Uncovering the potential molecular mechanism of liraglutide to alleviate the effects of high glucose on myoblasts based on high-throughput transcriptome sequencing technique.

BACKGROUND: Myoblasts play an important role in muscle growth and repair, but the high glucose environment severely affects their function. The purpose of this study is to explore the potential molecular mechanism of liraglutide in alleviating the effects of high glucose environments on myoblasts. METHODS: MTT, western blot, and ELISA methods were used to investigate the role of liraglutide on C2C12 myoblasts induced by high glucose. The high-throughput transcriptome sequencing technique was used to sequence C2C12 myoblasts from different treated groups. The DESeq2 package was used to identify differentially expressed-mRNAs (DE-mRNAs). Then, functional annotations and alternative splicing (AS) were performed. The Cytoscape-CytoHubba plug-in was used to identify multicentric DE-mRNAs. RESULTS: The MTT assay results showed that liraglutide can alleviate the decrease of myoblasts viability caused by high glucose. Western blot and ELISA tests showed that liraglutide can promote the expression of AMPKα and inhibit the expression of MAFbx, MuRF1 and 3-MH in myoblasts. A total of 15 multicentric DE-mRNAs were identified based on the Cytoscape-CytoHubba plug-in. Among them, Top2a had A3SS type AS. Functional annotation identifies multiple signaling pathways such as metabolic pathways, cytokine-cytokine receptor interaction, cAMP signaling pathway and cell cycle. CONCLUSION: Liraglutide can alleviate the decrease of cell viability and degradation of muscle protein caused by high glucose, and improves cell metabolism and mitochondrial activity. The molecular mechanism of liraglutide to alleviate the effect of high glucose on myoblasts is complex. This study provides a theoretical basis for the clinical effectiveness of liraglutide in the treatment of skeletal muscle lesions in diabetes.

Repurposing TAK875 as a novel STAT3 inhibitor for treating inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disease associated with a high recurrence rate and an elevated risk of colon cancer. In this study, we screened a bioactive compound library using a luciferase reporter assay and identified the compound TAK875 as a novel inhibitor of signal transducer and activator of transcription 3 (STAT3). Surface plasmon resonance analysis, differential scanning fluorimetry, and isothermal titration calorimetry demonstrated that TAK875 directly bound to recombinant STAT3. TAK875 suppressed the lipopolysaccharide (LPS)-induced release of nitric oxide, inducible nitric oxide synthase, and inflammatory factors in RAW264.7 cells, likely by inhibiting STAT3 phosphorylation. In addition, TAK875 inhibited the differentiation of CD4+ T cells into T-helper 17 cells, which may partially account for its anti-inflammatory effect. TAK875 also alleviated the LPS-induced accumulation of intracellular reactive oxygen species, thus displaying its antioxidant effects. Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo.

Effect of nasal high-flow oxygen humidification on patients after cardiac surgery.

Background: Although high-flow humidified oxygen therapy (HFNC) has emerged as an important treatment for respiratory failure, few studies have reported on whether HFNC is appropriate for patients with hypoxemia after cardiac surgery, and the clinical efficacy of HFNC in patients undergoing cardiac surgery is unclear. Objective: To investigate the clinical effect of HFNC after cardiac surgery. Methods: Convenience sampling was used to select 76 patients who underwent invasive mechanical ventilation and oxygen therapy after valve replacement or coronary artery bypass grafting from July 2019 to June 2021. The patients were divided into the routine group and the HFNC group according to the oxygen therapy provided after the operation. The patients in the routine group (N = 38) were treated with oxygen inhalation by face mask after the operation, while those in the HFNC group (N = 38) were treated with HFNC via nasal cavity. The arterial partial pressure of oxygen (PaO2), the arterial partial pressure of carbon dioxide (PaCO2) and the oxygenation index (OI) were observed and compared between the two groups at 6 h, 12 h and 24 h after treatment. The sputum viscosity, incidence of second intubation and the intensive care unit (ICU) stay time were evaluated. Results: The difference in PaCO2 between the two groups was statistically significant at 24 h after treatment (p < 0.05). The PaO2 in the HFNC group was significantly higher than in the routine group at 24 h after treatment, and the OI of the routine group was lower than in the HFNC group at 6 h, 12 h and 24 h after treatment (p < 0.05). The sputum viscosity in the HFNC group was better than in the routine group at 12 h and 24 h after treatment. The second intubation rate and ICU stay time in the HFNC group were lower than in the routine group (p < 0.05). Conclusion: Compared with conventional mask oxygen inhalation, HFNC can effectively reduce sputum viscosity, improve oxygenation, reduce the incidence of repeated intubation and meet patients' comfort needs. It is an advantageous respiratory support strategy for patients after cardiac surgery compared with invasive mechanical ventilation to oxygen therapy and is beneficial to the recovery of cardiopulmonary function.

Endovascular therapy versus medical management for acute ischemic stroke with large infarct core: Systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the efficacy and safety of endovascular therapy (EVT) versus best medical management (BMM) in patients with acute ischemic stroke (AIS) with large infarct core. METHODS: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials for published randomized clinical trials (RCTs) from inception to February 18, 2023. We defined patients with large core infarcts as having an Alberta Stroke Program early computed tomography score (ASPECTS) of 3-5. The primary outcome was functional independence, defined as a score of 0-2 on the modified Rankin scale (mRS) at 90 days. Secondary outcome was independent ambulation defined as mRS 0-3 at 90 days. Safety outcomes were mortality at 90 days, symptomatic intracranial hemorrhage (sICH) and any intracranial hemorrhage (ICH). RESULTS: The overall treatment effect was more favourable to EVT group. EVT was significantly correlated with improvement of functional independence at 90 days (mRS 0-2) (RR = 2.40; 95 % CI, 1.82-3.16; P < 0.01; I2 = 0 %) and independent ambulation (mRS 0-3) (RR = 1,78; 95 % CI, 1.28-2.48; P < 0.01; I2 = 58 %) at 90 days. 90-day mortality was not significantly different between the two groups(RR = 0.95; 95 % CI, 0.78-1.16; P > 0.05; I2 = 0 %). The risk of sICH and any ICH was higher in EVT group than in BMM group. CONCLUSION: Compared with BMM, EVT may improve functional outcomes in patients with ASPECTS 3-5, despite being associated with an increased risk of sICH and any ICH.

Biodistribution and Internal Dosimetry of 68 Ga-DOTA-IBA PET Imaging for Patients With Bone Metastases.

PURPOSE: We have developed a new pharmaceutical, ibandronic acid (IBA), and preliminarily demonstrated that it is an efficient bisphosphonate for the diagnosis and treatment of bone metastases. This study aims to examine the biodistribution and internal dosimetry of the diagnostic 68 Ga-DOTA-IBA in patients. PATIENTS AND METHODS: 68 Ga-DOTA-IBA was intravenously injected based on 1.81-2.57 MBq/Kg into 8 patients with bone metastases. Each patient underwent 4 sequential static whole-body PET scans at 0.1, 0.45, 0.8, and 1.8 hours after injection. The acquisition time for each scan was 20 minutes with 10 bed positions. Image registrations and volume of interest delineation were first performed on Hermes, whereas percentage injected activity (%IA), absorbed dose, and effective dose were measured for source organs, using OLINDA/EXM v2.0. Dosimetrics for the bladder was based on a bladder voiding model. RESULTS: No adverse effects were observed on all patients. After the injection, 68 Ga-DOTA-IBA rapidly accumulated in bone metastases and cleared from nonbone tissues, as indicated by visual analysis and %IA measured on the sequential scans. High activity uptake was presented in the expected target organs, that is, bone, red marrow, and the drug-excretion organs such as kidneys and bladder. The mean total body effective dose is 0.022 ± 0.002 mSv/MBq. CONCLUSIONS: 68 Ga-DOTA-IBA has high bone affinity and is promising in the diagnosis of bone metastases. Dosimetric results show that the absorbed doses for critical organs and total body are within the safety limit and with high bone retention. It also has the potential to be used in 177 Lu-therapy as a theranostic pair.

Systemic administration of mesenchymal stem cells loaded with a novel oncolytic adenovirus carrying a bispecific T cell engager against hepatocellular carcinoma.

We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC.

Prospective Comparison of the Imaging Value of 99m Tc-MDP Bone Scan and 68 Ga-FAPI-04 PET/CT in Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome.

PURPOSE: This study aimed to explore the imaging value of 68 Ga-FAPI-04 PET/CT in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome and compare it with that of 99m Tc-MDP bone scan. METHODS: Nineteen participants with SAPHO syndrome underwent 68 Ga-FAPI-04 PET/CT and 99m Tc-MDP bone scan. Demographic data and clinical features were recorded, SAPHO imaging features were analyzed, and the osteoarticular lesion detection rate in both methods was calculated. RESULTS: This prospective study recruited 4 men and 15 women aged 52.4 ± 8.6 years. The anterior chest wall was involved in all participants (100%). Palmoplantar pustulosis was the most common (36.8%) skin symptom. 99m Tc-MDP bone scan and 68 Ga-FAPI-04 PET/CT together detected 84 osteoarticular lesions, of which 91.7% (77/84) were detected by the former and 96.4% (81/84) by the latter. Furthermore, 68 Ga-FAPI-04 PET/CT detected 5 cases of knee and hip joint synovitis. CONCLUSIONS: 68 Ga-FAPI-04 PET/CT was more sensitive than 99m Tc-MDP bone scan when evaluating osteoarticular lesions in SAPHO syndrome and could also evaluate synovial lesions. 68 Ga-FAPI-04 PET/CT could be a good imaging method for SAPHO syndrome but requires further verification in a more extensive research cohort.

Zinc finger and SCAN domain-containing protein 18 is a potential DNA methylation-modified tumor suppressor and biomarker in breast cancer.

Introduction: Zinc finger and SCAN domain-containing protein 18 (ZSCAN18) has been investigated as a putative biomarker of multiple human cancers. However, the expression profile, epigenetic modification, prognostic value, transcription regulation, and molecular mechanism of ZSCAN18 in breast cancer (BC) remain unknown. Methods: In the study, we present an integrated analysis of ZSCAN18 in BC based on public omics datasets with the use of multiple bioinformatics tools. Genes potentially regulated through restoration of ZSCAN18 expression in MDA-MB-231 cells were investigated to identify pathways associated with BC. Results: We observed that ZSCAN18 was downregulated in BC and mRNA expression was significantly correlated with clinicopathological parameters. Low expression of ZSCAN18 was found in the HER2-positive and TNBC subtypes. High expression of ZSCAN18 was associated with good prognosis. As compared to normal tissues, the extent of ZSCAN18 DNA methylation was greater with fewer genetic alterations in BC tissues. ZSCAN18 was identified as a transcription factor that might be involved in intracellular molecular and metabolic processes. Low ZSCAN18 expression was associated with the cell cycle and glycolysis signaling pathway. Overexpression of ZSCAN18 inhibited mRNA expression of genes associated with the Wnt/ß-catenin and glycolysis signaling pathways, including CTNNB1, BCL9, TSC1, and PFKP. ZSCAN18 expression was negatively correlated with infiltrating B cells and dendritic cells (DCs), as determined by the TIMER web server and reference to the TISIDB. ZSCAN18 DNA methylation was positively correlated with activated B cells, activated CD8+ and CD4+ T cells, macrophages, neutrophils, and activated DCs. Moreover, five ZSCAN18-related hub genes (KDM6B, KAT6A, KMT2D, KDM1A, and HSPBP1) were identified. ZSCAN18, ZNF396, and PGBD1 were identified as components of a physical complex. Conclusion: ZSCAN18 is a potential tumor suppressor in BC, as expression is modified by DNA methylation and associated with patient survival. In addition, ZSCAN18 plays important roles in transcription regulation, the glycolysis signaling pathway, and the tumor immune microenvironment.

Malignant Melanoma of the External Auditory Canal on 68 Ga-FAPI PET/CT.

ABSTRACT: External ear melanomas are relatively rare and usually occur in the regions of helix and ear lobes. Rarer still are primary melanomas of the external auditory canal. We report findings of melanoma of the external auditory canal on 68 Ga-FAPI PET/CT in a 56-year-old man who presented with sharp pain in the external auditory canal for 7 months.

Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway.

The activating receptor natural killer group 2D (NKG2D) expressed by Natural killer (NK) cells functions as a "master-switch" in governing the awakening status of NK cells. The NKG2D-mediated cytotoxicity has been declared to be related with the expression levels of NKG2D ligands (NKG2DLs) expressed on tumor cells. Therefore, selective induction of NKG2DLs could be a reliable approach to enhance the efficacy of NK cell-mediated immunotherapy. Our existing study demonstrated that Ciclopirox Olamine (CPX), an off-patent antifungal agent, effectively elevated the expression of NKG2DLs on leukemia cells and sensitized leukemia cells to NK-cell mediated cytolysis. Induction of ROS production and AKT phosphorylation by CPX is essential for the up-regulation of NKG2DLs expressions. Inhibition of AKT by using AKT inhibitor MK2206 decreased both NKG2DLs expressions and NK cell cytotoxicity. These data indicated that increased sensitivity of CPX-treated leukemia cells to NK cell cytolysis was attributed to higher NKG2DLs expressions, resulting from activated AKT signaling pathway. Our findings support the ongoing development of CPX as an anti-tumor agent and suggest its promising immunotherapeutic value in the medication of leukemia.

Hypoglycemic drug liraglutide alleviates low muscle mass by inhibiting the expression of MuRF1 and MAFbx in diabetic muscle atrophy.

BACKGROUND: Low muscle mass, that is, muscular atrophy, is an independent risk factor for type 2 diabetes mellitus (T2DM). Few studies investigated whether hypoglycemic drugs can alleviate low muscle mass and related mechanisms. METHODS: This study recruited 51 type 2 diabetes mellitus (T2DM) patients, who were divided into two groups based on skeletal muscle index (SMI) evaluated by Dual-energy X-ray absorptiometry (DXA): the experiment group (n = 25, SMI < 7 kg/m 2 ) and the control group (n = 26, SMI≥7 kg/m 2 ). GLP-1 levels were measured by ELISA. In vitro, 10 KK-A y mice (11- to 12-week-old) were assigned into two groups: liraglutide group (n = 5) and saline group (n = 5). Real-time PCR and Western blot were used to determine the expression levels of muscle specific ubiquitin protease E3, MuRF1, and MAFbx. RESULTS: T2DM patients with a higher SMI had significantly higher GLP-1 levels (t = 3.77, p < 0.001). SMI were positively associated with GLP-1 levels (ß = 0.435, p = 0.001) and inversely associated with age (ß = 0.299, p = 0.015). The incidence of low muscle mass at below the second quartiles was 10.55 times that of above the second quartiles (odds ratio = 10.556, p < 0.001). Liraglutide-treatment mice showed significant decrease in food intake, final body weight, fasting blood glucose, and significant increase in skeletal muscle mass, which coincided with the significant decrease in the expression levels of ubiquitin protease E3 MuRF1 and MAFbx. In vitro studies showed that liraglutide promoted myogenic differentiation and attenuated dexamethasone (DEX)-induced myotube atrophy. Ectopic expression of MuRF1 and MAFbx antagonized the beneficial effects of liraglutide on DEX-induced myotube atrophy. CONCLUSION: T2DM patients have muscular atrophy, and liraglutide alleviates muscular atrophy at least in part by inhibiting the expression of MuRF1 and MAFbx.

Discovery and SAR Study of Quinoxaline-Arylfuran Derivatives as a New Class of Antitumor Agents.

A novel class of quinoxaline-arylfuran derivatives were designed, synthesized, and preliminarily evaluated for their antiproliferative activities in vitro against several cancer cell lines and normal cells. The representative derivative QW12 exerts a potent antiproliferative effect against HeLa cells (IC50 value of 10.58 µM), through inducing apoptosis and triggering ROS generation and the accumulation of HeLa cells in vitro. Western blot analysis showed that QW12 inhibits STAT3 phosphorylation (Y705) in a dose-dependent manner. The BLI experiment directly demonstrated that QW12 binds to the STAT3 recombination protein with a KD value of 67.3 µM. Furthermore, molecular docking investigation showed that QW12 specifically occupies the pY+1 and pY-X subpocket of the SH2 domain, thus blocking the whole transmission signaling process. In general, these findings indicated that the study of new quinoxaline-aryfuran derivatives as inhibitors of STAT3 may lead to new therapeutic medical applications for cancer in the future.

Irisin as a predictor of bone metabolism in Han Chinese Young Men with pre-diabetic individuals.

BACKGROUND: Irisin is a novel myokine both in mice and humans, and it can also be secreted by adipose tissue and the liver in a small amounts. There are few studies on irisin and bone metabolism. The aim of this study was to assess the relationship between serum irisin levels and bone metabolism and analyze its related factors in Han young male with pre-diabetic individuals. METHODS: This cross-sectional study included 41 pre-diabetes and 45 normal glucose tolerance (NGT). Anthropometric measurements, including height, weight, waist circumference (WC), and bone mineral content (BMC), were performed. All patients underwent an oral glucose tolerance test (OGTT) after 8 h of fasting, and the levels of glucose, insulin, lipids, serum irisin and bone turnover markers were measured. RESULTS: The levels of serum irisin (4.4 ± 1.4 vs. 6.3 ± 1.5 µg/mL), P1NP and OC were significantly lower and CTX was significantly higher in the pre-diabetes group (P < 0.05). BMC did not differ in the two groups (P > 0.05). Serum irisin levels negatively correlated with BMI (r =-0.325), FPG (r =-0.329), TG (r =-0.339) (P < 0.05) in NGT individuals. Serum irisin levels positively correlated with P1NP (r = 0.398), OC (r = 0.351), HDL-C (r = 0.432) and negatively correlated with FPG (r = -0.725), 2 h-PG (r = -0.360) (P < 0.05) in pre-diabetic individuals. Multiple regression analysis revealed that Serum irisin (ß = 9.768, P = 0.025) and WC (ß = -2.355, P = 0.002) were significant independent predictors for P1NP. CONCLUSION: Bone turnover markers were changed rather than bone mineral content in young men with pre-diabetes. In pre-diabetes individuals, serum irisin levels were reduced and close relationship with P1NP. Falling irisin levels may be a predictor of decreased bone formation in Han young men with pre-diabetes individuals.

SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity.

A series of novel naphthoquinone-furan-2-cyanoacryloyl hybrids were designed; they were synthesized and preliminarily evaluated for their anti-proliferative activities in vitro against several cancer cell lines and normal cells. The most potent compound, 5c, inhibited the proliferation of HeLa cells (IC50 value of 3.10 ± 0.02 µM) and colony survival, and it induced apoptosis while having relatively weaker effects on normal cells. Compound 5c also triggered ROS generation and accumulation, thus partially contributing to the observed cell apoptosis. A Western blotting analysis demonstrated that compound 5c inhibited the phosphorylation of STAT3. Furthermore, a biolayer interferometry (BLI) analysis confirmed that compound 5c had a direct effect on STAT3, with a KD value of 13.0 µM. Molecular docking showed that 5c specifically occupied the subpockets in the SH2 domain, thereby blocking the whole transmission signaling process. Overall, this study provides an important structural reference for the development of effective antitumor agents.

Transcriptome analysis of tea (Camellia sinensis) leaves in response to ammonium starvation and recovery.

The tea plant is a kind of ammonium-preferring crop, but the mechanism whereby ammonium (NH4 +) regulate its growth is not well understood. The current study focused on the effects of NH4 + on tea plants. Transcriptomic analysis was performed to investigate the early- and late-stage NH4 + deprivation and resupply in tea plants shoots. Through short- and long-term NH4 + deficiency, the dynamic response to NH4 + stress was investigated. The most significant effects of NH4 + deficiency were found to be on photosynthesis and gene ontology (GO) enrichment varied with the length of NH4 + deprivation. Enriched KEGG pathways were also different when NH4 + was resupplied at different concentrations which may indicate reasons for tolerance of high NH4 + concentration. Using weighted gene co-expression network analysis (WGCNA), modules related to significant tea components, tea polyphenols and free amino acids, were identified. Hence, NH4 + could be regarded as a signaling molecule with the response of catechins shown to be higher than that of amino acids. The current work represents a comprehensive transcriptomic analysis of plant responses to NH4 + and reveals many potential genes regulated by NH4 + in tea plants. Such findings may lead to improvements in nitrogen efficiency of tea plants.

Crop-type-driven changes in polyphenols regulate soil nutrient availability and soil microbiota.

Crop rotation is a typical agronomic practice to mitigate soil deterioration caused by continuous cropping. However, the mechanisms of soil biotic and abiotic factors in response to different cropping patterns in acidic and polyphenol-rich tea nurseries remain unclear. In this study, the composition and function of microbial communities were comparatively investigated in soils of tea seedlings continuously planted for 2 years (AC: autumn-cutting; SC: summer-cutting) and in soils rotation with strawberries alternately for 3 years (AR: autumn-cutting). The results showed that AR significantly improved the survival of tea seedlings but greatly reduced the contents of soil polyphenols. The lower soil polyphenol levels in AR were associated with the decline of nutrients (SOC, TN, Olsen-P) availability, which stimulates the proliferation of nutrient cycling-related bacteria and mixed-trophic fungi, endophytic fungi and ectomycorrhizal fungi, thus further satisfying the nutrient requirements of tea seedlings. Moreover, lower levels of polyphenols facilitated the growth of plant beneficial microorganisms (Bacillus, Mortierella, etc.) and suppressed pathogenic fungi (Pseudopestalotiopsis, etc.), creating a more balanced microbial community that is beneficial to plant health. Our study broadens the understanding of the ecological role of plant secondary metabolites and provides new insights into the sustainability of tea breeding.

Genome-wide identification, characterization, and expression analysis of the ammonium transporter gene family in tea plants (Camellia sinensis L.).

As a preferred nitrogen form, ammonium (NH4 + ) transport via specific transporters is particularly important for the growth and development of tea plants (Camellia sinensis L.). However, our understanding of the functions of the AMT family in tea plants is limited. We identified and named 16 putative AMT genes according to phylogenetic analysis. All CsAMT genes were divided into three groups, distributed on 12 chromosomes with only one segmental duplication repetition. The CsAMT genes showed different expression levels in different organs, and most of them were expressed mainly in the apical buds and roots. Complementation analysis of yeast mutants showed that CsAMTs restored the uptake of NH4 + . This study provides insights into the genome-wide distribution and spatial expression of AMT genes in tea plants.

Low Skeletal Muscle Area at the T12 Paravertebral Level as a Prognostic Marker for Community-Acquired Pneumonia.

RATIONALE AND OBJECTIVES: This study aimed to investigate whether the dorsal skeletal muscle area at 12th thoracic level (T12SMA) could be used as a predictor of in-hospital mortality and long-term survival among patients with community-acquired pneumonia (CAP). MATERIALS AND METHODS: A retrospective study was conducted on 1701 CAP patients who underwent chest computed tomography (CT) examinations at the First Hospital of Qinhuangdao. The primary outcome was in-hospital mortality. The T12SMA was analyzed. Multivariate regression logistic models were constructed to identify the prognostic markers of hospital mortality. Cox regression logistic models were constructed to identify the risk factors of long-term survival. RESULTS: The multiple logistic regression analysis showed that T12SMA [odds ratio (OR) = 0.946; p = 0.007], CURB-65 (OR = 1.521; p = 0.008), creatinine (OR = 1.003; p = 0.001), albumin (OR = 0.908; p = 0.001) and intensive care unit (ICU) (OR = 2.715; p = 0.007) were independent risk factors for predicting the in-hospital mortality. The cox regression logistic analysis showed that T12SMA (OR = 0.968; p = 0.000), age (OR= 1.036; p = 0.000), sex (OR= 1.435; p = 0.002), CURB-65 (OR = 1.311; p = 0.000), albumin (OR = 0.952; p = 0.000), creatinine (OR = 1.002; p = 0.000) and ICU (OR = 1.606; p = 0.001) were prognostic markers of long-term survival. CONCLUSION: T12SMA, CURB-65, creatinine, albumin and ICU were independent risk factors for in-hospital mortality among patients with CAP. And low T12SMA affected the in-hospital mortality and long-term survival of patients with CAP.

A Novel CD3/BCMA Bispecific T-cell Redirecting Antibody for the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is a B-cell malignancy for which new treatments are urgently needed. Redirecting the activity of T cells by bispecific antibodies against tumor cells is a potent approach. The B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein and therefore is an ideal therapeutic target for T-cell redirecting therapies. The main objective of this work is to target the BCMA by generating BCMA-specific murine monoclonal antibody and construct a cluster of differentiation 3 (CD3)/BCMA-directed tandem diabodies (Tandab). In brief, using standard hybridoma technology, we developed a novel BCMA-specific monoclonal antibody (clone 69G8), that specifically bind with BCMA+ cell lines and MM patient sample; whereas BCMA- cells were not recognized. For T cells by bispecific antibodies application, we constructed a Tandab (CD3/BCMA) simultaneously targeting both CD3 and BCMA and our studies demonstrated that Tandab (CD3/BCMA) was functional with specific binding capability both for CD3+ cells and BCMA+ cells. It induced selective, dose-dependent lysis of BCMA+ cell lines, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA- cells were not affected. Furthermore, we demonstrated that Tandab activity correlates with BCMA expression, with higher potency observed in highly BCMA expressing tumor cells. In vivo, the purified Tandab (CD3/BCMA) significantly inhibited the tumor growth in a subcutaneous NCI-H929 xenograft model. Taken together, these results show that the Tandab (CD3/BCMA) displays potent and selective anti-MM activities and represents a promising immunotherapeutic for the treatment of MM.

Determination of lipid profiles of Dezhou donkey meat using an LC-MS-based lipidomics method.

Intramuscular fat (IMF) is an important factor affecting meat quality, but lipid and metabolic profiles of donkey meat remain unclear. The present study was conducted to investigate lipid characteristics in different parts of Dezhou donkey using lipidomics. The results show that IMF was more abundant in longissimus dorsi muscle (LDM) than rump muscle (RM) and hamstring muscle (HM), and mainly composed of triglycerides (TGs) rich in saturated fatty acid (SFAs) and monounsaturated fatty acid (MUFAs). A total of 1143 lipids belonging to 14 subclasses were identified in donkey meat, of which 73 lipids (23 upregulated and 50 downregulated) including glycerolipids (GLs), glycerophospholipids (GPs) and sphingolipids (SPs) were significantly different and are therefore potential biomarkers in LDM versus RM versus HM analyses (variable importance in projection >1, p < 0.05). Notably, 21 TGs upregulated in LDM were rich in MUFAs at sn-1 and SFAs at 2 and 3 positions of TG. Donkey muscle accumulated far more SFAs at the sn-3 position of TG, while more SFAs were present at the sn-1 positions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and the percentages of SFAs at the three positions in TG, PC, and PE in the LDM group were much higher. The abundance of MUFAs at the sn-2 positions of TG, PC, and PE was significantly greater than in sn-1 or 3 positions, and the percentages of 18:1n-9 at the sn-1 and 2 position of TGs in LDM were significantly higher than in RM and HM groups. Polyunsaturated fatty acids (e.g.,18:2n-6, 18:3n-3, and 20:4n-6) tended to occur at the sn-1 position in TG, but at the sn-2 position in PC and PE. Significantly differential lipids were mainly enriched in GP, GL, and SP pathways, all considered key pathways for regulating IMF. The results reveal the components, structures and metabolic pathways of lipid molecules in donkey meat, and provide novel insight into the development of donkey meat products and accurate regulation of IMF. PRACTICAL APPLICATION: Intramuscular fat (IMF) is an important factor affecting meat quality, which is directly related to meat flavor, juiciness, and tenderness, but lipid and metabolic profiles of IMF remain unclear. The current results provide basic information for the development of donkey meat products, and broaden our understanding of the regulation of IMF.