Fluorescent Pdots Facilitate High-Resolution Mapping of the Intact Meningeal Vascular Network and Eye-Brain Connections.

Meningeal vascular network is significant in neurology and neurosurgery. However, high-resolution imaging of intact meningeal vascular network is lacking. In this work, we develop a practical experimental method to ensure that the intact meninges are morphologically unfolded and fixed in an agarose gel. With the help of high-brightness polymer dots (Pdots) as probe, macroscopic and detailed imaging of the vascular network on the intact dorsal meninges can be performed. Meningeal vessels are symmetrically distributed along the superior sagittal sinus, and the distribution of meningeal vessels had a certain degree of hierarchy. The meninges are thicker blood vessels and capillary networks from the outside to the inside. Moreover, the diameter of the capillaries is 3.96 ± 0.89 µm. Interestingly, meningeal primo vessels in the central nervous system of mice is imaged with the diameter of 4.18 ± 1.18 µm, which has not been reported previously. It is worth mentioning that we found that orthotopic xenografts of brain tumors caused the appearance of corneal neovascularization and morphological changes in optic nerve microvessels. In conclusion, our work provides an effective Pdots-based imaging method for follow-up research on meningeal vascular-related diseases, and illustrates that the eye can serve as a window for the prevention and diagnosis of brain diseases.

Glymphatic function and its influencing factors in different glucose metabolism states.

BACKGROUND: Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized. AIM: To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states, the present study employed diffusion tensor imaging along the perivascular space (DTI-ALPS) index. METHODS: Sample size was calculated using the pwr package in R software. This cross-sectional study enrolled 22 patients with normal glucose metabolism (NGM), 20 patients with prediabetes, and 22 patients with type 2 diabetes mellitus (T2DM). A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system. The mini-mental state examination (MMSE) was used to assess general cognitive function. The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated. Further, the correlation between DTI-ALPS and clinical features was assessed. RESULTS: The left-side, right-side, and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group. The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group. DTI-ALPS index lateralization was not observed. The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group. After controlling for sex, the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level; the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level. The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group. The left-side, right-side, and mean DTI-ALPS index in the T2DM group were positively correlated with height. The left-side and mean DTI-ALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels. CONCLUSION: Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage. Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states. This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis.

Bulk and single-cell transcriptome reveal the immuno-prognostic subtypes and tumour microenvironment heterogeneity in HCC.

BACKGROUND & AIMS: Accumulating evidences suggest tumour microenvironment (TME) profoundly influence clinical outcome in hepatocellular carcinoma (HCC). Existing immune subtypes are susceptible to batch effects, and integrative analysis of bulk and single-cell transcriptome is helpful to recognize immune subtypes and TME in HCC. METHODS: Based on the relative expression ordering (REO) of 1259 immune-related genes, an immuno-prognostic signature was developed and validated in 907 HCC samples from five bulk transcriptomic cohorts, including 72 in-house samples. The machine learning models based on subtype-specific gene pairs with stable REOs were constructed to jointly predict immuno-prognostic subtypes in single-cell RNA-seq data and validated in another single-cell data. Then, cancer characteristics, immune landscape, underlying mechanism and therapeutic benefits between subtypes were analysed. RESULTS: An immune-related signature with 29 gene pairs stratified HCC samples individually into two risk subgroups (C1 and C2), which was an independent prognostic factor for overall survival. The machine learning models verified the immune subtypes from five bulk cohorts to two single-cell transcriptomic data. Integrative analysis revealed that C1 had poorer outcomes, higher CNV burden and malignant scores, higher sensitivity to sorafenib, and exhibited an immunosuppressive phenotype with more regulators, e.g., myeloid-derived suppressor cells (MDSCs), Mø_SPP1, while C2 was characterized with better outcomes, higher metabolism, more benefit from immunotherapy, and displayed active immune with more effectors, e.g., tumour infiltrating lymphocyte and dendritic cell. Moreover, both two single-cell data revealed the crosstalk of SPP1-related L-R pairs between cancer and immune cells, especially SPP1-CD44, might lead to immunosuppression in C1. CONCLUSIONS: The REO-based immuno-prognostic subtypes were conducive to individualized prognosis prediction and treatment options for HCC. This study paved the way for understanding TME heterogeneity between immuno-prognostic subtypes of HCC.

No Difference in Reintervention at 1-Year Between Ultrasound-Guided versus Blind Dorsal Carpal Ganglion Aspiration.

Purpose: The purpose of this retrospective comparative study was to compare the efficacy of dorsal carpal ganglion aspiration in patients who underwent either "blind" (using surface anatomy alone) or ultrasound-guided (US-guided) aspiration. Methods: Outcome measures were conducted during the coronavirus disease 2019 pandemic via telephone for a minimum of 12 months after aspiration, with efficacy defined by reintervention with either repeat aspiration or surgical excision. Results: Data are reported for 141 patients (46 blind; 95 US-guided) at an average of 28 months (range, 12-55 months) from aspiration. Reintervention was not significantly different based on the mode of aspiration-26% and 24% for blind aspiration and US-guided, respectively. Patient-perceived recurrence was higher at 65% for the entire cohort. Patients who received steroid injection at the time of aspiration perceived lower rates of recurrence-44% versus 77% for patients who received a steroid injection and patients who did not, respectively. Conclusions: This study found no significant difference between blind or US-guided aspiration in reintervention at a minimum of 1-year follow-up. Patients who received steroids at the time of aspiration perceived lower rates of recurrence. Type of study/level of evidence: Therapeutic III.

Health as expanding consciousness: Change of psychological situation in nursing students.

AIM: This study aims to explore the mind of Chinese nursing students transitioning to online education in the pandemic using health as expanding consciousness (HEC) as methodology. DESIGN: A qualitative, descriptive study based on interviews. METHODS: This qualitative study was conducted from September to November 2021 by students in the Guangzhou university of Chinese medicine. Thirteen participants were recruited using purposive sampling. A questionnaire containing two sections with demographic information, the General Self-Efficacy Scale (GSES) and the Connor-Davidson resilience scale (CD-RISC)-10 was collected to explore the health of participants. RESULTS: A total of 13 participants were enrolled in the study (69% female). Students ranged in age between 19 and 24 years and the mean age was 22 years. All students lived with their families. Five participants (38%) had a master's degree in nursing, three (23%) were in fourth year of college, four (30%) were in third year of college and one (7%) was in their second year of college respectively. More than half of the participants had high levels of mental toughness and self-efficacy. Four generic categories were identified form a unitary-transformative paradigm perspective. The respondents reported three health pattern phases: Curriculum Transformation, Curriculum adaptation and Curriculum expansion. CONCLUSION: This research backs up Newman's hypothesis, and supports the theoretical framework. HEC explains well the psychology of nursing students during the epidemic. More research is needed in the future to develop comprehensive, targeted emotional regulation therapies for nursing students.

Microbiome analysis reveals universal diagnostic biomarkers for colorectal cancer across populations and technologies.

The gut microbial dysbiosis is a risk of colorectal cancer (CRC) and some bacteria have been reported as potential markers for CRC diagnosis. However, heterogeneity among studies with different populations and technologies lead to inconsistent results. Here, we investigated six metagenomic profiles of stool samples from healthy controls (HC), colorectal adenoma (CA) and CRC, and six and four genera were consistently altered between CRC and HC or CA across populations, respectively. In FengQ cohort, which composed with 61 HC, 47 CA, and 46 CRC samples, a random forest (RF) model composed of the six genera, denoted as signature-HC, distinguished CRC from HC with an area under the curve (AUC) of 0.84. Similarly, another RF model composed of the four universal genera, denoted as signature-CA, discriminated CRC from CA with an AUC of 0.73. These signatures were further validated in five metagenomic sequencing cohorts and six independent 16S rRNA gene sequencing cohorts. Interestingly, three genera overlapped in the two models (Porphyromonas, Parvimonas and Peptostreptococcus) were with very low abundance in HC and CA, but sharply increased in CRC. A concise RF model on the three genera distinguished CRC from HC or CA with AUC of 0.87 and 0.67, respectively. Functional gene family analysis revealed that Kyoto Encyclopedia of Genes and Genomes Orthogroups categories which were significantly correlated with markers in signature-HC and signature-CA were mapped into pathways related to lipopolysaccharide and sulfur metabolism, which might be vital risk factors of CRC development. Conclusively, our study identified universal bacterial markers across populations and technologies as potential aids in non-invasive diagnosis of CRC.

Tumor oxygenation nanoliposome synergistic hypoxia-inducible-factor-1 inhibitor enhanced Iodine-125 seed brachytherapy for esophageal cancer.

Iodine-125 (125I) brachytherapy has become one of the most effective palliative treatment options for advanced esophageal cancer. However, resistance toward 125I brachytherapy caused by pre-existing tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) signaling pathway activation represents a significant limitation in esophageal cancer treatment. To circumvent these problems, herein, we proposed an innovative strategy to alleviate radioresistance of brachytherapy by co-encapsulating catalase (CAT) and HIF-1 inhibitor-acriflavine (ACF) into the hydrophilic cavities of liposome, termed as "ACF-CAT@Lipo". Under overexpressed H2O2 stimulation in the tumor region, the fabricated ACF-CAT@Lipo can generate an amount of O2 and alleviate tumor hypoxia in vitro and in vivo. Furthermore, cooperating with ACF, the expression of hypoxia-related protein (e.g. HIF-1α, VEGF, MMP-2) are obviously decreased. Importantly, the copious oxygenation and the significant inhibition expression of HIF-1α can further improve the radiosensitivity of 125I brachytherapy and finally realize the eradication of esophageal cancer in vivo. The oxygen enrichment and HIF-1 inhibition function of ACF-CAT@Lipo provides a new strategy to overcome the brachytherapy resistance of esophageal cancer therapy.

High-Resolution Imaging of the Ocular Vasculature of Conjunctivitis in Mice Using Highly Bright Polymer Dots.

Ocular diseases are mainly caused by vascular aberrations in the eye, and accurate imaging and analysis of the ocular vascular structure is crucial. In this study, poly(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT) polymer dots (Pdots), with the advantages of easy synthesis, high brightness, and low toxicity, are used as nanoprobes to perform high-resolution imaging of the vasculature of the eyeball and optic nerve. Moreover, rapid imaging of the choroidal microvessels is carried out by stereoscopic fluorescence microscopy with a resolution of up to 1.6 µm. The comprehensive 3D vascular information of retinal aorta and optic nerve microvessels is obtained by combining tissue clearing and multiphoton microscopy. In addition, the vascular density of Schlemm's canal and iris blood vessels is compared between the conjunctivitis mice and the normal mice. These results suggest that PFBT Pdots have great application potential in the fast and accurate imaging of ocular diseases.

Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.

Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O2) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnOx NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnOx NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen (1O2). Moreover, MnOx NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis. Consequently, this combined strategy based on coadministration with Cyan and MnOx NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.

Metabolism-Related Gene Pairs to Predict the Clinical Outcome and Molecular Characteristics of Early Hepatocellular Carcinoma.

Recurrence is the main factor affecting the prognosis of early hepatocellular carcinoma (HCC), which is not accurately evaluated by clinical indicators. The metabolic heterogeneity of HCC hints at the possibility of constructing a stratification model to predict the clinical outcome. On the basis of the relative expression orderings of 2939 metabolism-related genes, an individualized signature with 10 metabolism-related gene pairs (10-GPS) was developed from 250 early HCC samples in the discovery datasets, which stratified HCC patients into the high- and low-risk subgroups with significantly different survival rates. The 10-GPS was validated in 311 public transcriptomic samples from two independent validation datasets. A nomogram that included the 10-GPS, age, gender, and stage was constructed for eventual clinical evaluation. The low-risk group was characterized by lower proliferation, higher metabolism, increased activated immune microenvironment, and lower TIDE scores, suggesting a better response to immunotherapy. The high-risk group displayed hypomethylation, higher copy number alterations, mutations, and more overexpression of immune-checkpoint genes, which might jointly lead to poor outcomes. The prognostic accuracy of the 10-GPS was further validated in 47 institutional transcriptomic samples and 101 public proteomic samples. In conclusion, the 10-GPS is a robust predictor of the clinical outcome for early HCC patients and could help evaluate prognosis and characterize molecular heterogeneity.

Multifunctional Imaging of Vessels, Brown Adipose Tissue, and Bones in the Visible and Second Near-infrared Region Using Dual-Emitting Polymer Dots.

Dual-emitting polymer dots (dual-Pdots) in the visible and second near-infrared (NIR-II) region can facilitate the high-resolution imaging of the fine structure and improve the signal-to-noise ratio in in vivo imaging. Herein, combining high brightness of Pdots and multi-scale imaging, we synthesized dual-Pdots using a simple nano-coprecipitation method and performed multi-functional imaging of vessels, brown adipose tissue, and bones. Results showed that in vivo blood vessel imaging had a high resolution of up to 5.9 µm and bone imaging had a signal-to-noise ratio of 3.9. Moreover, dual-Pdots can accumulate in the interscapular brown adipose tissue within 2 min with a signal-to-noise ratio of 5.8. In addition, the prepared dual-Pdots can image the lymphatic valves and the frequency of contraction. Our study provides a feasible method of using Pdots as nanoprobes for multi-scale imaging in the fields of metabolic disorders, skeletal system diseases, and circulatory systems.

Imaging of fluorescent polymer dots in relation to channels and immune cells in the lymphatic system.

Polymer dots (Pdots) have been applied to imaging lymph nodes (LNs) and lymphatic vessels (LVs) in living mice and rats. However, the mechanism of absorption, distribution, metabolism, and excretion of Pdots in LNs and LVs is still unclear. Therefore, the relationship between Pdots and immune cells, LVs and collagen fibers in lymphatics was studied by multiple in vivo and ex vivo microscopic imaging methods and detection techniques. Flow cytometry showed that Pdots could be phagocytosed by macrophages and monocytes, and had no relationship with B cells, T cells and dendric cells in LNs. Silver staining, immunofluorescence and two-photon microscope showed that Pdots gathered in collagen fibers and LVs of LNs. Furthermore, immunofluorescence imaging results verified that Pdots were distributed in the extracellular space of collecting LVs endothelial cells. In addition, Pdots in the collecting LVs were basically cleared by leaking into the surrounding tissue or draining LNs after 21 days of injection. During the long-time observation, Pdots also helped monitor the contraction frequency and variation range of LV. Our study lays a foundation on the research of Pdots as the carrier to study lymphatic structure and function in the future.

Long Non-Coding RNA PNKY Modulates the Development of Choroidal Neovascularization.

Long non-coding RNAs (lncRNAs) have been widely implicated in human diseases. Our aim was to explore the regulatory role of changes in the expression levels of PNKY and its linked signaling networks in mediating stress-induced choroidal neovascularization. PNKY expression levels were reduced in mice by laser and exposure of endothelial cell to hypoxic stress. PNKY silencing exacerbated the formation of CNV in a laser-induced CNV model and an ex vivo model, while overexpression inhibited CNV development. Silencing or overexpression of PNKY altered the viability, proliferation, migration, and tube-forming capacity of endothelial cells in vitro. Mechanistically, through the lncRNA-RNA binding protein-miRNA interaction analysis involving loss of function and gain-of-function experiments, we found that lncRNA PNKY inhibited the binding of miR124 to PTBP1 and maintained the homeostasis of choroidal vascular function by promoting Bcl-2 like protein 11 (BIM), and its dysfunction led to exacerbation of CNV lesion. Therefore, this study suggests that the lncPNKY/PTBP1-miR-124 axis is involved in regulating the development of CNV, providing a potential therapeutic target for the treatment of CNV.

Preoperative MRI-based vertebral bone quality (VBQ) score assessment in patients undergoing lumbar spinal fusion.

BACKGROUND CONTEXT: The importance of bone status assessment in spine surgery is well recognized. The current gold standard for assessing bone mineral density is dual-energy X-ray absorptiometry (DEXA). However, DEXA has been shown to overestimate BMD in patients with spinal degenerative disease and obesity. Consequently, alternative radiographic measurements using data routinely gathered during preoperative evaluation have been explored for the evaluation of bone quality and fracture risk. Opportunistic quantitative computed tomography (QCT) and more recently, the MRI-based vertebral bone quality (VBQ) score, have both been shown to correlate with DEXA T-scores and predict osteoporotic fractures. However, to date the direct association between VBQ and QCT has not been studied. PURPOSE: The objective of this study was to evaluate the correlation between VBQ and spine QCT BMD measurements and assess whether the recently described novel VBQ score can predict the presence of osteopenia/osteoporosis diagnosed with QCT. STUDY DESIGN/SETTING: Cross-sectional study using retrospectively collected data. PATIENT SAMPLE: Patients undergoing lumbar fusion from 2014-2019 at a single, academic institution with available preoperative lumbar CT and T1-weighted MRIs were included. OUTCOME MEASURES: Correlation of the VBQ score with BMD measured by QCT, and association between VBQ score and presence of osteopenia/osteoporosis. METHODS: Asynchronous QCT measurements were performed. The average L1-L2 BMD was calculated and patients were categorized as either normal BMD (>120 mg/cm3) or osteopenic/osteoporotic (≤120 mg/cm3). The VBQ score was calculated by dividing the median signal intensity of the L1-L4 vertebral bodies by the signal intensity of the cerebrospinal fluid on midsagittal T1-weighted MRI images. Inter-observer reliability testing of the VBQ measurements was performed. Demographic data and the VBQ score were compared between the normal and osteopenic/osteoporotic group. To determine the area-under-curve (AUC) of the VBQ score as a predictor of osteopenia/osteoporosis receiver operating characteristic (ROC) analysis was performed. VBQ scores were compared with QCT BMD using the Pearson's correlation. RESULTS: A total of 198 patients (53% female) were included. The mean age was 62 years and the mean BMI was 28.2 kg/m2. The inter-observer reliability of the VBQ measurements was excellent (ICC of 0.90). When comparing the patients with normal QCT BMD to those with osteopenia/osteoporosis, the patients with osteopenia/osteoporosis were significantly older (64.9 vs. 56.7 years, p<.0001). The osteopenic/osteoporotic group had significantly higher VBQ scores (2.6 vs. 2.2, p<.0001). The VBQ score showed a statistically significant negative correlation with QCT BMD (correlation coefficient = -0.358, 95% CI -0.473 - -0.23, p<.001). Using a VBQ score cutoff value of 2.388, the categorical VBQ score yielded a sensitivity of 74.3% and a specificity of 57.0% with an AUC of 0.7079 to differentiate patients with osteopenia/osteoporosis and with normal BMD. CONCLUSIONS: We found that the VBQ score showed moderate diagnostic ability to differentiate patients with normal BMD versus osteopenic/osteoporotic BMD based on QCT. VBQ may be an interesting adjunct to clinically performed bone density measurements in the future.

Research on the synthesis of nanoparticles of betulinic acid and their targeting antitumor activity.

Betulinic acid (BA), a natural pentacyclic lupine-type triterpene, has shown its prominent efficiency on the selective antitumor activity. However, its poor water solubility and bioavailability have limited its application. Herein, targeting nanoparticles were prepared to improve BA-based liposome (BL)'s restricted chemotherapeutic efficacy. Multi-layers membranes from the cancer cells were added as highly penetrative targeting ligands to functionalize the BA-based liposomes. In vitro experiments including the MTT assay and the fluorescence imaging of live/dead staining were adopted to prove its great inhibition in the growth of tumor cells. And it manifests that the antitumor efficacy of BL coated with cell membranes (BLCM) achieves nearly 4.3 times as that of BL under the same conditions in the MTT experiments. In addition, the fluorescence imaging stained with DAPI-FITC was applied to prove the targeting positioning effects on the BLCM. In a nutshell, the nanomedicine has good targeting antitumor efficacy and has great potential in being applied for the personalized cancer clinical treatment.

Study on the Multitarget Mechanism and Active Compounds of Essential Oil from Artemisia argyi Treating Pressure Injuries Based on Network Pharmacology.

In order to comprehensively explore multitarget mechanism and key active compounds of Artemisia argyi essential oil (AAEO) in the treatment of pressure injuries (PIs), we analyzed the biological functions and pathways involved in the intersection targets of AAEO and PIs based on network pharmacology, and the affinity of AAEO active compounds and core targets was verified by molecular docking finally. In our study, we first screened 54 effective components according to the relative content and biological activity. In total, 103 targets related to active compounds of AAEO and 2760 targets associated with PIs were obtained, respectively, and 50 key targets were overlapped by Venny 2.1.0. The construction of key targets-compounds network was achieved by the STRING database and Cytoscape 3.7.2 software. GO analysis from Matespace shows that GO results are mainly enriched in biological processes, including adrenergic receptor activity, neurotransmitter clearance, and neurotransmitter metabolic process. KEGG analysis by the David and Kobas website shows that the key targets can achieve the treatment on PIs through a pathway in cancer, PI3K-Akt signaling pathway, human immunodeficiency virus 1 infection, MAPK signaling pathway, Wnt signaling pathway, etc. In addition, molecular docking results from the CB-Dock server indicated that active compounds of AAEO had good activity docking with the first 10 key targets. In conclusion, the potential targets and regulatory molecular mechanisms of AAEO in the treatment of PIs were analyzed by network pharmacology and molecular docking. AAEO can cure PIs through the synergistic effect of multicomponent, multitarget, and multipathway, providing a theoretical basis and new direction for further study.

Integrated analysis of transcription factor-mRNA-miRNA regulatory network related to immune characteristics in medullary thyroid carcinoma.

Background: Medullary thyroid carcinoma (MTC), a thyroid C cell-derived malignancy, is poorly differentiated and more aggressive than papillary, follicular and oncocytic types of thyroid cancer. The current therapeutic options are limited, with a third of population suffering resistance. The differential gene expression pattern among thyroid cancer subtypes remains unclear. This study intended to explore the exclusive gene profile of MTC and construct a comprehensive regulatory network via integrated analysis, to uncover the potential key biomarkers. Methods: Multiple datasets of thyroid and other neuroendocrine tumors were obtained from GEO and TCGA databases. Differentially expressed genes (DEGs) specific in MTC were identified to construct a transcription factor (TF)-mRNA-miRNA network. The impact of the TF-mRNA-miRNA network on tumor immune characteristics and patient survival was further explored by single-sample GSEA (ssGSEA) and ESTIMATE algorithms, as well as univariate combined with multivariate analyses. RT-qPCR, cell viability and apoptosis assays were performed for in vitro validation. Results: We identified 81 genes upregulated and 22 downregulated in MTC but not in other types of thyroid tumor compared to the normal thyroid tissue. According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments. The 103 DEGs exclusively seen in MTC were involved in signal release, muscle contraction, pathways of neurodegeneration diseases, neurotransmitter activity and related amino acid metabolism, and cAMP pathway. Based on the identified 15 hub genes, a TF-mRNA-miRNA linear network, as well as REST-cored coherent feed-forward loop networks, namely REST-KIF5C-miR-223 and REST-CDK5R2-miR-130a were constructed via online prediction and validation by public datasets and our cohort. Hub-gene, TF and miRNA scores in the TF-mRNA-miRNA network were related to immune score, immune cell infiltration and immunotherapeutic molecules in MTC as well as in neuroendocrine tumor of lung and neuroblastoma. Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors. Conclusion: The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.

Preparation of carbon dots-based nanoparticles and their research of bioimaging and targeted antitumor therapy.

Carbon dots (CDs) are nanomaterials with excellent photoluminescence property, usually used in the field of bioimaging tumor cells. However, its practical applicability in cancer therapeutics is limited by CDs' insensitive surface properties to complicated tumor microenvironment in vivo. Herein, a new type of innovative biomimetic nanoparticles has been formed with HeLa cell membranes (CM) and multifunctional CDs containing antitumor and bioimaging activities. The CDs are prepared by a facile one-step microwave-assisted procedure. Gallic acid is used as carbon resource and antitumor active molecule. Gelatin is treated as the nitrogen resource. Citric acid monohydrate is used as the auxiliary carbon source and the Hela CM is used for tumor targeting. A series of fluorescence analyses has proved its homotypic targeting and ability of diagnosis. Besides, in vitro and in vivo antitumor experiments further indicate their better antitumor efficiency. The findings show the totally new nanoparticles' feasibilities of dealing with the clinical therapy problems as well as applying for the integration of diagnosis and targeting therapy.

Photosynthetic Oxygenation-Augmented Sonodynamic Nanotherapy of Hypoxic Tumors.

Reactive oxygen species (ROS) has been employed as a powerful therapeutic agent for eradicating tumor via oxidative stress. As an emerging ROS-involving noninvasive anticancer therapeutic modality, sonodynamic therapy (SDT) with high tissue penetration depth and benign remote spatiotemporal selectivity has been progressively utilized as the distinct alternative for ROS-based tumor treatment. However, the hypoxic tumor microenvironment substantially restricts the sonodynamic effect. In this work, an oxygen self-sufficient hybrid sonosensitizer on the basis of photosynthetic microorganisms cyanobacteria (Cyan) integrated with ultrasmall oxygen-deficient bimetallic oxide Mn1.4 WOx nanosonosensitizers, termed as M@C, is designed and engineered to overcome the critical issue of hypoxia-induced tumor resistance and strengthen the SDT effect. The sustained photosynthetic oxygen production by Cyan under light illumination can promote Mn1.4 WOx nanosonosensitizers to produce more ROS against cancer cells both in vitro and in vivo under ultrasound (US) irradiation. Especially, the sustained oxygen evolution for suppressing the gene expression of hypoxia-inducible factor 1alpha (HIF-1α) further boosts and augments the SDT efficiency. Thus, this work provides the paradigm that the rationally engineered biohybrid microorganism-based multifunctional sonosensitizers can serve as an effective bioplatform for augmenting the therapeutic efficiency of SDT, particularly for the treatment of hypoxic tumors.