metastasis in LNs using gadolinium-embedded iron oxide nanoplates (GdIOP). The GdIOP were modulated with suitable size in vivo through surface functionalization by zwitterionic dopamine sulfonate (ZDS) molecules. The efficient uptake of GdIOP@ZDS nanoparticles through drainage effect because of the presence of large amount of macrophages and dendritic cells generates both T1 and T2 contrasts in LNs. In contrast, the low uptake of protein-corona-free GdIOP@ZDS nanoparticles by melanoma B16 tumor cells promises pseudocontrast imaging of potential tumor metastasis in LNs. The combination of T1 and T2 imaging modalities allows self-confirmed detection of a metastatic tumor with about 1.2 mm in the minimal dimension in LNs, which is close to the detection limit of submilimeter level of MRI scans. This study provides an efficient and noninvasive strategy to detect tumor metastasis in LNs with greatly enhanced diagnostic accuracy.