From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma.

Multiple myeloma (MM), marked by abnormal proliferation of plasma cells and production of monoclonal immunoglobulin heavy or light chains in the majority of patients, has traditionally been associated with poor survival, despite improvements achieved in median survival in all age groups since the introduction of novel agents. Survival has significantly improved with the development of new drugs and new treatment options, such as chimeric antigen receptor T-cell therapy (CAR-T), which have shown promise and given new hope in MM therapy. CARs are now classified as first-, second-, and third-generation CARs based on the number of monovalent to trivalent co-stimulatory molecules incorporated into their design. The scope of this review was relatively narrow because it was mainly about a comparison of the literature on the clinical application of CAR-T therapy in MM. Thus, our goal is to provide an overview of the new advances of CAR-T cells in the cure of MM, so in this review we looked at the progress of the clinical use of CAR-T cells in MM to try to provide a reference for their clinical use when managing MM.

LncRNA CHROMR/miR-27b-3p/MET axis promotes the proliferation, invasion, and contributes to rituximab resistance in diffuse large B-cell lymphoma.

Long non-coding RNAs (LncRNAs) could regulate chemoresistance through sponging microRNAs (miRNAs) and sequestering RNA binding proteins. However, the mechanism of lncRNAs in rituximab resistance in diffuse large B-cell lymphoma (DLBCL) is largely unknown. Here, we investigated the functions and molecular mechanisms of lncRNA CHROMR in DLBCL tumorigenesis and chemoresistance. LncRNA CHROMR is highly expressed in DLBCL tissues and cells. We examined the oncogenic functions of lncRNA CHROMR in DLBCL by a panel of gain-or-loss-of-function assays and in vitro experiments. LncRNA CHROMR suppression promotes CD20 transcription in DLBCL cells and inhibits rituximab resistance. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assay reveal that lncRNA CHROMR sponges with miR-27b-3p to regulate mesenchymal-epithelial transition factor (MET) levels and Akt signaling in DLBCL cells. Targeting the lncRNA CHROMR/miR-27b-3p/MET axis reduces DLBCL tumorigenesis. Altogether, these findings provide a new regulatory model, lncRNA CHROMR/miR-27b-3p/MET, which can serve as a potential therapeutic target for DLBCL.

[Clinical Characteristics and Correlation with Prognosis of DLBCL with Bone Marrow Involvement and Chromosomal Abnormalities].

OBJECTIVE: To investigate the clinical characteristics of diffuse large B-cell lymphoma(DLBCL) patients with bone marrow involvement and chromosome abnormalities, and further analyze the correlation between the degree of chromosome abnormality and prognosis. METHODS: The clinical data of 88 patients diagnosed with DLBCL with bone marrow involvement and complete chromosomal findings in Shanxi Province Cancer Hospital were retrospectively analyzed. The χ2 test was used to analyze their clinical characteristics, and the Kaplan-Meier method was used in PFS and OS, and log-rank method in comparison. RESULTS: Chromosome abnormalities were detected in 31 of the 88 patients(35.2%), 15 of whom had complex karyotype(17.0%). The positive rate of BCL-2, BCL-6, C-MYC and Ki-67≥80% was high in patients with complex karyotype, and most of them are double expressor lymphoma. Survival analysis showed that patients with complex karyotype of DLBCL had poorer PFS and OS compared to those with normal karyotype and 1-2 chromosomal abnormalities. CONCLUSION: In DLBCL patients with bone marrow involvement and chromosome abnormalities, patients with complex karyotype have a shorter survival time.

[Modified styrene-maleic anhydride copolymer-based chromatographic stationary phase for phospholipid separation and analysis].

Phospholipids are important signaling molecules, and their metabolism is closely related to various diseases, such as neurodegenerative diseases and cancers. Phospholipids are typically characterized with extreme complexity and structural diversity. For example, phospholipids present in many different forms, such as sn position isomers, double-bond position isomers, double-bond stereochemical isomers, and enantiomers. Therefore, further research on novel separation and analytical techniques for phospholipids is of great importance. As an amphiphilic alternating copolymer, styrene-maleic anhydride copolymer (SMA) can be inserted into the phospholipid bilayer of biofilms to form lipid nanodisks with membrane proteins as the centers, thereby solubilizing membrane proteins and phospholipids. Thus, the introduction of SMA into a chromatographic stationary phase can potentially improve the separation and analysis of phospholipids. In this paper, SMA was successfully grafted onto the surface of silica gel via the "click" reaction and free radical polymerization. After further ring-opening modification of SMA with methyl methionine hydrochloride (MME·HCl), a novel SMA-modified stationary phase material (Sil-SMA-MME) was fabricated. The Sil-SMA-MME stationary phase was characterized using thermogravimetric analysis and Fourier transform infrared spectroscopy (FT-IR), and the results indicated the successful fabrication of the target material. The retention mechanism of the packed Sil-SMA-MME chromatographic column was investigated using hydrophilic nucleosides and nucleic acid bases via high performance liquid chromatography (HPLC) and UV detection. According to the retention characteristics of the nucleosides and nucleic acid bases in different mobile phases, the Sil-SMA-MME chromatographic column exhibited a typical hydrophilic-interaction-based retention mechanism, similar to that of a commercially available amino (SiO2-NH2) column. The separation performance of the Sil-SMA-MME column was evaluated using three types of small-molecule substances, including amides, nucleoside/nucleic acid bases, and phenols. Cyanoacetamide, 2-iodoacetamide, benzamide, p-aminobenzamide, and nicotinamide were used to evaluate the chromatographic performance of the developed Sil-SMA-MME column. When acetonitrile-H2O (96∶4, v/v) was used as the mobile phase, the five compounds exhibited good peak shapes and could be baseline-separated within 8 min. The highest column efficiency achieved was 90900 N/m. By contrast, under the same chromatographic conditions, the test substances were not separated effectively on the SiO2-NH2 column. Regardless of the mobile phase ratio, the peaks of benzamide and 2-iodoacetamide overlapped. These results demonstrate that the developed Sil-SMA-MME column has good separation selectivity. The separation performance of the Sil-SMA-MME column for phospholipid samples was also investigated by HPLC and evaporative light scattering detection (ELSD) to explore its feasibility for phospholipid separation and analysis. Different phospholipid standards were used to evaluate the separation performance of the column. Under certain mobile phase conditions, baseline separation could be achieved for dipalmityl phosphatidyl serine sodium (DPPS), diolyl phosphatidyl choline (DOPC), and dipalmityl phosphatidyl ethanolamine (DPPE), as well as four phosphatidyl choline (PC) standards, namely, lysophosphatidylcholine (LysoPC), dimyristoyl phosphatidyl choline (DMPC), distearyl phosphatidyl choline (DSPC), and dipalmitoyl phosphatidyl choline (DPPC). The separation potential of the developed Sil-SMA-MME column was further evaluated by separating and analyzing phospholipid extracts from Antarctic krill oil and human serum. The results showed that the developed Sil-SMA-MME column has good potential for phospholipid separation and analysis.

The prognostic index PRIMA-PI combined with Ki67 as a better predictor of progression of disease within 24 months in follicular lymphoma.

Background: Progression of disease within 24 months (POD24) is a risk factor for poor survival in follicular lymphoma (FL), and there is currently no optimal prognostic model to accurately predict patients with early disease progression. How to combine traditional prognostic models with new indicators to establish a new prediction system, to predict the early progression of FL patients more accurately is a future research direction. Methods: This study retrospectively analyzed patients with newly diagnosed FL patients in Shanxi Provincial Cancer Hospital from January 2015 to December 2020. Data from patients undergoing immunohistochemical detection (IHC) were analyzed using χ2 test and multivariate Logistic regression. Also, we built a nomogram model based on the results of LASSO regression analysis of POD24, which was validated in both the training set and validation set, and additional external validation was performed using a dataset (n = 74) from another center, Tianjin Cancer Hospital. Results: The multivariate Logistic regression results suggest that high-risk PRIMA-PI group, Ki-67 high expression represent risk factors for POD24 (P<0.05). Next, PRIMA-PI and Ki67 were combined to build a new model, namely, PRIMA-PIC to reclassify high and low-risk groups. The result showed that the new clinical prediction model constructed by PRIMA-PI with ki67 has a high sensitivity to the prediction of POD24. Compared to PRIMA-PI, PRIMA-PIC also has better discrimination in predicting patient's progression-free survival (PFS) and overall survival (OS). In addition, we built nomogram models based on the results of LASSO regression (histological grading, NK cell percentage, PRIMA-PIC risk group) in the training set, which were validated using internal validation set and external validation set, we found that C-index and calibration curve showed good performance. Conclusion: As such, the new predictive model-based nomogram established by PRIMA-PI and Ki67 could well predict the risk of POD24 in FL patients, which boasts clinical practical value.

CD73 Dysregulates Monocyte Anti-Tumor Activity in Multiple Myeloma.

Purpose: Multiple myeloma (MM) is characterized by immune cell dysfunction in the tumor microenvironment (TME). We aimed at evaluating the effect of CD73, an overexpressed factor in some tumors, on anti-tumor immune function in the TME of MM. Patients and Methods: We analyzed the expression of CD73 in T-, B-, and natural killer (NK)-lymphocytes and monocytes in bone marrow (BM), peripheral blood (PB) from MM patients and healthy controls, and residual CD138+ cells using flow cytometry. The anti-tumor activity of these monocytes was confirmed by co-culture with RPMI-8226 cells treated with a CD73 inhibitor. We determined the interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ levels using a cytometric bead array. Monocyte phagocytosis in cell culture sediment was then observed and measured. Results: CD73 was highly expressed in T-, B-, and NK-lymphocytes and monocytes from the BM and PB isolated from patients with MM. Compared with healthy controls, MM samples exhibited significantly higher CD73 expression and TNF-α, IFN-γ, IL-10 levels in monocytes. Inhibiting CD73 in BM immune cells from MM samples significantly increased the secretion of IL-2, TNF-α, and IFN-γ, as well as the killing ability of immune cells. However, monocyte phagocytosis was seldom observed. Inhibiting CD73 in MM monocytes significantly increased the secretion of IL-2, TNF-α, and IFN-γ in monocytes and improved monocyte killing and phagocytosis. Conclusion: Monocytes from MM exhibited weakened anti-tumor effects, and CD73 was involved in forming an immunosuppressive microenvironment. Inhibiting CD73 partly restored the anti-tumor activity of monocytes, a potential strategy for the treatment of MM.

Application of circulating tumour DNA in terms of prognosis prediction in Chinese follicular lymphoma patients.

Background: Follicular lymphoma (FL), an indolent non-Hodgkin lymphoma (NHL), is generally incurable. Favourable prognosis and durable remission are crucial for FL patients. The genetic mutation spectrum provides novel biomarkers for determining the prognosis of FL patients, but its detection is easily affected by the collection of tumour tissue biopsies. In this study, we aimed to describe the mutational landscape of FL using circulating tumour DNA (ctDNA) samples and to explore the relationship between mutations and prognostic indicators of clinical outcome in patients with newly diagnosed follicular lymphoma and the prognostic value of such mutations. Methods: A total of 28 patients with newly diagnosed FL were included in this study. A targeted NGS-based 59-gene panel was used to assess the ctDNA mutation profiles. Differences in clinical factors between patients carrying mutations and those without mutations were analysed. We also explored the relationship between gene mutation status, mean VAFs (variant allele frequencies) and clinical factors. The Kaplan‒Meier method was applied to analyse the overall survival (OS) and progression-free survival (PFS) of patients carrying mutations and those without mutations. Results: ctDNA mutations were detectable in 21 (75%) patients. The most commonly mutated genes were CREBBP (54%, 15/28), KMT2D (50%, 14/28), STAT6 (29%, 8/28), CARD11 (18%, 5/28), PCLO (14%, 4/28), EP300 (14%, 4/28), BCL2 (11%, 3/28), and TNFAIP3 (11%, 3/28), with a mutation frequency of >10%. Patients with detectable ctDNA mutation tended to present with advanced Ann Arbor stage (III-IV) (p = 0.009), high FLIPI risk (3-5) (p = 0.023) and severe lymph node involvement (No. of involved areas ≥5) (p = 0.02). In addition, we found that the mean VAF was significantly higher in patients with advanced Ann Arbor stage, high-risk FLIPI, elevated lactate dehydrogenase (LDH: 0-248U/L), advanced pathology grade, bone marrow involvement (BMI) and lymph node involvement. Additionally, KMT2D, EP300, and STAT6 mutations were associated with inferior PFS (p < 0.05). Conclusion: We described the ctDNA mutation landscapes in Chinese patients with newly diagnosed FL and found that ctDNA VAF means reflect tumour burden. Moreover, PFS was shorter in patients with KMT2D, EP300 and STAT6 mutations.

LDP alleviates TKI-induced proteinuria through reversing the expression of RelA in renal tissues.

Tyrosine kinase inhibitors (TKIs), as an important tumor therapy, can induce severe proteinuria that significantly affects anti-tumor therapy. Existing therapies against proteinuria induced by other etiologies are currently ineffective for TKI-induced proteinuria. It has been shown that various types of proteinuria are related to podocyte damage caused by changes in the RelA signaling pathway. Our experiments confirmed that TKIs activate the renal RelA signaling pathway, and induce death of podocytes and destruction of the glomerular filtration barrier. Here we found that Liuwei Dihuang Pill (LDP) attenuated the inflammatory injury of podocytes through inhibiting activation of RelA, and subsequently relieved TKI-related proteinuria and prevented the progression of TMA and FSGS. Our finding indicated that LDP may be effective for the treatment of TKI-induced proteinuria, which is clinically significant.

WSP from "Nostoc commune" Vauch. suppresses gastric cancer migration via EGFRVIII signaling.

Introduction: A number of evidences have proved that "Nostoc commune" Vauch can improve human immunity and prevent diseases, however, the specific mechanism remains unclear. The biological activity of the main protein component of "Nostoc commune" Vauch extracellular matrix- a water-stress protein (WSP) still needs to be elucidated. Methods: In our study, we validated the role of WSP in gastric cancer metastasis at the cellular level, the organoid level and in mouse models, and also studied the role of EGFRVIII and downstream signaling molecules after WSP treatment. Results: We found that WSP can significantly inhibit the metastasis of gastric cancer cells. Interestingly, we found that the anti-metastasis ability of WSP on gastric cancer was related to membrane protein receptor EGFRVIII, which was realized by inhibiting the downstream EGFRVIII signaling pathway. In terms of mechanism, WSP can inhibit the downstream EGFRVIII signaling pathway Akt-PI3K and further inhibit the secretion of cancer-related metastasis proteins such as MMP2 and MMP9, thus, significantly affecting the metastasis of gastric cancer cells. Discussion: Given the anticancer properties of WSP, drug developers and manufacturers can further develop protein drugs for cancer patients using protein engineering techniques based on the properties of WSP.

Circulating tumor DNA mutation profile is associated with the prognosis and treatment response of Chinese patients with newly diagnosed diffuse large B-cell lymphoma.

Background: Characterization of gene mutation profiles can provide new treatment options for patients with diffuse large B-cell lymphoma (DLBCL). However, this method is challenged by the limited source of tissue specimens, especially those of DLBCL patients at advanced stages. Therefore, in the current study, we aimed to describe the gene mutation landscape of DLBCL using circulating tumor DNA (ctDNA) samples obtained from patients' blood samples, as well as to explore the relationship between ctDNA mutations and the prognosis and treatment response of patients with newly diagnosed DLBCL. Methods: A total of 169 newly diagnosed Chinese DLBCL patients were included in this study, among which 85 patients were divided into a training set and 84 were assigned into a validation set. The mutation profile of a 59-gene panel was analyzed by targeted next generation sequencing (NGS) of the patients' ctDNA samples. Differences in clinical factors between patients with and without ctDNA mutations were analyzed. In addition, we also explored gene mutation frequencies between GCB and non-GCB subtypes, and the relationship between gene mutation status, clinical factors, mean VAF (variant allele frequencies) and the patients' overall survival (OS) and progression-free survival (PFS). Results: ctDNA mutations were detected in 64 (75.3%) patients of the training set and 67 (79.8%) patients of the validation set. The most commonly mutated genes in both sets were PCLO, PIM1, MYD88, TP53, KMT2D, CD79B, HIST1H1E and LRP1B, with mutation frequencies of >10%. Patients with detectable ctDNA mutations trended to present advanced Ann Arbor stages (III-IV), elevated LDH (lactate dehydrogenase) levels, shorter OS and PFS, and a lower complete response (CR) rate to the R-CHOP regimen compared with DLBCL patients without ctDNA mutations. In addition, mean VAF (≥4.94%) and PCLO mutations were associated with poor OS and PFS. Conclusion: We investigated the ctDNA mutation landscape in Chinese patients with newly diagnosed DLBCL and found that ctDNA could reflect tumor burden and patients with detectable ctDNA mutations trended to have shorter OS and PFS and a lower CR rate.

Drug-related adverse events potentially predict the efficacy of apatinib on advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs).  METHODS: This analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib. RESULTS: Patients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p < 0.001) had significantly better OS than those without corresponding AEs, and the appearance of HFS (p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS. CONCLUSION: Among all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.

PET/CT Evaluation of the Effect of Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of T-Cell Lymphoblastic Lymphoma.

The aim of this study was to investigate the clinical value of positron emission tomography/computerized tomography scanning (PET/CT) in the evaluation of the effect of allogeneic hematopoietic stem cell transplantation in the treatment of T lymphoblastic lymphoma. 12 relevant research articles were collected through layer-by-layer screening in large databases such as Pubmed, Baidu Scholar, and China How Net, and analyzed and summarized using indicators such as progression-free survival (PFS), overall survival (OS), hazard ratio (HR), maximum standardized uptake value (SUV max), total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), elevated lactate dehydrogenase (LDH), and ß2-microglobulin (ß2-MG). The results showed that before treatment, 18F-FDG PET/CT baseline diagnosis could accurately stage the patients; during treatment, 18F-FDG PET/CT detection could provide effective treatment information; and after treatment, complications were found during 18F-FDG PET/CT detection. In summary, 18F-FDG PET/CT can monitor and evaluate treatment prognosis at baseline, middle, and late stages, and 18F-FDG PET/CT has become an indispensable and important examination technique in clinical work.

Mitochondrion-encoded circular RNAs are widespread and translatable in plants.

Nucleus-encoded circular RNAs (ncircRNAs) have been widely detected in eukaryotes, and most circRNA identification algorithms are designed to identify them. However, using these algorithms, few mitochondrion-encoded circRNAs (mcircRNAs) have been identified in plants, and the role of plant mcircRNAs has not yet been addressed. Here, we developed a circRNA identification algorithm, mitochondrion-encoded circRNA identifier, based on common features of plant mitochondrial genomes. We identified 7,524, 9,819, 1,699, 1,821, 1,809, and 5,133 mcircRNAs in maize (Zea mays), Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa), tomato (Solanum lycopersicum), cucumber (Cucumis sativus), and grape (Vitis vinifera), respectively. These mcircRNAs were experimentally validated. Plant mcircRNAs had distinct characteristics from ncircRNAs, and they were more likely to be derived from RNA degradation but not intron backsplicing. Alternative circularization was prevalent in plant mitochondria, and most parental genomic regions hosted multiple mcircRNA isoforms, which have homogenous 5' termini but heterogeneous 3' ends. By analysis of mitopolysome and mitoribosome profiling data, 1,463 mcircRNAs bound to ribosomes were detected in maize and Arabidopsis. Further analysis of mass spectrometry-based proteomics data identified 358 mcircRNA-derived polypeptides. Overall, we developed a computational pipeline that efficiently identifies plant mcircRNAs, and we demonstrated mcircRNAs are widespread and translated in plants.

A Chloroplast-Localized Glucose-6-Phosphate Dehydrogenase Positively Regulates Stripe Rust Resistance in Wheat.

Glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of the pentose phosphate pathway (PPP), plays a pivotal role in plant stress responses. However, the function and mechanism of G6PDHs in crop plants challenged by fungal pathogens remain poorly understood. In this study, a wheat G6DPH gene responding to infection by Puccinia striiformis f. sp. tritici (Pst), designated TaG6PDH2, was cloned and functionally identified. TaG6PDH2 expression was significantly upregulated in wheat leaves inoculated with Pst or treated with abiotic stress factors. Heterologous mutant complementation and enzymatic properties indicate that TaG6PDH2 encodes a G6PDH protein. The transient expression of TaG6PDH2 in Nicotiana benthamiana leaves and wheat protoplasts revealed that TaG6PDH2 is a chloroplast-targeting protein. Silencing TaG6PDH2 via the barley stripe mosaic virus (BSMV)-induced gene silencing (VIGS) system led to compromised wheat resistance to the Pst avirulent pathotype CYR23, which is implicated in weakened H2O2 accumulation and cell death. In addition, TaG6PDH2 was confirmed to interact with the wheat glutaredoxin TaGrxS4. These results demonstrate that TaG6PDH2 endows wheat with increased resistance to stripe rust by regulating reactive oxygen species (ROS) production.

A Nomogram for Predicting the Residual Back Pain after Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures.

OBJECTIVE: Current findings suggest that percutaneous vertebroplasty (PVP) is a suitable therapeutic approach for osteoporotic vertebral compression fractures (OVCFs). However, a significant minority of patients still experience residual back pain after PVP. The present retrospective study was designed to determine the risk factors for residual back pain after PVP and provides a nomogram for predicting the residual back pain after PVP. METHODS: We retrospectively reviewed the medical records of patients with single-segment OVCFs who underwent bilateral percutaneous vertebroplasty. Patients were divided into group N and group R according to the postoperative VAS score. Group R is described as the VAS score of residual back pain ≥ 4. Pre- and postoperative factors that may affect back pain relief were evaluated between two groups. Univariate and multivariate logistic regression analysis were performed to identify risk factors affecting residual back pain after PVP. We provided a nomogram for predicting the residual back pain and used the receiver operating characteristic curve (ROC), concordance index (C-index), calibration curve, and decision curve analyses (DCA) to evaluate the prognostic performance. RESULTS: Among 268 patients treated with PVP, 37 (13.81%) patients were classified postoperative residual back pain. The results of the multivariate logistical regression analysis showed that the presence of an intravertebral vacuum cleft (IVC) (OR 3.790, P=0.026), posterior fascia oedema (OR 3.965, P=0.022), severe paraspinal muscle degeneration (OR 5.804, P=0.01; OR 13.767, P < 0.001), and blocky cement distribution (OR 2.225, P=0.041) were independent risk factors for residual back pain after PVP. The AUC value was 0.780, suggesting that the predictive ability was excellent. The prediction nomogram presented good discrimination, with a C-index of 0.774 (0.696∼0.852) and was validated to be 0.752 through bootstrapping validation. The calibration curve of the nomogram demonstrated a good consistency between the probabilities predicted by the nomogram and the actual probabilities. The nomogram showed net benefits in the range from 0.06 to 0.66 in DCA. CONCLUSIONS: The presence of IVC, posterior fascia oedema, blocky cement distribution, and severe paraspinal muscle degeneration were significant risk factors for residual back pain after PVP for OVCFs. Patients with OVCFs after PVP who have these risk factors should be carefully monitored for the possible development of residual back pain. We provide a nomogram for predicting the residual back pain after PVP.

Four new dammarane triterpenoid glycosides from the leaves of Cyclocarya paliurus and their SIRT1 activation activities.

Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides SV (1-4), along with nine known dammarane triterpenoid glycosides (5-13) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC50 of 10 µM and 20 µM, respectively.

N6 -Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis.

The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N6 -methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7. SIGNIFICANCE: This study suggests that N6 -methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.

Compounds DRG and DAG, Two Phenol Glycosides, Inhibit TNF-α-stimulated Inflammatory Response through Blocking NF-kB/AKT/JNK Signaling Pathways in MH7A Cells.

Fourteen constituents were recently isolated from the roots of Dendropanax dentiger with cyclooxygenase-2 (COX-2) inhibitory effects. However, the effect of 14 constituents on rheumatoid arthritis (RA) and their action mechanism remain unclear. The study aimed to explore the anti-RA effect and potential mechanism of these constituents in tumor necrosis factor α (TNF-α)-stimulated human RA fibroblast-like synoviocytes (MH7A cells). The cell viability, nitric oxide (NO) production, inflammatory cytokine levels, and protein expressions were measured by cell counting kit-8 (CCK-8), Griess reagent, ELISA, and Western blot assays, respectively. Results showed that 14 constituents (40 µM) have no cytotoxicity for MH7A cells. Among them, two phenols including 3,4-dimethoxyphenyl-1-O-α-L-rhamnopyranosyl-(1→6)-O-ß-D-glucopyranoside (DRG) and 3,4-dimethoxyphenol-ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranoside (DAG) were shown to significantly inhibit the NO production with IC50 values of 5.25±0.34 and 5.35±0.31 µM, respectively. They also remarkably decreased the release of interleukin (IL)-2, 6, 8, and interferon (IFN)-γ, as well as prominently reduced the phosphorylation protein levels of p65, IkBα, AKT, and JNK at a concentration of 10 µM. Taken together, DRG and DAG could inhibit TNF-α-induced inflammatory response through blocking NF-kB/AKT/JNK signaling pathways in MH7A cells, thus could be promising against RA and other inflammation-related agents.

Clinical prognosis and bioinformatic analysis of primary thyroid lymphoma.

ABSTRACT: Primary thyroid lymphoma (PTL) is a rare malignant disease with the most common histological type of diffuse large B-cell lymphoma (DLBCL). Hashimoto's thyroiditis (HT) is closely related to the pathogenesis of PTL. The present study is to explore the clinical prognosis of PTL and analyze the gene correlations between PTL and HT.Thirty-nine patients diagnosed with PTL between 2010 and 2018 in our institute were retrospectively reviewed and clinical features were evaluated on PTL survival. Then, overlapping differentially expressed genes (DEGs) between PTL and HT were evaluated for gene ontology, pathways enrichment, protein-protein interaction network analysis. Furthermore, we used gene expression profiling interactive analysis to evaluate the differential expression of these hub genes.In this analysis, International Prognostic Index (IPI) score ≥3 and high ß2-MG (>3 mg/L) were associated with worse prognosis in PTL. Notably, a total of 15 both upregulated DEGs in DLBCL and HT were identified and 10 hub genes with a high degree of connectivity were picked out. Among these 10 hub genes, IL6, IL10, CXCL10, and CXCR3 were higher expressed in DLBCL than the normal tissue but have no significant prognosis of DLBCL.High IPI score and high ß2-MG level have a poor prognosis in PTL. Besides, IL6, IL10, CXCL10, and CXCR3 are associated with both DLBCL and HT and may be used for the early diagnosis of PTL.

Comparision of biportal endoscopic and microscopic decompression in treatment of lumbar spinal stenosis: A comparative study protocol.

BACKGROUND: Microscopic bilateral decompression (MBD) has been suggested as an alternative to open laminectomy and fusion. Recently, percutaneous biportal endoscopic decompression (PBED) has begun to attract attention. The purpose of this retrospective study was to evaluate postoperative pain, functional disability, symptom reduction and satisfaction, and specific surgical parameters between the MBD and PBED techniques in patients with lumbar spinal stenosis (LSS). METHODS: A retrospective review of LSS patients performed with MBD or PBED technique between May 2015 and June 2018 was conducted. Institutional review board approval in People's Hospital of Ningxia Hui Nationality Autonomous Region was obtained prior to conducting chart review and analysis. We received informed consent from all patients before surgery. The primary outcomes assessed were the preoperative to postoperative changes in leg/back pain and disability/function, patient satisfaction with the procedure, and postoperative quality of life. The secondary outcomes including duration of postoperative hospital stay, time to mobilization, postoperative analgesic use, complication rates, and baseline patient characteristics were prospectively collected. RESULTS: The hypothesis was that the PBED technique would achieve better clinical outcomes as compared to the MBD technique in LSS.