Risk stratification for 1- to 2-cm gastric gastrointestinal stromal tumors: visual assessment of CT and EUS high-risk features versus CT radiomics analysis.

OBJECTIVES: To investigate the ability of CT and endoscopic sonography (EUS) in predicting the malignant risk of 1-2-cm gastric gastrointestinal stromal tumors (gGISTs) and to clarify whether radiomics could be applied for risk stratification. METHODS: A total of 151 pathologically confirmed 1-2-cm gGISTs from seven institutions were identified by contrast-enhanced CT scans between January 2010 and March 2021. A detailed description of EUS morphological features was available for 73 gGISTs. The association between EUS or CT high-risk features and pathological malignant potential was evaluated. gGISTs were randomly divided into three groups to build the radiomics model, including 74 in the training cohort, 37 in validation cohort, and 40 in testing cohort. The ROIs covering the whole tumor volume were delineated on the CT images of the portal venous phase. The Pearson test and least absolute shrinkage and selection operator (LASSO) algorithm were used for feature selection, and the ROC curves were used to evaluate the model performance. RESULTS: The presence of EUS- and CT-based morphological high-risk features, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not differ between very-low and intermediate risk 1-2-cm gGISTs (p > 0.05). The radiomics model consisting of five radiomics features showed favorable performance in discrimination of malignant 1-2-cm gGISTs, with the AUC of the training, validation, and testing cohort as 0.866, 0.812, and 0.766, respectively. CONCLUSIONS: Instead of CT- and EUS-based morphological high-risk features, the CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs. KEY POINTS: • The presence of EUS- and CT-based morphological high-risk factors, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not correlate with the pathological malignant potential of 1-2-cm gGISTs. • The CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs.

Preoperative prediction of malignant potential of 2-5 cm gastric gastrointestinal stromal tumors by computerized tomography-based radiomics.

BACKGROUND: The use of endoscopic surgery for treating gastrointestinal stromal tumors (GISTs) between 2 and 5 cm remains controversial considering the potential risk of metastasis and recurrence. Also, surgeons are facing great difficulties and challenges in assessing the malignant potential of 2-5 cm gastric GISTs. AIM: To develop and evaluate computerized tomography (CT)-based radiomics for predicting the malignant potential of primary 2-5 cm gastric GISTs. METHODS: A total of 103 patients with pathologically confirmed gastric GISTs between 2 and 5 cm were enrolled. The malignant potential was categorized into low grade and high grade according to postoperative pathology results. Preoperative CT images were reviewed by two radiologists. A radiological model was constructed by CT findings and clinical characteristics using logistic regression. Radiomic features were extracted from preoperative contrast-enhanced CT images in the arterial phase. The XGboost method was used to construct a radiomics model for the prediction of malignant potential. Nomogram was established by combing the radiomics score with CT findings. All of the models were developed in a training group (n = 69) and evaluated in a test group (n = 34). RESULTS: The area under the curve (AUC) value of the radiological, radiomics, and nomogram models was 0.753 (95% confidence interval [CI]: 0.597-0.909), 0.919 (95%CI: 0.828-1.000), and 0.916 (95%CI: 0.801-1.000) in the training group vs 0.642 (95%CI: 0.379-0.870), 0.881 (95%CI: 0.772-0.990), and 0.894 (95%CI: 0.773-1.000) in the test group, respectively. The AUC of the nomogram model was significantly larger than that of the radiological model in both the training group (Z = 2.795, P = 0.0052) and test group (Z = 2.785, P = 0.0054). The decision curve of analysis showed that the nomogram model produced increased benefit across the entire risk threshold range. CONCLUSION: Radiomics may be an effective tool to predict the malignant potential of 2-5 cm gastric GISTs and assist preoperative clinical decision making.

TMEM16A Protein: Calcium-Binding Site and its Activation Mechanism.

TMEM16A mediates the calcium-activated transmembrane flow of chloride ions and a variety of physiological functions. The binding of cytoplasmic calcium ions of TMEM16A and the consequent conformational changes of it are the key issues to explore the structure-function relationship. In recent years, researchers have explored this issue through electrophysiological experiments, structure resolving, molecular dynamic simulation, and other methods. The structures of TMEM16 family members determined by cryo-Electron microscopy (cryo-EM) and X-ray crystallization provide the primary basis for the investigation of the molecular mechanism of TMEM16A. However, the binding and activation mechanism of calcium ions in TMEM16A are still unclear and controversial. This mini-review discusses four Ca2+ sensing sites of TMEM16A and analyzes activation properties of TMEM16A by them, which will help understand the structure-function relationship of TMEM16A and throw light on the molecular design targeting the TMEM16A channel.

Could computed tomography be used as a surrogate of endoscopic ultrasonography in the screening and surveillance of small gastric Gastrointestinal stromal tumors?

PURPOSE: To investigate whether computed tomography (CT) could be used for screening and surveillance of small gastric gastrointestinal stromal tumors (gGISTs). METHOD: A total of 162 pathologically confirmed small gGISTs (≤2 cm) between September 2007 and November 2019 were retrospectively enrolled. Thirty-six lesions received contrast-enhanced CT after they were identified by endoscopy and EUS, and forty-three lesions received CT alone before surgery. The detection rate of CT for ≤1 cm gGISTs (micro-gGISTs) and 1-2 cm gGISTs (mini-gGISTs) was investigated, and the detection rate of CT alone was compared with that of CT following endoscopy and EUS. The relationship between EUS- and CT-detected high-risk features were assessed. RESULTS: CT demonstrated a favorable detection rate for mini-gGISTs previously identified by EUS and endoscopy, whereas CT alone showed an inferior detection rate (100 % vs. 75 %, p = 0.02). CT showed a poor detection rate for micro-gGISTs, both for lesions received CT after identified by EUS and endoscopy, and those received CT alone (33.3 % vs. 14.8 %, p = 0.372). CT-detected heterogeneous enhancement pattern and presence of calcification were strongly correlated with heterogeneous echotexture (Spearman's ρ=0.66, p < 0.001) and echogenic foci (Spearman's ρ=0.79, p < 0.001) on EUS, respectively. CT-detected necrosis was moderately correlated with cystic spaces on EUS (Spearman's ρ=0.42, p = 0.02). No correlation was found between EUS- and CT- assessed irregular border. CONCLUSIONS: CT could potentially be considered as a surrogate of EUS for surveillance of mini-gGISTs instead of micro-gGISTs, whereas couldn't be used as a screening modality for either micro- or mini-gGISTs.

A Quantitative Analysis of Drug Loading Efficiency and Real-Time Drug Release in ZrO2 Nanoparticles with Energy Spectrum Computed Tomography.

Energy spectrum computed tomography (CT) can quantify the concentrations of substances in vitro and in vivo. In this study, we designed a single-shell system of doxorubicin (DOX) loaded in zirconium dioxide nanoparticles (DOX@ZrO2 NPs) as a novel chemotherapy drug delivery system. The concentration of DOX@ZrO2 NPs in tissue was monitored with energy spectrum CT to calculate the release of DOX from the NPs. The standard curve of the gradient concentrations of ZrO2 NPs and base material content fit a logarithmic equation. HepG2 cells were incubated with 200 µmL DOX@ZrO2 for different times. The concentration in the cells detected with energy spectrum CT correlated strongly with the concentration of chemotherapeutics in the cells (r = 0.98, P < 0.05). The data indicate that energy spectrum CT is a reliable means of real-time monitoring of the transport of NPs and release of the NP payload in local tissue. The finding could improve the accuracy of clinical imaging and promote the therapeutic use of NPs. Free of clinical trial registeration: There were no animal and human materials involved in this experiment.

Desmoid-type fibromatosis: Tumour response assessment using magnetic resonance imaging signal and size criteria.

INTRODUCTION: This study aimed to establish a specified magnetic resonance imaging (MRI) signal and size criterion for assessing the response of desmoid-type fibromatosis (DF). METHODS: This retrospective study included 129 patients with DF who received non-surgical therapy. All patients underwent pretreatment and 6-month-interval follow-up MRI for >3 years (6 follow-up visits). The correlation between signal grade and size was determined. Signal grade and size among three response groups (partial response [PR], stable disease [SD], progression disease [PD]) were compared. The specified signal and size criterion was established, used to assess tumour response at each follow-up, and compared with the reference. The Response Evaluation Criteria in Solid Tumours (RECIST)1.1 criterion at the end of the 3rd year was considered the reference. RESULTS: MRI signals were moderately correlated with size changes (r = -0.56 and -0.41 for T2 grade and contrast-enhanced T1 grade, respectively). Changes in T2 grade and size in the three response groups were significantly different (all p < 0.01). The signal and size criterion accurately predicted 95% of PR patients at 2nd follow-up and 81.2% of PD patients at the 3rd follow-up, while only 13.1% of PR and 56.3% of PD patients were predicted by RECIST1.1. However, the accuracy of the signal & size criterion for predicting SD was lower than that of RECIST1.1. CONCLUSIONS: MRI signal is useful in assessing the response of DF. Signal & size criterion can identify patients with PR and PD earlier than RECIST1.1.

A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7.

The LIN28:pre-let-7:TUTase ternary complex regulates pluripotency and oncogenesis by controlling processing of the let-7 family of microRNAs. The complex oligouridylates the 3' ends of pre-let-7 molecules, leading to their degradation via the DIS3L2 exonuclease. Previous studies suggest that components of this complex are potential therapeutic targets in malignancies that aberrantly express LIN28. In this study we developed a functional epitope selection approach to identify nanobody inhibitors of the LIN28:pre-let-7:TUT4 complex. We demonstrate that one of the identified nanobodies, Nb-S2A4, targets the 106-residue LIN28:let-7 interaction (LLI) fragment of TUT4. Nb-S2A4 can effectively inhibit oligouridylation and monouridylation of pre-let-7g in vitro. Expressing Nb-S2A4 allows maturation of the let-7 species in cells expressing LIN28, highlighting the therapeutic potential of targeting the LLI fragment.

Intelligent Detection Platform for Simultaneous Detection of Multiple MiRNAs Based on Smartphone.

As a marker of malignant tumors, miRNA is closely related to the occurrence and metastasis of tumors. How to achieve rapid and sensitive real-time detection is important for clinical prevention and treatment of cancer. In this study, an intelligent detection platform based on smartphone image processing technology made point-of-care testing a reality. This new smart approach could detect multiple targets simultaneously and sensitively. Hydrogel microparticles of different coding modes (shapes, numbers) were prepared by flow lithography to detect different miRNAs. After sandwich immunoassays, different shapes of hydrogels showed different fluorescence intensities depending on their targets. Images were captured by a smartphone and then analyzed by image recognition processing software installed on the smartphone. The concentration of miRNA was obtained within 10 s. The entire reaction process did not exceed 2 h. This intelligent and portable detection platform for miRNAs was reliable and the limit of detection reached the femtomole level. This work provided a demonstration of intelligent, portable, real-time detection of tumor markers.

Shape Coding Microhydrogel for a Real-Time Mycotoxin Detection System Based on Smartphones.

How to create a portable and quick way to detect multiple coexisting toxins is closely related to everyone's health. In this paper, we have established a real-time mycotoxin detection system that combined shape-encoded hydrogel particle preparation technology and image processing technology with smartphone portable devices. First, hydrogel microparticles containing a specific recognition toxin aptamer were programmable synthesized by stop-flow lithography. The hydrogel particles prepared by us had clear, variable signals and high coding capacity. Then, the indirect competitive detection based on aptamers was simple and rapid; the total reaction time was no more than 1 h 45 min and the image processing process was no more than 10 s. Finally, images could be captured by cameras on portable devices and smartphones. The self-built Android app that used the image recognition program installed on the smartphone would analyze the image and return the results in real time. The results showed that the detection limit reached 0.1 ng/mL, which was lower than the standard. In summary, this platform provides a fast, portable, high-throughput detection solution for real-time detection of mycotoxins, with excellent application prospects.

Near-infrared light remotely up-regulate autophagy with spatiotemporal precision via upconversion optogenetic nanosystem.

In vivo noninvasively manipulating biological functions by the mediation of biosafe near infrared (NIR) light is becoming increasingly popular. For these applications, upconversion rare-earth nanomaterial holds great promise as a novel photonic element, and has been widely adopted in optogenetics. In this article, an upconversion optogenetic nanosystem that was promised to achieve autophagy up-regulation with spatiotemporal precision was designed. The implantable, wireless, recyclable, less-invasive and biocompatible system worked via two separated parts: blue light-receptor optogenetics-autophagy upregulation plasmids, for protein import; upconversion rods-encapsulated flexible capsule (UCRs-capsule), for converting tissue-penetrative NIR light into local visible blue light. Results validated that this system could achieve up-regulation of autophagy in vitro (in both HeLa and 293T cell lines) and remotely penetrate tissue (∼3.5 mm) in vivo. Since autophagy serves at a central position in intracellular signalling pathways, which is correlative with diverse pathologies, we expect that this method could establish an upconversion material-based autophagy up-regulation strategy for fundamental and clinical applications.

Development of a novel rat model of heterogeneous hepatic injury by injection with colchicine via the splenic vein.

AIM: To develop a novel rat model of heterogeneous hepatic injury. METHODS: Seventy male Sprague-Dawley rats were randomly divided into a control group (n = 10) and a colchicine group (n = 60). A 0.25% colchicine solution (0.4 mL/kg) was injected via the splenic vein in the colchicine group to develop a rat model of heterogeneous hepatic injury. An equal volume of normal saline was injected via the splenic vein in the control group. At days 3, 7, and 14 and weeks 4, 8, and 12 after the operation, at least seven rats of the colchicine group were selected randomly for magnetic resonance imaging (MRI) examinations, and then they were euthanized. Ten rats of the control group underwent MRI examinations at the same time points, and then were euthanized at week 12. T2-weighted images (T2WI) and diffusion weighted imaging (DWI) were used to evaluate the heterogeneous hepatic injury. The heterogeneous injury between the left and right hepatic lobes was assessed on liver sections according to the histological scoring criteria, and correlated with the results of MRI study. RESULTS: Obvious pathological changes occurred in the hepatic parenchyma in the colchicine group. Hepatic injury scores were significantly different between the left and right lobes at each time point (P < 0.05). There was a significant difference in apparent diffusion coefficient (ADC) of DWI and liver-to-muscle ratio (LMR) of T2WI between the left and right lobes of rats in the colchicine group (P < 0.05) at each time point, and similar results were observed between the colchicine and control groups. Besides, there was a significant correlation between hepatic injury scores and ADC values or LMR (r = -0.682, P = 0.000; r = -0.245, P = 0.018). CONCLUSION: Injection with colchicine via the splenic vein can be used to successfully develop a rat model of heterogeneous hepatic injury. DWI and T2WI may help evaluate the heterogeneous injury among liver lobes.

Near-Infrared Light-Excited Upconverting Persistent Nanophosphors in Vivo for Imaging-Guided Cell Therapy.

Optical imaging for biological applications is in need of more sensitive tool. Persistent luminescent nanophosphors enable highly sensitive in vivo optical detection and almost completely avoid tissue autofluorescence. Nevertheless, the actual persistent luminescent nanophosphors necessitate ex vivo activation before systemic operation, which severely restricted the use of long-term imaging in vivo. Hence, we introduced a novel generation of optical nanophosphors, based on (Zn2SiO4:Mn):Y3+, Yb3+, Tm3+ upconverting persistent luminescent nanophosphors; these nanophosphors can be excited in vivo through living tissues by highly penetrating near-infrared light. We can trace labeled tumor therapeutic macrophages in vivo after endocytosing these nanophosphors in vitro and follow macrophages biodistribution by a simple whole animal optical detection. These nanophosphors will open novel potentials for cell therapy research and for a variety of applications in diagnosis in vivo.

Targeted delivery of tungsten oxide nanoparticles for multifunctional anti-tumor therapy via macrophages.

Tumor-associated macrophages are highly versatile effector cells that have been used to kill tumor cells. Herein, the macrophages as cell-based biocarriers are used for the targeted delivery of photothermal reagents for promoting the efficiency of killing tumor cells by activating the anti-tumor immune response and photothermal therapy (PTT). In this design, macrophages cause the phagocytosis of tumor cells and activate the anti-tumor immune response by secreting plenty of cytokines. Meanwhile, to improve the tumor-killing effect and track the collaborative therapy system in vivo, a novel nanoplatform based on tungsten oxide (W18O49, WO) nanoparticles and fluorescent dyes loaded in polylactic-co-glycolic acid (PLGA) for PTT has been successfully constructed. Subsequently, the nanoparticles are swallowed by macrophages acting as cell-based biocarriers to target the tumor and promote solid tumor ablation in vivo in animal experiments. This system is expected to bring a huge application potential in the visually guided dual-modal therapeutic platform for tumor targeting therapy in vivo.

Near-Infrared Light Triggered Upconversion Optogenetic Nanosystem for Cancer Therapy.

In vivo the application of optogenetic manipulation in deep tissue is seriously obstructed by the limited penetration depth of visible light that is continually applied to activate a photoactuator. Herein, we designed a versatile upconversion optogenetic nanosystem based on a blue-light-mediated heterodimerization module and rare-earth upconversion nanoparticles (UCNs). The UCNs worked as a nanotransducer to convert external deep-tissue-penetrating near-infrared (NIR) light to local blue light to noninvasively activate photoreceptors for optogenetic manipulation in vivo. In this, we demonstrated that deeply penetrating NIR light could be used to control the apoptotic signaling pathway of cancer cells in both mammalian cells and mice by UCNs. We believe that this interesting NIR-light-responsive upconversion optogenetic nanotechnology has significant application potentials for both basic research and clinical applications in vivo.

A visual guide to gene/optothermal synergy therapy nanosystem using tungsten oxide.

Combination of gene therapy and photothermal therapy (PTT) has drawn much attention in cancer therapy in recent years. However, this joint treatment process lacks fluorescence imaging visualization guidance that limits its clinical applications in oncotherapy. Herein, we report the use of gene therapy and tungsten oxide (W18O49, WO) synthetized with template method for combined PTT of cancer. In this system, a novel nanoplatform, with Bax gene, WO and indocyanine green (ICG) loaded in mesoporous silica nanoparticle had been successfully constructed, which was used as the near-infrared imaging-guided gene/optothermal multi-modal oncotherapy. These nanoparticles could achieve a synergistic therapy effect of gene therapy and PTT for tumor under 808nm near-infrared (NIR) laser excitation. In vivo animal experiments showed that they could cause solid tumor regression under 808nm NIR light irradiation, revealing the potential of these nanocomposites as a fluorescence imaging-guided multi-modal therapeutic nanosystem for tumor visual synergistic treatment.

Near-infrared persistent luminescence phosphors ZnGa2O4:Cr3+ as an accurately tracker to photothermal therapy in vivo for visual treatment.

The photothermal therapy agents induced by 808 nm near infrared light laser have good potential for photothermal therapy (PTT) in vivo, with the advantages of harmless treatment, minimally invasion, high efficiency and deep tissue penetration. For the traditional photothermal therapy agents, however, it was impossible to track them in vivo because of the low signal-to-noise ratio, so we cannot conduct the extra near infrared light laser to radiate tumors sites accurately. Herein, we introduce a new complex: indocyanine green (ICG), near-infrared persistent luminescence (PL) phosphors ZnGa2O4:Cr3+ (ZGC) and mesoporous silica nanoparticles (MSNs) (ICG@mZGC nanoparticles) were assembled for long-lasting optical imaging to guide PTT. The results revealed that the novel nanoparticle, ICG@mZGC, could lower signal-to-noise ratio, enable highly sensitive optical detection during optical imaging-guided PTT and perform a good effect of photothermal therapy in vivo, and thus providing possibilities for mZGC to improve the localization precision of tumor sites in photothermal therapy in the body.