Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research.

Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients' tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method for determination of phytohormones in the medicinal plant saffron.

Saffron (Crocus sativus L.) is a valuable Chinese herb with high medicinal value. Saffron pistils are used as medicine, so increasing the number of flowers can increase the yield. Plant hormones have essential roles in the growth and development of saffron, as well as the response to biotic and abiotic stresses (especially in floral initiation), which may directly affect the number of flowers. Quantitative analysis of plant hormones provides a basis for more efficient research on their synthesis, transportation, metabolism, and action. However, starch (which interferes with extraction) is present in high levels, and hormone levels are extremely low, in saffron corms, thereby hampering accurate determination of plant-hormone levels in saffron. Herein, we screened an efficient and convenient pre-treatment method for plant materials containing abundant amounts of starch. Also, we proposed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of abscisic acid (ABA) and auxin (IAA). Then, the method was applied for the detection of hormone-content differences between flowering and non-flowering top buds, as well as between lateral and top buds. Our method showed high sensitivity, reproducibility, and reliability. Specifically, good linearity in the range 2-100 ng ml-1 was achieved in the determination of ABA and IAA, and the correlation coefficient (R2) was >0.9982. The relative standard deviation was 2.956-14.51% (intraday) and 9.57-18.99% (interday), and the recovery range was 89.04-101.1% (n = 9). The matrix effect was 80.38-90.50% (n = 3). The method was thoroughly assessed employing various "green" chemistry evaluation tools: Blue Applicability Grade Index (BAGI), Complementary Green Analytical Procedure Index (Complex GAPI) and Red Green Blue 12 Algorithm (RGB12). These tools revealed the good greenness, analytical performance, applicability, and overall sustainability alignment of our method. Quantitative results showed that, compared with saffron with a flowering phenotype cultivated at 25 °C, the contents of IAA and ABA in the terminal buds of saffron cultivated at 16 °C decreased significantly. When cultivated at 25 °C, the IAA and ABA contents in the terminal buds of saffron were 1.54- and 4.84-times higher than those in the lateral buds, respectively. A simple, rapid, and accurate UPLC-MS/MS method was established to determine IAA and ABA contents. Using this method, a connection between the contents of IAA and ABA and the flowering phenotype was observed in the quantification results. Our data lay a foundation for studying the flowering mechanism of saffron.

The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism.

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.

Electrically controllable optical switch metasurface based on vanadium dioxide.

We report a voltage-tunable reflective gold wire grid metasurface on vanadium dioxide thin film, which consists of a metal-insulator-metal (MIM) structure. We excite surface plasmon polariton (SPP) modes on the gold surface by fabricating a one-dimensional structured gold wire grid. Joule heating of laser-induced graphene (LIG) can be controlled by the voltage at the bottom, allowing vanadium dioxide in the structure to complete the transition from the insulating state to the metallic state. The phase transition of vanadium dioxide strongly disrupts the plasmon modes excited by the gold wire grid above, thereby realizing a huge change in the reflection spectrum. This acts as a tunable metasurface optical switch with a maximum modulation depth (MD) of over 20 dB. We provide a more effective and simple method for creating tunable metasurfaces in the near-infrared band, which can allow metasurfaces to have wider applications in optical signal processing, optical storage, and holography.

Fano-Like Resonance of Heat-Reconfigurable Silicon Grating Metasurface Tuned by Laser-Induced Graphene.

We propose a heat-reconfigurable metasurface composed of the silicon-based gold grating. The asymmetric Fano-like line shape is formed due to the mutual coupling of the local surface plasmon (LSP) in the gap between the two layers of Au gratings and the surface propagating plasmon (SPP) on the surface of the Au gratings. Then, we effectively regulate the Fano resonance by applying a bias voltage to laser-induced graphene (LIG), to generate Joule heat, so that the resonant dip of one mode of the Fano resonance can shift up to 28.5 nm. In contrast, the resonant dip of the other mode barely changes. This effectively regulates the coupling between two resonant modes in Fano resonance. Our study presents a simple and efficient method for regulating Fano-like interference in the near-infrared band.

Analysis of Clinical Characteristics, Treatment, and Prognostic Factors of 106 Breast Cancer Patients With Solitary Pulmonary Nodules.

OBJECTIVE: The clinical features of solitary pulmonary nodules (SPN) in breast cancer patients were retrospectively analyzed, and the clinical features of primary lung cancer (PLC) and metastatic pulmonary breast cancer (MBC) in breast cancer patients were compared, and the treatment plan, curative effect and influencing factors were analyzed. METHODS: The clinical data of 106 patients of SPN combined with breast cancer surgery in our hospital from January 2015 to June 2020 were analyzed. There were 65 patients of PLC and 41 patients of MBC. Record the characteristics of the primary breast cancer lesion in our patient, the interval between the initial diagnosis of breast cancer and the appearance of SPN, the previous treatment history of our patient, and the characteristics and surgical method of SPN. The survival status of all patients during the follow-up period was recorded. RESULTS: The onset age, interval, maximum nodule diameter, ER expression positive rate and radiotherapy history ratio of PLC patients were higher than those of MBC patients, and the lymph node positive rate and triple negative rate were lower than those of MBC patients (P < 0.05). Median survival was 51 months in patients with PLC and 37 months in patients with MBC. The 1, 3, and 5 year overall survival rates in patients with PLC were higher than those in patients with MBC (P < 0.05). Vascular tumor thrombus, SPN type and chemotherapy were all independent factors affecting the prognosis of patients with breast cancer combined with SPN (P < 0.05). CONCLUSION: PLC patients and MBC patients have significant differences in pathological characteristics, like the onset age, interval, maximum nodule diameter, ER expression positive rate, radiotherapy history ratio, the lymph node positive rate, and triple negative rate. Septum, vascular tumor thrombus, SPN type, and chemotherapy are all independent factors that affect the curative effect of breast cancer patients with SPN. Based on the nature of SPN, it can provide reference for clinicians to decide the treatment plan, improve patients' quality of life and prolong their survival time.

lncRNA PVT1 promotes cetuximab resistance of head and neck squamous cell carcinoma cells by inhibiting miR-124-3p.

BACKGROUND: Cetuximab has been widely used in the clinical treatment of head and neck squamous cell carcinoma (HNSCC). However, whether long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) is correlated with cetuximab resistance remains unclear. METHODS: Western blot and qRT-PCR were performed to quantify the levels of genes and proteins, respectively. Cell functions were measured using Cell Counting Kit-8 (CCK-8), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry assays. The methylation level was tested using methylation-specific PCR (MSP). RESULTS: PVT1 was upregulated and positively correlated with the poor prognosis of HNSCC. PVT1 overexpression markedly promoted the survival and weakened the cetuximab sensitivity of HNSCC cells, while miR-124-3p overexpression showed opposite effects. Mechanistically, the silence of PVT1 indirectly promoted miR-124-3p expression by reducing its promoter methylation. Importantly, miR-124-3p overexpression impeded the regulatory roles of PVT1 overexpression. CONCLUSION: PVT1 decreased the sensitivity of HNSCC cells to cetuximab by enhancing methylation-mediated inhibition of miR-124-3p, which might provide a new insight for the cetuximab chemoresistance of HNSCC.

High performance polypyrrole/SWCNTs composite film as a promising organic thermoelectric material.

Conducting polymer thermoelectric (TE) materials have received great attention due to their unique properties. In this work, polypyrrole (PPy)/single-walled carbon nanotubes (SWCNTs) composite films with improved TE performance have been prepared by chemical interfacial polymerization at the cyclohexane/water interface under a controlled temperature. Attributed to the smooth surface, higher conjugation length and more ordered molecular structure of the interfacial polymerized PPy film, the electrical conductivity can be as high as ∼500 S cm-1. To further enhance the TE properties of PPy, SWCNT was added to construct a PPy/SWCNTs composite. Due to the synergistic effect between the two phases and the energy filtering effect at the interfaces between PPy and SWCNTs, the Seebeck coefficient of the composite enhanced significantly with the increase SWCNTs content. The composite shows an optimal power factor of 37.6 ± 2.3 µW mK-2 when the content of SWCNTs is 0.8 mg. This value is one of the largest values among the reported PPy based composites fabricated by the chemical polymerization method. The results indicate that interfacial polymerization under a controlled temperature is a promising way to improve the TE performance of conducting polymer based composite materials.

Upregulated C-C Motif Chemokine Ligand 2 Promotes Ischemic Stroke via Chemokine Signaling Pathway.

BACKGROUND: This study aims to evaluate the potential effect and the underlying mechanism of C-C motif chemokine ligand 2 (CCL2) in ischemic stroke. METHODS: An integrated bioinformatics analysis was performed to identify the differentially expressed (DE) genes and their related pathways in ischemic stroke. In vivo study of a rat model of middle cerebral artery occlusion (MCAO) was further established to assess the effect of CCL2 on severity of neurologic impairments. The expression levels of proinflammatory cytokines were also evaluated using the ELISA assay, and Western blot was also used to determine the expression of CCL2 and other DE proteins in the related pathways. RESULTS: A total of 88 DE genes were identified from the microarray dataset of ischemic stroke. The bioinformatics analysis revealed that CCL2 was highly expressed in ischemic stroke tissue and promoted the ischemic stroke progression via activation of the chemokine signaling pathway and cytokine-cytokine receptor interaction pathway. The in vivo study of the ischemic stroke rat model also showed that the CCL2 expression was elevated in the MCAO/R rats, with significant neurological impairments and ischemic infarct area in the brain tissue being observed. The administration of CCL2 inhibitors significantly inhibited the inflammatory response, attenuated the neurological impairments, and decreased the ischemic infarct area in the MCAO/R rats. Furthermore, the downregulation of CCL2 also inhibited the expression of the pathway-related proteins including CCL7, CCR2, CXCL16, and TNF-α. CONCLUSIONS: These results indicate that the CCL2/chemokine signaling pathway is responsible for ischemic stroke progression and might represent a potential therapeutic target for ischemic stroke treatment.

Integrated Analysis of mRNA-miRNA-lncRNA ceRNA Network in Human HR+/Her-2- Breast Cancer and Triple Negative Breast Cancer.

Breast cancer is a heterogeneous disease highly diverse in different subtypes, including hormone receptor positive and hormone receptor negative subtypes with variable malignancy, therapy regimen, and different prognosis. In this study, we develop a hormone receptor-specific mRNA-miRNA-lncRNA ceRNA network to identify whether several RNAs play fundamental roles in development and metastasis of breast cancer. To understand the association of ceRNA expression profiles in different breast cancer subgroups, the expression profiles and clinical information of 428 HR+/Her-2- breast cancer samples and 113 triple negative breast cancer samples were downloaded from The Cancer Genome Atlas database (TCGA). We comprehensively integrated and compared expression profiles of mRNAs, miRNAs, and lncRNAs between the two subgroups mentioned. Aberrantly expressed hormone receptor specific RNAs were identified, whereas lncRNA-miRNA interactions predicted by miRcode and miRNA-targeted mRNA interactions were validated by miRTarBase, Targetscan, and miRDB database. In this study, mRNA-miRNA-lncRNA ceRNA network was constructed that consisted of 44 miRNA-lncRNA interaction pairs and 2 miRNA-mRNA interaction pairs, and visualized by Cytoscape software. Prognostic markers of HR-specific subtype of breast cancer associated with overall survival were identified by Kaplan-Meier survival analysis. Finally, SFRP1, AC006449.1, and MUC2 were novel clinical predictors that may also provide a new therapeutic target in the future.

Erythropoietin Attenuates Cardiac Dysfunction in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Diabetic Cardiomyopathy.

PURPOSE: Enhanced endoplasmic reticulum (ER) stress and down-regulated SERCA2a expression play crucial roles in diabetes. We aimed to verify whether erythropoietin (EPO) attenuates cardiac dysfunction by suppressing ER stress in diabetic rats. METHODS: Forty male SD rats were randomly divided into four groups: control, EPO-treated control, vehicle-treated diabetic, and EPO-treated diabetic groups. The animals in the EPO-treated control and diabetic groups were administered recombinant human EPO (1000 U/kg body weight) once per week for 12 weeks. RT-PCR and Western blotting assays were performed to detect the expression of 78-kDa glucose-regulated protein precursor (GRP78) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). We cultured neonatal rat cardiomyocytes and investigated the protective effects of EPO against high glucose (HG)-induced apoptosis. Intracellular calcium levels were measured through confocal microscopy. RESULTS: We observed increased myocardial GRP78 expression and decreased myocardial SERCA2a expression in diabetic rats. EPO prevented the changes in GRP78, SERCA2a expression and cardiac dysfunction in diabetic rats. The levels of GRP78 protein were significantly reduced in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (GRP78 protein 0.09 ± 0.03 vs. 0.54 ± 0.04, P < 0.01). The levels of the SERCA2a proteins were significantly increased in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (SERCA2a protein 0.60 ± 0.05 vs. 0.13 ± 0.04, P < 0.01). A reduction in apoptosis was observed in the cardiomyocytes treated with 20 U/mL EPO compared with the cardiomyocytes cultured under HG conditions (apoptosis rate 18.9 ± 1.94 vs. 37.9 ± 1.59%, P < 0.01). CONCLUSIONS: This study demonstrates that EPO treatment improved the parameters of cardiac function following HG-induced injury by suppressing ER stress and inducing SERCA2a expression.

[Treatment of moderate-grade and high-grade malignant lymphoma with autologous hematopoietic stem cell transplantation].

BACKGROUND & OBJECTIVE: High dose chemotherapy (HDCT) supported by autologous hematopoietic stem cell transplantation (ASCT) is one of the most effective approaches for the chemo-sensitive lymphoma. The purpose of this study was to investigate the effectiveness of HDCT combined with radiotherapy supported by HSCT in treatment of poor- prognostic moderate-grade and high-grade malignant lymphoma. METHODS: Eleven patients [11 cases of non-Hodgkin's lymphoma (NHL) and 2 cases of recurrent Hodgkin's lymphoma (HD)] were enrolled from December 1995 to May 2001. Status on ASCT was 8 cases with 1st complete remission (CR(1)), 4 cases with second complete remission (CR2), 1 case with second partial remission (PR2). The preparative regimens consisted of HDCT alone (4 patients), HDCT with involved-field (IF) radiotherapy (6 patients), total body irradiation (TBI) with HDCT (3 patients). Two patients were supported by bone marrow transplantation (ABMT) and 11 by autologous peripheral blood stem cell transplantation (APBSCT). RESULTS: The numbers of mono-nuclear cell (MNC) and granulocyte- macrophage colony-forming cells (CFU-GM) reinfused were 2.55 (range, 2.07-3.31) x 10(9)/L, 1.43 (range, 0.6-2.36) x 10(9)/L in this study, respectively. Hematopoietic reconstitution was observed in all patients when they were followed-up on October 2001. WBC>or=1.0 x 10(9)/L and Platelet >50 x 10(9)/L were at day 6 (range,7-35) and day 8 (range,6-32), respectively. The median CR duration was 16 months (range, 4-57 months). The 1- and 3-year survival rates were 76.9% and 46.2%, respectively. CONCLUSION: HDCT with ASCT is valuable to treatment in patients with chemo-sensitive moderate-grade and high-grade NHL and recurrent HD.