Publications by authors named "Jia Liu"

3,988 Publications

  • Page 1 of 1

The MRI enhancement ratio and plaque steepness may be more accurate for predicting recurrent ischemic cerebrovascular events in patients with intracranial atherosclerosis.

Eur Radiol 2022 Jun 30. Epub 2022 Jun 30.

Department of Neurology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, No. 305 E Zhongshan Rd, Nanjing, 210002, Jiangsu Province, China.

Objectives: To assess the complementary value of high-resolution multi-contrast MRI (hrMRI) in identifying symptomatic patients with intracranial atherosclerosis (ICAS) who are likely to experience recurrent ischemic cerebrovascular events.

Methods: In this retrospective cohort study, eighty patients with acute ischemic events attributed to ICAS who underwent hrMRI examination between January 2015 and January 2019 were included. Median follow-up for all patients was 30 months (range: 1 to 52 months) and recurrent ischemic cerebrovascular events were recorded. Cox regression analysis and time-dependent ROC were performed to quantify the association between the plaque characteristics and recurrent events.

Results: During the follow-up, 14 patients experienced recurrent ischemic cerebrovascular events. Young males and those with diabetes and poor medication persistence were more likely to experience recurrent events. ICAS in patients with recurrence had significantly higher enhancement ratio and steepness which is defined as the ratio between the plaque height and length than those without (p < 0.001 and p = 0.015, respectively). After adjustment of clinical factors, enhancement ratio (HR, 13.13 [95% CI, 3.58-48.20], p < 0.001) and plaque steepness (HR, 110.27 [95% CI, 4.75-2560.91], p = 0.003) were independent imaging biomarkers associated with recurrent events. Time-dependent ROC indicated that integrated high enhancement ratio and steepness into clinical risk factors improved discrimination power with the ROC increased from 0.79 to 0.94 (p = 0.008).

Conclusions: The enhancement ratio and plaque steepness improved the accuracy over traditional clinical risk factors in predicting recurrent ischemic cerebrovascular events for patients with ICAS.

Key Points: • High-resolution magnetic resonance imaging helps clinicians to evaluate high-risk Intracranial plaque. • The higher enhancement ratio and plaque steepness (= height/length) were the primary biomarkers associated with future ischemic cerebrovascular events. • High-resolution magnetic resonance imaging combined with clinical characteristics showed a higher accuracy for the prediction of recurrent events in patients with intracranial atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-022-08893-2DOI Listing
June 2022

Mutations in GCK May Lead to MODY2 by Reducing Glycogen Synthesis.

Adv Biol (Weinh) 2022 Jun 30:e2200097. Epub 2022 Jun 30.

Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.

Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity-onset diabetes of the young type-2 (MODY2, also known as GCK-MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4-8.3 mmol L , and rarely develops complications from diabetes. The treatment of MODY2 prefers a manageable diet rather than the use of insulin. Previous studies have identified GCK mutations only by online software prediction or enzyme kinetic analysis and thermolability assays which are complicated to be conducted. In this study, six mutations in the GCK gene, including four novel mutations and two mutations that are previously reported, are identified. All the six locations are highly conserved according to the sequencing alignment. Moreover, missense mutations are strongly predicted to be pathogenic using online programs. Functional studies show that mutations in GCK mutation do not affect insulin secretion but affect glycogen synthesis. These findings demonstrate that GCK mutations decrease glycogen synthesis, which leads to hyperglycemia in MODY2. Meanwhile, this study provides a new perspective and methods for identifying pathogenic mutations in GCK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adbi.202200097DOI Listing
June 2022

circRNA: Regulatory factors and potential therapeutic targets in inflammatory dermatoses.

J Cell Mol Med 2022 Jun 29. Epub 2022 Jun 29.

Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China.

The skin is the largest organ of the human body and acts as the first line of defence against injury and infection. Skin diseases are among the most common health problems and are associated with a considerable burden that encompasses financial, physical and mental consequences for patients. Exploring the pathogenesis of skin diseases can provide insights into new treatment strategies. Inflammatory dermatoses account for a large proportion of dermatoses and have a great impact on the patients' body and quality of life. Therefore, it is important to study their pathogenesis and explore effective treatment. Circular RNAs (circRNAs) are a special type of RNA molecules that play important regulatory roles in several diseases and are involved in skin pathophysiological processes. This review summarizes the biogenesis, properties and functions of circRNAs as well as their roles in the pathogenesis of inflammatory dermatoses, including psoriasis, lupus erythematosus, atopic dermatitis, lichen planus and severe acne and their potential as therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.17473DOI Listing
June 2022

Plasma Homocysteine Level Is Independently Associated With Conventional Atherogenic Lipid Profile and Remnant Cholesterol in Adults.

Front Cardiovasc Med 2022 13;9:898305. Epub 2022 Jun 13.

Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Background: Homocysteine (Hcy) is an independent risk factor for cardiovascular disease, while mechanisms are unclear. Despite inconsistent and limited, epidemiological and experimental studies indicated that hyperhomocysteinemia (HHcy) affected lipid metabolism. This study aims to investigate the association of plasma Hcy with traditional lipid profiles and remnant cholesterol (RC) in Chinese adults.

Methods: In total, 7,898 subjects aged 20-79 years who underwent a physical examination at Beijing Chao-Yang Hospital in Beijing were included in this study. Fasting plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], Hcy, and other metabolic risk factors were measured by routine automated laboratory methods. RC was calculated as TC minus HDL-C and LDL-C. The linear regression model and logistic regression model were used to assess the relationship between Hcy and lipids after adjusting potential confounders.

Results: Of the subjects, the median level of plasma Hcy was 13.0 μmol/L and 32.3% had HHcy. Plasma Hcy was negatively associated with HDL-C, ApoA1, and Lp(a) and positively associated with TG levels after adjusting age, sex, body mass index, blood pressure, alanine transaminase, aspartate transaminase, creatinine, uric acid, and glucose. HHcy significantly increased the risk of low HDL-C [odds ratio (OR) 1.26; 95%CI (1.11-1.44); < 0.001]. The net mediation effects of ApoA1 on the relationship between Hcy and HDL-C before and after adjusting confounders were 46.9 and 30.6%, respectively. More interestingly, the RC level was significantly elevated in subjects with HHcy after adjusting other influencing factors ( = 0.025). Hcy presented a positive correlation with RC levels after adjusting the above confounding factors (β = 0.073, = 0.004), and the correlation was still significant even after controlling other lipids, including TG, LDL-C, HDL-C, ApoA1, ApoB, and Lp(a).

Conclusion: Our study showed that plasma Hcy was not only significantly associated with conventional atherogenic lipids but also independently correlated with RC levels beyond other lipids after controlling potential confounders. This finding proposes that identifying Hcy-related dyslipidemia risk, both traditional lipids and RC residual risk, is clinically relevant as we usher in a new era of targeting Hcy-lowering therapies to fight against dyslipidemia or even cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2022.898305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234129PMC
June 2022

Epidemiological and virological surveillance of influenza viruses in China during 2020-2021.

Infect Dis Poverty 2022 Jun 29;11(1):74. Epub 2022 Jun 29.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention; WHO Collaborating Centre for Reference and Research on Influenza; Key Laboratory for Medical Virology and Viral Diseases, National Health Commission, Beijing, China.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, seasonal influenza activity declined globally and remained below previous seasonal levels, but intensified in China since 2021. Preventive measures to COVID-19 accompanied by different epidemic characteristics of influenza in different regions of the world. To better respond to influenza outbreaks under the COVID-19 pandemic, we analyzed the epidemiology, antigenic and genetic characteristics, and antiviral susceptibility of influenza viruses in the mainland of China during 2020-2021.

Methods: Respiratory specimens from influenza like illness cases were collected by sentinel hospitals and sent to network laboratories in Chinese National Influenza Surveillance Network. Antigenic mutation analysis of influenza virus isolates was performed by hemagglutination inhibition assay. Next-generation sequencing was used for genetic analyses. We also conducted molecular characterization and phylogenetic analysis of circulating influenza viruses. Viruses were tested for resistance to antiviral medications using phenotypic and/or sequence-based methods.

Results: In the mainland of China, influenza activity recovered in 2021 compared with that in 2020 and intensified during the traditional influenza winter season, but it did not exceed the peak in previous years. Almost all viruses isolated during the study period were of the B/Victoria lineage and were characterized by genetic diversity, with the subgroup 1A.3a.2 viruses currently predominated. 37.8% viruses tested were antigenically similar to reference viruses representing the components of the vaccine for the 2020-2021 and 2021-2022 Northern Hemisphere influenza seasons. In addition, China has a unique subgroup of 1A.3a.1 viruses. All viruses tested were sensitive to neuraminidase inhibitors and endonuclease inhibitors, except two B/Victoria lineage viruses identified to have reduced sensitivity to neuraminidase inhibitors.

Conclusions: Influenza activity increased in the mainland of China in 2021, and caused flu season in the winter of 2021-2022. Although the diversity of influenza (sub)type decreases, B/Victoria lineage viruses show increased genetic and antigenic diversity. The world needs to be fully prepared for the co-epidemic of influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus globally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40249-022-01002-xDOI Listing
June 2022

Optimal induction chemotherapy regimen for locoregionally advanced nasopharyngeal carcinoma: an update Bayesian network meta-analysis.

Eur Arch Otorhinolaryngol 2022 Jun 29. Epub 2022 Jun 29.

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.

Background And Purpose: Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been established as standard of care for locoregionally advanced nasopharyngeal carcinoma (LANPC). No direct comparison between different IC regimens has been performed. We conducted Bayesian network meta-analysis to evaluate the efficacy and safety of IC regimens in LANPC.

Materials And Methods: We systematically searched studies comparing different regimens of IC plus CCRT versus CCRT alone for LANPC. Pairwise meta-analysis and Bayesian network meta-analysis were conducted using Review Manger, Stata and R software.

Results: Eight eligible studies with a total of 2382 patients were involved. Compared with CCRT alone, IC + CCRT significantly improved PFS (HR = 0.68 [95% CI 0.59-0.79]) and OS (HR = 0.72 [95% CI 0.61-0.86]) in conventional meta-analysis. In Bayesian network meta-analysis, GP (gemcitabine and cisplatin) had advantage in prolonging PFS, OS and DMFS. GP had adverse but manageable impacts on hemoglobin and platelet. Meanwhile, treatment compliance of GP was higher than that of other regimens.

Conclusion: Based on existing evidences, GP could likely to be recommended as an optimal IC regimen for LANPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00405-022-07435-2DOI Listing
June 2022

Efficient Production of L-homophenylalanine by  Enzymatic-Chemical Cascade Catalysis.

Angew Chem Int Ed Engl 2022 Jun 28. Epub 2022 Jun 28.

Jiangnan University, State Key Laboratory of Food Science and Technology, 1800 Lihu Road, Wuxi, China, 214122, Wuxi, CHINA.

L-Homophenylalanine (L-HPA) is a vital building block for the synthesis of numerous chiral drugs. However, the high cost of starting materials limits the industrial production of L-HPA. In this study, an enzymatic-spontaneous chemical cascade route for L-HPA production was designed based on retrosynthetic analysis. This route, using simple benzaldehyde and pyruvate as starting materials, is extremely cost-effective. The enzymes were screened and further assembled in E.coli, and TipheDH was identified as the rate-limiting enzyme. Therefore, TipheDH was engineered to improve its specific activity (by 82%) and expression level (by 254%), thus generating the best strain (W14). W14 exhibited the optimum enzyme activity ratio (1.7:1.1:1:1.8) and demonstrated production of 100.9 g/L of L-HPA (with 94% conversion, >99% ee) in a 5-L reactor. This route effectively exploits the power of cascades and offers insight into avenues for synthesizing other valuable chemicals from inexpensive building blocks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202207077DOI Listing
June 2022

LncRNA TMPO-AS1 promotes esophageal squamous cell carcinoma progression by forming biomolecular condensates with FUS and p300 to regulate TMPO transcription.

Exp Mol Med 2022 Jun 27. Epub 2022 Jun 27.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.

Esophageal squamous cell carcinoma (ESCC) is one of the most life- and health-threatening malignant diseases worldwide, especially in China. Long noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and tumor progression. However, the roles and mechanisms of lncRNAs in ESCC require further exploration. Here, in combination with a small interfering RNA (siRNA) library targeting specific lncRNAs, we performed MTS and Transwell assays to screen functional lncRNAs that were overexpressed in ESCC. TMPO-AS1 expression was significantly upregulated in ESCC tumor samples, with higher TMPO-AS1 expression positively correlated with shorter overall survival times. In vitro and in vivo functional experiments revealed that TMPO-AS1 promotes the proliferation and metastasis of ESCC cells. Mechanistically, TMPO-AS1 bound to fused in sarcoma (FUS) and recruited p300 to the TMPO promoter, forming biomolecular condensates in situ to activate TMPO transcription in cis by increasing the acetylation of histone H3 lysine 27 (H3K27ac). Targeting TMPO-AS1 led to impaired ESCC tumor growth in a patient-derived xenograft (PDX) model. We found that TMPO-AS1 is required for cell proliferation and metastasis in ESCC by promoting the expression of TMPO, and both TMPO-AS1 and TMPO might be potential biomarkers and therapeutic targets in ESCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-022-00791-3DOI Listing
June 2022

Pore Strategy Design of a Novel NiTi-Nb Biomedical Porous Scaffold Based on a Triply Periodic Minimal Surface.

Front Bioeng Biotechnol 2022 8;10:910475. Epub 2022 Jun 8.

State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai, China.

The pore strategy is one of the important factors affecting the biomedical porous scaffold at the same porosity. In this work, porous scaffolds were designed based on the triply periodic minimal surface (TPMS) structure under the same porosity and different pore strategies (pore size and size continuous gradient distribution) and were successfully prepared using a novel NiTiNb alloy and selective laser melting (SLM) technology. After that, the effects of the pore strategies on the microstructure, mechanical properties, and permeability of porous scaffolds were systematically investigated. The results showed that the NiTiNb scaffolds have a low elastic modulus (0.80-1.05 GPa) and a high ductility (15.3-19.1%) compared with previous works. The pore size has little effect on their mechanical properties, but increasing the pore size significantly improves the permeability due to the decrease in specific surfaces. The continuous gradient distribution of the pore size changes the material distribution of the scaffold, and the smaller porosity structure has a better load-bearing capacity and contributes primarily to the high compression strength. The local high porosity structure bears more fluid flow, which can improve the permeability of the overall scaffold. This work can provide theoretical guidance for the design of porous scaffolds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2022.910475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214207PMC
June 2022

Adipose Tissue Insulin Resistance Is Positively Associated With Serum Uric Acid Levels and Hyperuricemia in Northern Chinese Adults.

Front Endocrinol (Lausanne) 2022 10;13:835154. Epub 2022 Jun 10.

Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.

Objective: Adipose tissue plays a crucial role in serum uric acid (UA) metabolism, but the relative contribution of adipose tissue insulin resistance (IR) to serum UA levels and hyperuricemia have not explicitly been illustrated. Herein, we aimed to investigate the association between the adipose tissue insulin resistance index (Adipo-IR) and hyperuricemia in this cross-sectional study. The homeostasis model assessment of insulin resistance (HOMA-IR) index, another widely applied marker to determine systemic IR, was also explored.

Methods: A total of 5821 adults were included in this study. The relationship between Adipo-IR or HOMA-IR and serum UA levels was assessed by multivariate linear regression. Binary logistic regression analyses were applied to determine the sex-specific association of the Adipo-IR tertiles and HOMA-IR tertiles with hyperuricemia. Participants were then divided into normal BMI (18.5 ≤ BMI < 24) and elevated BMI (BMI ≥ 24) groups for further analysis.

Results: Both Adipo-IR and HOMA-IR were positively correlated with serum UA ( < 0.001). Compared with the lowest tertile, the risks of hyperuricemia increased across Adipo-IR tertiles (middle tertile: OR 1.52, 95%CI 1.24-1.88; highest tertile: OR 2.10, 95%CI 1.67-2.63) in men after full adjustment ( for trend < 0.001). In women, only the highest tertile (OR 2.09, 95%CI 1.52-2.87) was significantly associated with hyperuricemia. Those associations remained significant in participants with normal BMI status. As for HOMA-IR, only the highest tertile showed positive relationships with hyperuricemia in both genders after full adjustment ( for trend < 0.001). The association between HOMA-IR and hyperuricemia disappeared in men with normal BMI status.

Conclusions: Adipo-IR was strongly associated with serum UA and hyperuricemia regardless of BMI classification. In men with normal BMI, Adipo-IR, rather than HOMA-IR, was closely associated with hyperuricemia. Altogether, our finding highlights a critical role of adipose tissue IR on serum UA metabolism and hyperuricemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2022.835154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226335PMC
June 2022

Treatment of multiple gingival recessions with concentrated growth factor membrane and coronally advanced tunnel technique via digital measurements: A randomized controlled clinical trial.

J Dent Sci 2022 Apr 9;17(2):725-732. Epub 2021 Nov 9.

Department of Periodontology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Beijing, PR China.

Background/purpose: Research into biomaterial alternatives to connective tissue grafts (CTG) is a research hotspot. The purpose of this clinical trial was to compare the effectiveness of root coverage through tunnel technique with concentrated growth factor (CGF) vs CTG in treating multiple gingival recessions using digital measurements.

Materials And Methods: Seventy Cairo Class I multiple gingival recessions (in 28 patients) were treated with either CGF or CTG combined with coronally advanced tunnel technique. Digital models were obtained at baseline, 2 weeks, 6 weeks, and 6 months post-op to compare the gain in gingival height, area, volume, and thickness. Tooth sensitivity, post-operative pain, and healing index were also recorded.

Results: Complete root coverage at 6 months post-op were 47.06% in the CGF group and 77.78% in the CTG groups. Mean root coverages were 80.55% and 96.18%, respectively. No statistical difference was demonstrated between the two groups in terms of gingival area gain at 2 weeks post-op, but the CTG group had greater increases in gingival height, area, volume, and thickness in the period after 2 weeks post-op. Pain scores were statistically significantly lower in the CGF group. At 6 months post-op, sensitivity scores decreased more significantly in the CTG group.

Conclusion: Digital measurements revealed post-operative gingival shrinkage was more pronounced in the CGF group than in the CTG group when combined with coronally advanced tunnel technique. Despite the ease-of-use and minimal post-operative discomfort, it is difficult to achieve similar root coverage outcomes to CTG when using CGF alone in treating multiple gingival recessions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jds.2021.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201548PMC
April 2022

Serum Untargeted Metabolomics Reveal Potential Biomarkers of Progression of Diabetic Retinopathy in Asians.

Front Mol Biosci 2022 9;9:871291. Epub 2022 Jun 9.

Department of Ophthalmology, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Beijing, China.

To reveal molecular mechanisms of diabetic retinopathy (DR) in Asians and facilitate the identification of new therapeutic targets through untargeted metabolomics. To determine the differences in serum metabolites and metabolic pathways between different stages of diabetic retinopathy in patients with type 2 diabetic mellitus (T2DM) and proliferative DR (PDR) and non-proliferative DR (NPDR) and identify differential metabolites between T2DM and DR (NPDR and PDR) patients. This prospective observational registration study described the differential metabolites between 45 T2DM patients and 15 control cases with no significant differences in clinical characteristics. Their biospecimens and clinical information were collected and recorded in their medical reports. DR phenotypes of the subjects were verified by retina specialists. Serum metabolites were analyzed using high-resolution mass spectrometry with liquid chromatography. Untargeted metabolomics was performed on serum samples from 15 T2DM patients, 15 non-proliferative diabetic retinopathy patients, 15 proliferative diabetic retinopathy patients, and 15 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis (PLS-DA), hierarchical clustering analysis (HCA), and generalized linear regression models. Through untargeted metabolomics, 931 features (523 in positive and 408 in negative modes) with 102 common metabolites highly relevant to the presence of DR were detected. In the adjusted analysis, 67 metabolic features differed significantly between T2DM and NPDR patients. Pathway analysis revealed alterations in metabolisms of amino acids and fatty acids. Glutamate, phosphatidylcholine, and 13-hydroperoxyoctadeca-9,11-dienoic acid (13-PHODE) were key contributors to these pathway differences. A total of 171 features distinguished PDR patients from T2DM patients, and pathway analysis revealed alterations in amino acid metabolism, fatty acid metabolism, nitrogen metabolism, and tricarboxylic acid cycle. Aspartate, glutamate, glutamine, ornithine, N-acetyl-l-glutamate, N-acetyl-l-aspartate, citrate, succinate, N-(L-arginino)succinate, 2-oxoglutarate, 13-hydroperoxyoctadeca-9,11-dienoic acid, methionine, lysine, threonine, phenylalanine, N(pi)-methyl-l-histidine, phosphatidylcholine, and linoleate were major contributors to the pathway differences. Between NPDR patients and PDR patients, there were 79 significant differential metabolites. Enrichment pathway analysis showed changes in amino acid metabolism, fatty acid metabolism, pantothenate, and CoA biosynthesis. Aspartate, glutamine, N-acetyl-l-glutamate, N-acetyl-l-aspartate, pantothenate, dihomo-gamma-linolenate, docosahexaenoic acid, and icosapentaenoic acid were key factors for the differences of these pathways. This study demonstrated that the pathways of arginine biosynthesis metabolism, linoleic acid metabolism, alanine, aspartate, and glutamate metabolism, as well as d-glutamine and d-glutamate metabolism, were dysregulated in DR patients of the Asian population. Increased levels of glutamate, aspartate, glutamine, N-acetyl-l-glutamate, and N-acetyl-l-aspartate and decreased levels of dihomo-gamma-linolenate, docosahexaenoic, and icosapentaenoic were considered as the metabolic profile that could distinguish PDR from NPDR in Asians. Phosphatidylcholine and 13-PHODE were identified as two major novel metabolite markers in advanced stages of DR in our study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2022.871291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224596PMC
June 2022

Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia.

Blood Cancer J 2022 Jun 24;12(6):96. Epub 2022 Jun 24.

Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, P. R. China.

Chimeric antigen receptor-engineered T (CAR-T) cells have shown promising efficacy in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, challenges remain including long manufacturing processes that need to be overcome. We presented the CD19-targeting CAR-T cell product GC007F manufactured next-day (FasTCAR-T cells) and administered to patients with R/R B-ALL. A total of 21 patients over 14 years of age with CD19  R/R B-ALL were screened, enrolled and infused with a single infusion of GC007F CAR-T at three different dose levels. The primary objective of the study was to assess safety, secondary objectives included pharmacokinetics of GC007F cells in patients with R/R B-ALL and preliminary efficacy. We were able to demonstrate in preclinical studies that GC007F cells exhibited better proliferation and tumor killing than conventional CAR-T (C-CAR-T) cells. In this investigator-initiated study all 18 efficacy-evaluable patients achieved a complete remission (CR) (18/18, 100.00%) by day 28, with 17 of the patients (94.4%) achieving CR with minimal residual disease (MRD) negative. Fifteen (83.3%) remained disease free at the 3-month assessment, 14 patients (77.8%) maintaining MRD negative at month 3. Among all 21 enrolled patients, the median peak of CAR-T cell was on day 10, with a median peak copy number of 104899.5/µg DNA and a median persistence period of 56 days (range: 7-327 days). The incidence of cytokine release syndrome (CRS) was 95.2% (n = 20), with severe CRS occurring in 52.4% (n = 11) of the patients. Six patients (28.6%) developed neurotoxicity of any grade. GC007F demonstrated superior expansion capacity and a less exhausted phenotype as compared to (C-CAR-T) cells. Moreover, this first-in-human clinical study showed that the novel, next-day manufacturing FasTCAR-T cells was feasible with a manageable toxicity profile in patients with R/R B-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-022-00688-4DOI Listing
June 2022

Suppressing Redox Shuttling with Lithiated Nafion-Modified Separators for Li-O Batteries.

ChemSusChem 2022 Jun 24:e202200769. Epub 2022 Jun 24.

Nation & Local United Engineering Laboratory for Power Batteries, Faculty of Chemistry, Northeast Normal University, Changchun, Jilin, 130024, P. R. China.

Although the employment of redox mediator (RM) is an effective strategy to reduce the overpotential by avoiding the direct electrochemical oxidization of Li O during charging, an unexpected redox shuttling in Li-O system leads to RM degradation and continuous deterioration of Li anode, finally resulting in a limited cycling stability. Here, a functional lithiated Nafion-modified separator was firstly introduced to inhibit the shuttle effect by coulombic/electrostatic interactions in RM-involved Li-O batteries. The fabrication of the separator involved easily accessible raw materials and an easy-to-operate process, which made it suitable for large-scale production. The enhancement of lithiated process on electrochemical properties was systematically investigated. In addition, the influence of decorated amount on cycling stability was also studied. Furthermore, the functional contribution of lithiated Nafion on inhibition of redox shuttling and the working mechanism for cells with and without as-prepared separators were proposed. This work can give an insight into the development of functional separator (i. e., activity issue) and the suppression of parasitic reactions (i. e., selectivity issue) in Li-O batteries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cssc.202200769DOI Listing
June 2022

Early-phase insulin hypersecretion associated with weight loss outcome after LSG: a prospective cohort study in Asian patients with BMI ≥28 kg/m.

Surg Obes Relat Dis 2022 May 18. Epub 2022 May 18.

Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address:

Background: Obesity has become a global problem that poses a serious threat to human health. Laparoscopic sleeve gastrectomy (LSG) is an effective long-term treatment. However, the weight loss of some patients after LSG is still insufficient. It is necessary to investigate the factors associated with inadequate weight loss after LSG.

Objective: The objective of this study was to explore whether preoperative insulin secretion could be associated with weight loss after LSG in patients with obesity.

Setting: This is a single-center prospective cohort study conducted in a university hospital.

Methods: Patients from a prospective database who underwent LSG were analyzed. All 178 participants underwent a 75-g oral glucose tolerance test (OGTT) to assess preoperative insulin and c-peptide secretion before LSG. The areas under the curve (AUCs) for glucose, insulin, and c-peptide were determined in the OGTT. The percentage of excess weight loss (%EWL) and the percentage of total weight loss (%TWL) were used to estimate the effect of weight loss after LSG. Regression models were used to assess the correlation between preoperative insulin and c-peptide secretion with %EWL ≥75% and TWL ≥35% at 12 months after LSG.

Results: The AUCs of insulin and c-peptide were significantly lower in the %EWL ≥75% and %TWL ≥35% groups at 0-30 minutes, 0-60 minutes, and 0-120 minutes during the OGTT. At 30, 60, and 120 minutes during the OGTT, c-peptide levels were significantly lower in the %EWL ≥75% group and %TWL ≥35% group. The preoperative c-peptide level at 30 minutes during the OGTT (C) was significantly negatively correlated with %EWL (β = -.37, P < .001) and %TWL (β = -.28, P = .011). Univariate logistic regression analysis showed that preoperative C was associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative C had an 8-fold higher %TWL ≥35% after LSG than those with a high C (odds ratio: 8.41 [95% confidence interval: 1.46-48.58], P = .017). Similarly, patients with a low preoperative C had a 7-fold higher EWL% ≥75% after LSG than patients with a high C (odds ratio: 7.25 [95% confidence interval: 1.11-47.50], P = .039).

Conclusions: The rate of weight loss after LSG is low among patients with preoperative hyperinsulinemia. The preoperative c-peptide level at 30 minutes during the OGTT is associated with weight loss after LSG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.soard.2022.05.013DOI Listing
May 2022

Nanosilicate-Reinforced Silk Fibroin Hydrogel for Endogenous Regeneration of both Cartilage and Subchondral Bone.

Adv Healthc Mater 2022 Jun 24:e2200602. Epub 2022 Jun 24.

School of Medicine, Southeast University, Nanjing, 210009, China.

Osteochondral defects are characterized by injuries to both cartilage and subchondral bone, which is a result of trauma, inflammation, or inappropriate loading. Due to the unique biological properties of subchondral bone and cartilage, developing a tissue engineering scaffold that can promote dual-lineage regeneration of cartilage and bone simultaneously remains a great challenge. In this study, we fabricated a microporous nanosilicate-reinforced enzymatically-crosslinked silk fibroin (SF) hydrogel by introducing two-dimensional montmorillonite (MMT) nanoparticles via intercalation chemistry. In vitro studies showed that SF-MMT nanocomposite hydrogel had improved mechanical properties and hydrophilicity, as well as the bioactivities to promote the osteogenic differentiation of bone marrow stem cells (BMSCs) with an increased ALP activity and calcium deposition and maintain chondrocyte phenotype with a higher aggrecan expression and a lower matrix-degrading enzyme expression (MMP3/13, ADAMTS4/5) compared with SF hydrogel. Global proteomic analysis verified the dual-lineage bioactivities of SF-MMT nanocomposite hydrogel, which were probably regulated by multiple signaling pathways. Besides, it was observed that the biophysical interaction of cells and SF-MMT nanocomposite hydrogel was partially mediated by clathrin-mediated endocytosis and its downstream processes. In vivo, SF-MMT nanocomposite hydrogel effectively promoted subchondral bone and cartilage regeneration in rabbit osteochondral defect model as evidenced by macroscopic, micro-CT, and histological evaluation. In conclusion, we developed a functionalized SF-MMT nanocomposite hydrogel with dual-lineage bioactivity for osteochondral regeneration, indicating its potential in osteochondral tissue engineering. Statement of significance Osteochondral defects involve the injuries of both articular cartilage and subchondral bone. Due to the distinct properties of these two tissues, it remains a great challenge to induce the dual-lineage regeneration of cartilage and bone simultaneously. This study developed an SF-MMT nanocomposite hydrogel by enzymatic crosslinking and intercalation chemistry, which effectively enhanced the osteogenic differentiation of BMSCs and the maintenance of chondrocyte phenotype, thereby promoting the dual-lineage regeneration of articular cartilage and subchondral bone in osteochondral defects. Therefore, SF-MMT nanocomposite hydrogel with dual-lineage bioactivity is a promising scaffold for osteochondral tissue engineering. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202200602DOI Listing
June 2022

Activation of peroxydisulfate via photothermal synergistic strategy for wastewater treatment: Efficiency and mechanism.

J Hazard Mater 2022 08 25;436:129224. Epub 2022 May 25.

State Key Laboratory of Pollution Control and Resource Reuse, Shanghai Institute of Pollution Control and Ecological Security, School of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.

Peroxydisulfate (PDS)-based advanced oxidation processes (AOPs) have been demonstrated to be an effective technology for the removal of refractory organic contaminants from the aquatic environment. Herein, a photothermal synergistic strategy is developed to realize the green activation of PDS under solar light irradiation. An innovative solar photothermal reaction system and its corresponding evaluation method are established. The results show that there is a synergistic effect between light and light-generated thermal effects on the activation of PDS for effectively removing fulvic acid (FA). The maximum degradation percentage of FA increases from 42.6% to 90.8% after introducing ZrC nanoparticles as photothermal materials. The maximum temperature of the whole system is up to 66.4 ℃ after 120 min irradiation at 0.007 wt% solid content of ZrC, which is higher by 26.9% compared with that in the absence of ZrC nanoparticles. Furthermore, the underlying mechanism and PDS activation efficiency are deeply investigated. This work provides a viable strategy for directly using solar radiation to activate PDS for degrading refractory organic compounds, which creates a new avenue toward the utilization of solar energy for wastewater treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2022.129224DOI Listing
August 2022

SPAG5 as a novel biomarker and potential therapeutic target via regulating AKT pathway in multiple myeloma.

Leuk Lymphoma 2022 Jun 22:1-8. Epub 2022 Jun 22.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

SPAG5, as a spindle-associated protein in mitosis, has been observed to have oncogenic activities in solid tumors. Here, we identified that SPAG5 expression was correlated with the deterioration of plasma cell malignancy and SPAG5 overexpression (OE) predicted unfavorable outcomes in multiple myeloma (MM). SPAG5 knockdown led to anti-MM effects in MM cell lines and animal xenograft models by regulating cell growth and apoptosis. Furthermore, gene set enrichment analysis (GSEA) revealed that PI3K/AKT/mTOR pathway was enriched in MM samples with highly expressed SPAG5 from GSE datasets. There was a concurrent downregulation of phosphorylation levels in the AKT/mTOR pathway. Yet OE of SPAG5 could restore the cell growth and p-AKT levels in MM cells after treatment with the AKT inhibitor MK2206. Taken together, SPAG5 could serve as a novel biomarker, and targeting the SPAG5 might have therapeutic potential in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2022.2086247DOI Listing
June 2022

Long-term effects of total partial pancreatectomy among patients with pancreatic cancer: a population-based study.

Ann Transl Med 2022 May;10(10):539

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Total pancreatectomy (TP) for pancreatic cancer (PC) has been limited historically for fear of elevated perioperative morbidity and mortality. With advances in perioperative care, TP may be an alternative option to partial pancreatectomy (PP). Limited evidence clarified the indication for these two procedures in PC patients, especially in patients with different tumor staging and location. Thus, this study aims to compare the outcomes after TP and PP for PCs of different T stages and locations.

Methods: The study identified 14,456 PC patients with potentially curable primary tumor (T1-3) who received TP or PP from the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2016. Detailed clinical and tumor covariates were all collected. Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints of interest in this study. OS and CSS were compared between patients after TP and PP using log-rank analysis.

Results: For all patients, except for tumor location, TP group was comparable to the PP group. OS and CSS of the TP group were worse than of the PP group (median OS: 19 20 months, P=0.0058; median CSS: 24 26 months, P=0.00098, respectively). In stratifying analyses, TP was significantly related to worse OS and CSS than PP in pancreatic head and neck cancer patients with T2-stage tumors (median OS: 18 19 months, P=0.0016; median CSS: 22 24 months, P=0.00055, respectively), whereas for patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer, OS and CSS of the two groups were similar (all P>0.05).

Conclusions: Compared with PP, TP offered worse prognosis in pancreatic head and neck cancer patients with T2-stage tumors, furthermore, TP and PP achieved comparable prognosis in patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-22-2217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201187PMC
May 2022

Mitochondrial DNA Efflux Maintained in Gingival Fibroblasts of Patients with Periodontitis through ROS/mPTP Pathway.

Oxid Med Cell Longev 2022 8;2022:1000213. Epub 2022 Jun 8.

Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China.

Mitochondria have their own mitochondrial DNA (mtDNA). Aberrant mtDNA is associated with inflammatory diseases. mtDNA is believed to induce inflammation via the abnormal mtDNA release. Periodontitis is an infectious, oral inflammatory disease. Human gingival fibroblasts (HGFs) from patients with chronic periodontitis (CP) have shown to generate higher reactive oxygen species (ROS) that cause oxidative stress and have decreased mtDNA copy number. Firstly, cell-free mtDNA was identified in plasma from CP mice through qRT-PCR. Next, we investigated whether mtDNA efflux was maintained in primary cultures of HGFs from CP patients and the possible underlying mechanisms using adenovirus-mediated transduction live cell imaging and qRT-PCR analysis. Here, we reported that mtDNA was increased in plasma from the CP mice. Additionally, we confirmed that CP HGFs had significant mtDNA efflux from mitochondria compared with healthy HGFs. Furthermore, lipopolysaccharide (LPS) from can also cause mtDNA release in healthy HGFs. Mechanistically, LPS upregulated ROS levels and mitochondrial permeability transition pore (mPTP) opening by inhibition of pyruvate dehydrogenase kinase (PDK)2 expression, resulting in mtDNA release. Importantly, mtDNA efflux was even persistent in HGFs after LPS was removed and cells were passaged to the next three generations, indicating that mtDNA abnormalities were retained in HGFs in vitro, similar to the primary hosts. Taken together, our results elucidate that mtDNA efflux was maintained in HGFs from periodontitis patients through abnormal ROS/mPTP activity. Therefore, our work indicates that persistent mtDNA efflux may be a possible diagnostic and therapeutic target for patients with periodontitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2022/1000213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201712PMC
June 2022

Rare germline deleterious variants increase susceptibility for lung cancer.

Hum Mol Genet 2022 Jun 18. Epub 2022 Jun 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies (GWAS), they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology (EAGLE) study, a homogenous population including 1461 LC cases and 1316 controls. In single variant analyses, we identified a new RDV, rs77187983 (EHBP1, Odds Ratio [OR] = 3.13, 95% confidence interval [CI] = 1.34-7.30, P = 0.008) and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25-3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04-13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair (carrier frequency [CF] = 22.9% vs. 19.5%, P = 0.017) and Fanconi anemia (CF = 12.5% vs. 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing correction but were enriched in cases vs. controls from large scale public biobank resources, including TCGA, FinnGen, and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddac123DOI Listing
June 2022

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury.

Mol Biol Rep 2022 Jun 17. Epub 2022 Jun 17.

Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA.

Background: Endovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling.

Methods And Results: Carotid balloon injury was performed in female and male Sprague-Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206- or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy.

Conclusions: Decreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11033-022-07644-2DOI Listing
June 2022

Impaired sensitivity to thyroid hormones is associated with elevated homocysteine levels in the euthyroid population.

J Clin Endocrinol Metab 2022 Jun 16. Epub 2022 Jun 16.

Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China.

Background: Homocysteine (Hcy), a known risk factor for cardiovascular disease, has been reported to be linked with thyroid dysfunction. However, the association of thyroid hormones sensitivity with Hcy levels remains unknown. We aimed to investigate the relationship between thyroid hormones sensitivity and elevated Hcy levels in the euthyroid population.

Methods: A total of 8957 euthyroid adults were included in this study. Free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), Hcy levels and other clinical parameters were measured. Hyperhomocysteinemia (HHcy) was defined as serum Hcy level >15 μmol/L. Thyroid hormone sensitivity indices were calculated by thyroid feedback quantile-based index (TFQI), Chinese-referenced parametric TFQI (PTFQI), TSH index (TSHI) and thyrotropin thyroxine resistance index (TT4RI).

Results: Subjects with decreased sensitivity to thyroid hormones had higher Hcy levels (P for trend <0.001). Logistic regression analysis revealed the higher quartiles of TFQI, PTFQI, TSHI, and TT4RI were significantly associated with elevated Hcy levels, and these associations remained significant even after adjustment for multiple risk factors. After adjusting for age, sex, BMI, dyslipidemia, fatty liver, diabetes, and hypertension, the OR (95% CI) for having HHcy of the TFQI in the highest quartile was 1.393 (1.210, 1.603), the PTFQI in the highest quartile was 1.409 (1.225, 1.621), the TSHI in the highest quartile was 1.372 (1.190, 1.583), and the TT4RI in the highest quartile was 1.315 (1.141, 1.515) (all P < 0.001).

Conclusions: In euthyroid subjects, impaired sensitivity to thyroid hormones was associated with elevated Hcy levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgac371DOI Listing
June 2022

Glucose metabolism inhibitor PFK-015 combined with immune checkpoint inhibitor is an effective treatment regimen in cancer.

Oncoimmunology 2022 25;11(1):2079182. Epub 2022 May 25.

State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

Metabolic inhibition via PFKFB3 inhibition has demonstrated considerable tumor inhibitory effects in various studies; however, PFKFB3 inhibition did not show satisfactory tumor inhibition when used in clinical trials. PFKFB3 is a crucial metabolic enzyme that is highly upregulated in cancer cells and directly affects tumor glycolysis. Here, we showed that PFKFB3 inhibition suppresses tumors in vitro and in vivo in immune-deficient xenografts. However, this inhibition induces the upregulation of PD-L1 levels, which inactivated cocultured T-cells in vitro, compromises anti-tumor immunity in vivo, and reduced anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of PFKFB3 inhibition in immunocompetent and hu-PBMC NOG mouse models. Mechanistically, PFKFB3 inhibition increases phosphorylation of PFKFB3 at residue Ser461, which increases interaction with HIF-1α, and their colocalization into the nucleus, where HIF-1α transcriptionally upregulate PD-L1 expression and causes subsequent tumor immune evasion. Higher phos-PFKFB3 correlated with higher PD-L1 expression, lower CD8 and GRZMB levels, and shorter survival time in ESCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2022.2079182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9191911PMC
June 2022

Recent advances in exosome-mediated nucleic acid delivery for cancer therapy.

J Nanobiotechnology 2022 Jun 14;20(1):279. Epub 2022 Jun 14.

Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.

Cancer is a leading public health problem worldwide. Its treatment remains a daunting challenge, although significant progress has been made in existing treatments in recent years. A large concern is the poor therapeutic effect due to lack of specificity and low bioavailability. Gene therapy has recently emerged as a powerful tool for cancer therapy. However, delivery methods limit its therapeutic effects. Exosomes, a subset of extracellular vesicles secreted by most cells, have the characteristics of good biocompatibility, low toxicity and immunogenicity, and great designability. In the past decades, as therapeutic carriers and diagnostic markers, they have caught extensive attention. This review introduced the characteristics of exosomes, and focused on their applications as delivery carriers in DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), circular RNA (circRNA) and other nucleic acids. Meanwhile, their application in cancer therapy and exosome-based clinical trials were presented and discussed. Through systematic summarization and analysis, the recent advances and current challenges of exosome-mediated nucleic acid delivery for cancer therapy are introduced, which will provide a theoretical basis for the development of nucleic acid drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12951-022-01472-zDOI Listing
June 2022

Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications.

J Adv Res 2022 Jun 11. Epub 2022 Jun 11.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China. Electronic address:

Introduction: With the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions.

Objectives: Here, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism.

Methods: Hematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo.

Results: Intravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg.

Conclusion: IVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2022.06.002DOI Listing
June 2022

Quantitative detection of Ganodermati lucidum immunomodulatory protein-8 by a peptide-antigen-antibody sandwich ELISA.

J Microbiol Methods 2022 Jun 11;199:106518. Epub 2022 Jun 11.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China. Electronic address:

In order to rapidly determine the concentration of recombinant Ganoderma lucidum immunomodulatory protein-8 (rLZ-8) at a lower cost, a peptide-antigen-antibody sandwich ELISA method was developed based on a dodecapeptide LTPHKHHKHLHA with higher affinity for rLZ-8, which was identified from phage display after four rounds of screening. The binding mode between rLZ-8 and the peptide ligand was further simulated and revealed by molecular docking. Standard addition and repetitive testing were carried out to evaluate the accuracy, reproducibility and feasibility of the developed ELISA detection method. The method based on this peptide ligand was then successfully applied in the quantitative determination of rLZ-8 concentrations in fermentation broth. In summary, the peptide-antigen-antibody sandwich ELISA method developed here could be conveniently applied in the detection of rLZ-8 during fermentation and might provide new insights for the detection of other specific proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mimet.2022.106518DOI Listing
June 2022

HIV Digital Vaccine Strategy: Proposal for Applying Blockchain in Preventing the Spread of HIV.

Authors:
Jia Liu

JMIR Res Protoc 2022 Jun 13;11(6):e37133. Epub 2022 Jun 13.

Henan Center for Disease Control and Prevention, Zhengzhou, China.

Background: The HIV epidemic imposes a heavy burden on societal development. Protection of susceptible populations is the most feasible method for eliminating the spread of HIV. In the absence of a biological vaccine, the definitive solution is enabling susceptible populations to recognize and avoid high-risk sexual behavior.

Objective: The objective of this study is to use specific technologies and strategies to establish a system by which high-HIV-risk individuals can determine the HIV infection status of one another anonymously, conveniently, and credibly.

Methods: This study proposes an HIV digital vaccine (HDV) strategy, a decentralized application (Dapp) based on blockchain for use by individuals with a high risk of HIV and accredited testing agencies (ATAs). Following testing, only the HIV-negative results (or linked information) are uploaded to the blockchain, which results in high-risk individuals being able to determine the HIV-negative status of each other anonymously, conveniently, and credibly.

Results: Future work includes the following: (1) a survey of the willingness to use Dapps among high-HIV-risk populations, (2) a larger framework containing both HDV and people living with HIV (PLH) and discussing the influence of HDV on PLH and its possible solutions, and (3) coordinating with the blockchain development team, ATAs, community-based organizations, and third-party organizations to raise funds, develop the Dapp, formulate detailed plans, and publicize and promote it. The exact timeline for achieving these objectives cannot be determined at present.

Conclusions: The HDV strategy may reduce the occurrence of high-risk sexual behavior and effectively protect susceptible populations; combined with current strategies, it is a promising solution to prevent the spread of HIV. The included concepts of decentralized surveillance and surveillance as intervention may spark a change in current infectious disease prevention and control modes to introduce beneficial innovations in public health systems globally.

International Registered Report Identifier (irrid): PRR1-10.2196/37133.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/37133DOI Listing
June 2022

Myocyte enhancer factor 2D promotes hepatocellular carcinoma through AMOTL2/YAP signaling that inhibited by luteolin.

Int J Clin Exp Pathol 2022 15;15(5):206-214. Epub 2022 May 15.

Department of Pharmacology, School of Pharmacy, Qingdao University Qingdao, Shandong, China.

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. There is a lack of effective treatment. Previous studies have shown that myocyte enhancer factor 2D (MEF2D) promotes the progression of HCC. Underlying mechanisms have not been fully elucidated. In this study, we reported experimental results obtained using double luciferase. Our results showed that AMOTL2, a negative regulator of Hippo/YAP signaling, and the MEF2 cis-acting element in the upstream region of its promoter bind to MEF2D, inhibiting its transcriptional expression. Studies confirmed that MEF2D affected the protein expression level of AMOTL2 and the YAP signaling activation. It promoted the migration and proliferation of hepatoma cells. We found that luteolin, a natural flavonoid, has anti-tumor activity in HCC cells by affecting YAP signaling transduction. In conclusion, we demonstrated that AMOTL2/YAP signaling is associated with MEF2D-related HCC progression. Luteolin is a promising anti-HCC compound for regulating this signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187918PMC
May 2022

Analysis of the Efficacy and Safety of Avatrombopag Combined With MSCs for the Treatment of Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2022 27;13:910893. Epub 2022 May 27.

Medical Center of Hematology, The Second Affiliated Hospital, Army Medical University, Chongqing, China.

Platelet graft failure (PGF) is a frequent and serious complication after Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacks effective treatment strategies, which could affect the prognosis of patients and even cause death. The exact underlying mechanism of PGF remains unclear, and lacks standard treatment. Here, we conduct a retrospective study to evaluate the efficacy and safety of avatrombopag combined with mesenchymal stem cells (MSCs) in 16 patients with thrombocytopenia after allo-HSCT. Patients were administered the following treatment regimen: 20 mg/d avatrombopag; if the PLT count was less than 50×109/L for at least 2 weeks, the dose was increased to 40 mg/d; if the PLT count was 200-400×109/L, the dose was reduced; and if the PLT count was greater than 400×10^9/L, avatrombopag was terminated. Umbilical cord MSCs (1×106 cells/kg) infusion was performed every week for 4-6 weeks. Among the 16 patients, 13 patients (81.3%) achieved a complete response (CR), 2 patients (12.5%) got a partial response (PR), and 1 patient (6.3%) had no response (NR). The median time to obtain CR was 32 (7-426) days after treatment with avatrombopag combined with umbilical cord MSCs. The time to reach 20×109/L≤ PLT <50×109/L in the 2 patients with PR was 52 and 230 days after treatment, respectively. One patient had a severe pulmonary infection and died of cytomegalovirus pneumonia. Overall, our results indicated that combination of avatrombopag with MSCs can promote platelet recovery after transplantation, thereby improving the survival rate of patients and improving the quality of life of patients after transplantation, and providing a new method and strategy for the treatment of thrombocytopenia after allo-HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2022.910893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184517PMC
June 2022
-->