Publications by authors named "Ting Wei"

222 Publications

Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression.

Aliment Pharmacol Ther 2021 Sep 2. Epub 2021 Sep 2.

Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.

Background: Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear.

Aim: To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics.

Results: Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post-lipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = -0.48, FDR = 0.01) and pain (r = -0.41, FDR = 0.02) thresholds.

Conclusion: Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV-mediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.
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http://dx.doi.org/10.1111/apt.16591DOI Listing
September 2021

Study on the performance of carbonate-mineralized bacteria combined with eggshell for immobilizing Pb and Cd in water and soil.

Environ Sci Pollut Res Int 2021 Aug 11. Epub 2021 Aug 11.

School of Environmental Science and Engineering, Shaanxi University of Science & Technology, Xi'an, 710021, People's Republic of China.

Microbially induced carbonate precipitation (MICP) is an advanced bioremediation approach to remediate heavy metal (HM)-contaminated water and soil. In this study, metal-tolerant urease-producing bacterial isolates, namely, UR1, UR16, UR20, and UR21, were selected based on their urease activity. The efficiency of these isolates in water for Pb and Cd immobilizations was explored. Our results revealed that UR21 had the highest removal rates of Pb (81.9%) and Cd (65.0%) in solution within 72 h through MICP. The scanning electron microscopy-energy-dispersive x-ray and x-ray diffraction analysis confirmed the structure and the existence of PbCO and CdCO crystals in the precipitates. In addition, the strain UR21, in combination with urea/eggshell waste (EGS) or both, was further employed to investigate the effect of MICP on soil enzymatic activity, chemical fractions, and bioavailability of Pb and Cd. The outcomes indicated that the applied treatments reduced the proportion of soluble-exchangeable-Pb and -Cd, which resulted in an increment in carbonate-bound Pb and Cd in the soil. The DTPA-extractable Pb and Cd were reduced by 29.2% and 25.2% with the treatment of UR21+urea+EGS as compared to the control. Besides, the application of UR21 and EGS significantly increased the soil pH, cation exchange capacity, and enzyme activities. Our findings may provide a novel perceptive for an eco-friendly and sustainable approach to remediate heavy metal-contaminated environment through a combination of metal-resistant ureolytic bacterial strain and EGS.
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http://dx.doi.org/10.1007/s11356-021-15138-0DOI Listing
August 2021

A single mutation attenuates both the transcription termination and RNA-dependent RNA polymerase activity of T7 RNA polymerase.

RNA Biol 2021 Jul 27:1-16. Epub 2021 Jul 27.

Key Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology and Shenzhen College, Huazhong University of Science and Technology, Wuhan, Hubei China.

Transcription termination is one of the least understood processes of gene expression. As the prototype model for transcription studies, the single-subunit T7 RNA polymerase (RNAP) is known to respond to two types of termination signals, but the mechanism underlying such termination, especially the specific elements of the polymerase involved, is still unclear, due to a lack of knowledge with respect to the structure of the termination complex. Here we applied phage-assisted continuous evolution to obtain variants of T7 RNAP that can bypass the typical class I T7 terminator with stem-loop structure. Through selection and characterization, we discovered a single mutation (S43Y) that significantly decreased the termination efficiency of T7 RNAP at all transcription terminators tested. Coincidently, the S43Y mutation almost eliminates the RNA-dependent RNAP (RdRp) activity of T7 RNAP without impeding the major DNA-dependent RNAP (DdRp) activity of the enzyme. S43 is located in a hinge region and regulates the transformation between transcription initiation and elongation of T7 RNAP. Steady-state kinetics analysis and an RNA binding assay indicate that the S43Y mutation increases the transcription efficiency while weakening RNA binding of the enzyme. As an enzymatic reagent for transcription, the T7 RNAP S43Y mutant reduces the undesired termination in run-off RNA synthesis and produces RNA with higher terminal homogeneity.
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http://dx.doi.org/10.1080/15476286.2021.1954808DOI Listing
July 2021

High-Dimensional Mediation Analysis With Confounders in Survival Models.

Front Genet 2021 28;12:688871. Epub 2021 Jun 28.

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Mediation analysis is a common statistical method for investigating the mechanism of environmental exposures on health outcomes. Previous studies have extended mediation models with a single mediator to high-dimensional mediators selection. It is often assumed that there are no confounders that influence the relations among the exposure, mediator, and outcome. This is not realistic for the observational studies. To accommodate the potential confounders, we propose a concise and efficient high-dimensional mediation analysis procedure using the propensity score for adjustment. Results from simulation studies demonstrate the proposed procedure has good performance in mediator selection and effect estimation compared with methods that ignore all confounders. Of note, as the sample size increases, the performance of variable selection and mediation effect estimation is as well as the results shown in the method which include all confounders as covariates in the mediation model. By applying this procedure to a TCGA lung cancer data set, we find that lung cancer patients who had serious smoking history have increased the risk of death the methylation markers cg21926276 and cg20707991 with significant hazard ratios of 1.2093 (95% CI: 1.2019-1.2167) and 1.1388 (95% CI: 1.1339-1.1438), respectively.
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http://dx.doi.org/10.3389/fgene.2021.688871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273300PMC
June 2021

Re-Evaluate Fusion Genes in Prostate Cancer.

Cancer Inform 2021 21;20:11769351211027592. Epub 2021 Jun 21.

Division of Computational Biology, College of Medicine and Science, Mayo Clinic, Rochester, MN, USA.

Background: Thousands of gene fusions have been reported in prostate cancer, but their authenticity, incidence, and tumor specificity have not been thoroughly evaluated, nor have their genomic characteristics been carefully explored.

Methods: We developed FusionVet to dedicatedly validate known fusion genes using RNA-seq alignments. Using FusionVet, we re-assessed 2727 gene fusions reported from 36 studies using the RNA-seq data generated by The Cancer Genome Atlas (TCGA). We also explored their genomic characteristics and interrogated the transcriptomic and DNA methylomic consequences of the E26 transformation-specific (ETS) fusions.

Results: We found that nearly two-thirds of reported fusions are intra-chromosomal, and 80% of them were formed between 2 protein-coding genes. Although most (76%) genes were fused to only 1 partner, we observed many fusion hub genes that have multiple fusion partners, including ETS family genes, androgen receptor signaling pathway genes, tumor suppressor genes, and proto-oncogenes. More than 90% of the reported fusions cannot be validated by TCGA RNA-seq data. For those fusions that can be validated, 5% were detected from tumor and normal samples with similar frequencies, and only 4% (120 fusions) were tumor-specific. The occurrences of , and fusions were mutually exclusive, and their fusion statuses were tightly associated with overexpressions. Besides, we found fusions were significantly co-occurred with deletion but mutually exclusive with common genomic alterations such as mutation and mutation.

Conclusions: Most of the reported fusion genes cannot be validated by TCGA samples. The ETS family and androgen response genes were significantly enriched in prostate cancer-specific fusion genes. Transcription activity was significantly repressed, and the DNA methylation was significantly increased in samples carrying fusion.
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http://dx.doi.org/10.1177/11769351211027592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226361PMC
June 2021

GapClust is a light-weight approach distinguishing rare cells from voluminous single cell expression profiles.

Nat Commun 2021 07 7;12(1):4197. Epub 2021 Jul 7.

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Single cell RNA sequencing (scRNA-seq) is a powerful tool in detailing the cellular landscape within complex tissues. Large-scale single cell transcriptomics provide both opportunities and challenges for identifying rare cells playing crucial roles in development and disease. Here, we develop GapClust, a light-weight algorithm to detect rare cell types from ultra-large scRNA-seq datasets with state-of-the-art speed and memory efficiency. Benchmarking on diverse experimental datasets demonstrates the superior performance of GapClust compared to other recently proposed methods. When applying our algorithm to an intestine and 68 k PBMC datasets, GapClust identifies the tuft cells and a previously unrecognised subtype of monocyte, respectively.
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http://dx.doi.org/10.1038/s41467-021-24489-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263561PMC
July 2021

Hf-Nd-Sr Isotopic Composition of the Tibetan Plateau Dust as a Fingerprint for Regional to Hemispherical Transport.

Environ Sci Technol 2021 07 6;55(14):10121-10132. Epub 2021 Jul 6.

State Key Laboratory of Cryosphere Sciences, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou 730000, China.

Large areas of arid regions in the Tibetan Plateau (TP) are undergoing desertification and subsequent aeolian emission and transport. The contribution of TP soils to the atmospheric aerosol burden in Asia and elsewhere is not known. Here, we use Hf, Nd, and Sr isotopes to distinguish the TP from other Asian dust-producing regions and compare the signatures to sediments in major dust sink regions. We found that the Hf-Nd-Sr isotopes of TP soils showed unique spatial signatures. From north to south, Sr/Sr ratios gradually increased, while ε and ε values gradually decreased; from west to east, Sr/Sr and ε gradually increased, while ε changed indistinctly. The Hf-Nd-Sr isotopic compositions of TP soils were controlled by four geographic isotope regions: the northern, southern, western, and eastern TP. Compared with Asian large deserts, the TP showed a unique isotopic composition, which together exhibited a significant spatial change across Asia. Compared to dust isotopes in prominent sink areas, we found that the TP is an important dust source to eastern TP glaciers, the Chinese Loess Plateau, South China Sea, Japan, and Greenland. This study provides clear isotopic evidence that the TP is a major aeolian contributor in the Northern Hemisphere and may have important implications for the global aeolian cycle.
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http://dx.doi.org/10.1021/acs.est.0c04929DOI Listing
July 2021

Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors.

Front Pharmacol 2021 7;12:645862. Epub 2021 Jun 7.

Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, which are known to have high mutation rates, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). These mutant genes are potential therapeutic targets for LUAD. We analyzed a cohort of LUAD patients with somatic mutation and survival data in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors with clinical data and whole-exome sequencing (WES) mutation data to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from the Cancer Genome Atlas showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and gene set enrichment analysis showed that after CTNNA2 mutation occurred, changes were found in the DNA damage response pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways. Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.
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http://dx.doi.org/10.3389/fphar.2021.645862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215613PMC
June 2021

The concordance in lesion detection and characteristics between the Anatomical Intelligence and conventional breast ultrasound Scan method.

BMC Med Imaging 2021 Jun 21;21(1):102. Epub 2021 Jun 21.

Ultrasound Medical Center, Sichuan Cancer Hospital Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu, China.

Background: The aim of this study was to investigate the concordance in lesion detection, between conventional Handhold Ultrasound (HHUS) and The Anatomical Intelligence for Breast ultrasound scan method.

Result: The AI-breast showed the absolute agreement between the resident and an experienced breast radiologist. The ICC for the scan time, number, clockface location, distance to the nipple, largest diameter and mean diameter of the lesion obtained by a resident and an experienced breast radiologist were 0.7642, 0.7692, 0.8651, 0.8436, 0.7502, 0.8885, respectively. The ICC of the both practitioners of AI-breast were 0.7971, 0.7843, 0.9283, 0.8748, 0.7248, 0.8163, respectively. The k value of Anatomical Intelligence breast between experienced breast radiologist and resident in these image characteristics of boundary, morphology, aspect ratio, internal echo, and BI-RADS assessment were 0.7424, 0.7217, 0.6741, 0.6419, 0.6241, respectively. The k value of the two readers of AI-breast were 0.6531, 0.6762, 0.6439, 0.6137, 0.5981, respectively.

Conclusion: The anatomical intelligent breast US scanning method has excellent reproducibility in recording the lesion location and the distance from the nipple, which may be utilized in the lesions surveillance in the future.
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http://dx.doi.org/10.1186/s12880-021-00628-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215794PMC
June 2021

FOXA1 overexpression suppresses interferon signaling and immune response in cancer.

J Clin Invest 2021 Jul;131(14)

Department of Biochemistry and Molecular Biology.

Androgen receptor-positive prostate cancer (PCa) and estrogen receptor-positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.
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http://dx.doi.org/10.1172/JCI147025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279591PMC
July 2021

MET amplification attenuates lung tumor response to immunotherapy by inhibiting STING.

Cancer Discov 2021 Jun 7. Epub 2021 Jun 7.

Hubei Cancer Hospital.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 lung cancer patients under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progress-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted NK cells and decreased CD8+ T cell and NK cell populations in patients with MET-amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3'-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1500DOI Listing
June 2021

Presence of estrogen and progesterone receptors in proliferating and involuting infantile hemangiomas.

J Plast Reconstr Aesthet Surg 2021 Apr 20. Epub 2021 Apr 20.

Pediatric Otolaryngology, Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States.

Background: Studies in the literature have demonstrated the presence of sex hormone receptors in infantile hemangiomas (IHs), but further investigation is needed to determine the role of these receptors in their proliferation and involution. To date, there are no studies in the literature that aimed to quantitatively examine the expression of sex hormone receptors throughout the different phases of hemangioma development.

Objective: The objective of our study was to quantitatively evaluate the expression of estrogen (ER) and progesterone (PR) receptors in the proliferative and involuting phases of IHs through the use of real-time polymerase chain reaction (RT-PCR).

Methods: Twenty IHs (10 proliferating and 10 involuting) were harvested and prepared for molecular investigation. ER receptor alpha (ERα) and beta (ERβ) and the PR expression were examined by RT-PCR and western blot.

Results: RT-PCR analysis demonstrated that mRNA expression of ERα, ERβ, and PR was significantly lower in proliferating versus involuting IH. Western blot analysis revealed increased protein expression of ERα in involuting hemangiomas as compared to proliferating ones.

Conclusions: Our study demonstrates the variable expression of ER and PR receptors in proliferating and involuting hemangiomas. Further studies are needed to determine the exact role of these hormone receptors in the growth and involution of IHs.
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http://dx.doi.org/10.1016/j.bjps.2021.03.100DOI Listing
April 2021

Effect of exogenous silicon and methyl jasmonate on the alleviation of cadmium-induced phytotoxicity in tomato plants.

Environ Sci Pollut Res Int 2021 May 15. Epub 2021 May 15.

School of Environmental Science and Engineering, Shaanxi University of Science & Technology, Xi'an, 710021, People's Republic of China.

In the present study, a hydroponic experiment was performed to evaluate the effect of exogenous silicon (Si) and methyl jasmonate (MeJA) on the mitigation of Cd toxicity in tomato seedlings. The results revealed that Cd-stressed plants exhibited growth inhibition, increased lipid peroxidation, and impaired photosynthetic pigment accumulation. However, Si and MeJA applied alone or in combination significantly ameliorated the above-mentioned adverse effects induced by Cd. Among all treatments, Cd+Si+MeJA treatment elevated the dry mass of roots, stems, and leaves by 317.39%, 110.85%, and 119.71%, respectively. The chlorophyll a, chlorophyll b, and carotenoid contents in Cd+Si+MeJA-treated group were dramatically elevated (p < 0.05). Meanwhile, the malondialdehyde content in roots and shoots were reduced by 32.24% and 69.94%, respectively. The Si and MeJA applied separately or in combination also resulted in a prominent decrease of Cd influxes in tomato roots; therefore, a reduction of Cd content in tomato tissues were detected, and the Cd concentration in tomato roots were decreased by 27.19%, 25.18%, and 17.51% in Cd+Si, Cd+MeJA and Cd+Si+MeJA-treated plants, respectively. Moreover, in Cd+Si+MeJA-treated group, the percentage of Cd in cell wall fraction was enhanced while that in organelle fraction was decreased as compared with Cd-stressed plants. Collectively, our findings indicated that Si and MeJA application provide a beneficial role in enhancing Cd tolerance and reducing Cd uptake in tomato plants.
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http://dx.doi.org/10.1007/s11356-021-14252-3DOI Listing
May 2021

Nutritional Effects of the Enteral Nutritional Formula on Regulation of Gut Microbiota and Metabolic Level in Type 2 Diabetes Mellitus Mice.

Diabetes Metab Syndr Obes 2021 28;14:1855-1869. Epub 2021 Apr 28.

College of Food Science and Engineering, Shanghai Ocean University, Shanghai, 201306, People's Republic of China.

Purpose: Due to the adverse effects of antidiabetic drugs, nowadays, nutraceuticals have been of much interest to investigators. Therefore, the present study aimed to explore the potential effects of enteral nutritional (EN) formulas on the gut microbiota and metabolic regulation of type 2 diabetes mellitus (T2DM) mice and compare the differences between whey protein and soy protein.

Methods: EN formulas made of whey protein or soy protein were administered for five weeks and then mice tissue samples were obtained to examine the metabolic parameters and histopathology of the pancreas, liver, jejunum and colon. 16S rRNA V3-V4 region gene sequencing was used to analyze the changes in the gut microbiota.

Results: After the five-week intervention, the alpha diversity had recovered slightly, and the soy protein group (SPG) achieved a better effect than the whey protein group (LPG). The overall composition of gut microbiota was regulated. The abundance of Bacteroidetes and TM7 had raised significantly and the abundance of Firmicutes and Deferribacteres had declined after treatment, with no significant difference between the LPG and SPG. The types of beneficial bacteria were increased at the genus and species level. The level of hexokinase (HK) and pyruvate kinase (PK) had significantly recovered and inhibited the level of α-glucosidase. In addition, the EN formulas treatment reduced the levels of inflammatory factor (TNF-α) in liver and muscle. The level of glucose transporter type 2 (GLUT-2) levels in the liver and intestine also significantly increased. Moreover, the metabolism regulation of the SPG was better than that of the LPG. The EN formulas treatment improved the pancreas, liver, jejunum and colon histology.

Conclusion: The EN formulas regulated the overall structure of the gut microbiota and improved the metabolic level in streptozotocin/high-fat diet (STZ/HFD) diabetic mice. Therefore, EN formula may potentially become an effective nutritional adjunctive therapy for T2DM.
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http://dx.doi.org/10.2147/DMSO.S301454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089093PMC
April 2021

Inhibiting miR-22 Alleviates Cardiac Dysfunction by Regulating Sirt1 in Septic Cardiomyopathy.

Front Cell Dev Biol 2021 1;9:650666. Epub 2021 Apr 1.

Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms. miR-22 cardiac-specific knockout (miR-22) mice and miR-22 cardiac-specific transgenic (miR-22) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The echocardiogram results suggested that miR-22 CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22 CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22 CLP mice, while it had contrary role in the miR-22 group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy . Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions. Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.
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http://dx.doi.org/10.3389/fcell.2021.650666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047209PMC
April 2021

Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma.

Cancer Cell Int 2021 Apr 7;21(1):195. Epub 2021 Apr 7.

Department of Hematology, Guangzhou Red Cross Hospital, Jinan University, No. 396 Tongfuzhong Road, Haizhu District, 510220, Guangzhou, Guangdong, People's Republic of China.

Background: Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton's tyrosine kinase inhibitors (BTKis) are new drugs for B-cell lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor and ubiquitinase. CYLD can inactivate NFκB signaling pathway through ubiquitination and regulate the apoptosis of hematological tumors. The ubiquitination of CYLD can be regulated by phosphorylation, suggesting that the regulation of CYLD phosphorylation can be a potential mechanism to promote the apoptosis of hematological tumors. Therefore, we hypothesized that BTKis could promote the apoptosis of non-GCB-DLBCL by regulating the phosphorylation of CYLD, especially in rituximab resistant cases, and we proved this hypothesis through both in vivo and in vitro experiments.

Methods: The baseline expression levels of CYLD phosphorylation in non-GCB-DLBCL patients and cell lines were detected by Western Blotting. The non-GCB-DLBCL cell lines were treated with BTKis, and apoptosis induced by BTKis treatment was detected by Western blotting, cell viability assay and Annexin V assay. To verify whether the effect of BTKis on apoptosis in non-GCN-DLBCL cells is CYLD dependent, the expression of CYLD was knocked down by lentiviral shRNAs. To verify the effect of BTKis on the phosphorylation of CYLD and the apoptosis in vivo and in rituximab resistant non-GCB-DLBCL, the xeograft model and rituximab resistant non-GCB-DLBCL cells were generated by tumor cell inoculation and escalation of drug concentrations, respectively.

Results: BTKis induced apoptosis by down-regulating CYLD phosphorylationin in non GCB-DLBCL, xenograft mouse model, and rituximab-resistant cells, and this effect could be enhanced by rituximab. Knocking-down CYLD reversed apoptosis which was induced by BTKis. BTKis induced CYLD-dependent apoptosis in non-GCB-DLBCL including in rituximab-resistant cells.

Conclusions: The present results indicated that CYLD phosphorylation is a potential clinical therapeutic target for non-GCB-DLBCL, especially for rituximab-resistant relapsed/refractory cases.
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http://dx.doi.org/10.1186/s12935-021-01891-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025353PMC
April 2021

Progress in ultrasound-assisted extraction of the value-added products from microorganisms.

World J Microbiol Biotechnol 2021 Mar 25;37(4):71. Epub 2021 Mar 25.

School of Environment and Natural Resources, Renmin University of China, Beijing, 100872, China.

Extracting value-added products from microorganisms is an important research focus for the future. Among the many extraction methods, ultrasound-assisted extraction (UAE) has attracted more attention owing to its advantages in reducing working time, increasing yield, and improving the quality of the extract. This review summarizes the use of UAE value-added products from microorganisms, with the main extracted substances are pigments, lipids, polysaccharides, and proteins. In addition, this work also summarizes the mechanism of UAE and highlights the factors that affect UAE operation, such as ultrasonic power intensity or power density, operation mode, and energy consumption, which need to be considered. All extraction products from microorganisms showed that UAE can effectively improve the extraction yields of value-added products. It also highlights the existing problems of the technology and possible future prospects. In general, the UAE of value-added substances from microorganisms is feasible and has the potential for development.
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http://dx.doi.org/10.1007/s11274-021-03037-yDOI Listing
March 2021

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.

Nat Commun 2021 03 9;12(1):1521. Epub 2021 Mar 9.

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
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http://dx.doi.org/10.1038/s41467-021-21860-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943793PMC
March 2021

Water science under the global epidemic of COVID-19: Bibliometric tracking on COVID-19 publication and further research needs.

J Environ Chem Eng 2021 Aug 15;9(4):105357. Epub 2021 Mar 15.

State Key Laboratory of Eco-Hydraulics in Northwest Arid Region, Xi'an University of Technology, Xi'an 710048, PR China.

There are overwhelming increases of studies and over 200,000 publications related to all the aspects of COVID-19. Among them, 262 papers were published by authors from 67 countries regarding COVID-19 with water science and technology. Although the transmission routes of SARS-CoV-2 in water cycle have not been proved, the water and wastewater play an important role in the control of COVID-19 pandemic. Accordingly, it is scholarly relevant and interesting to look into publications of COVID-19 in water science and technology to track the investigations for moving forward in the years to come. It is believed that, through the literature survey, the question on what we know and what we do not know about COVID-19 so far can be clear, thus providing useful information for helping curbing the epidemic from water sector. This forms the basis of the current study. As such, a bibliometric analysis was conducted. It reveals that wastewater-based epidemiology (WBE) has recently gained global attention with the source and survival characteristics of coronavirus in the aquatic environment; the methodology of virus detection; the water hygiene; and the impact of the COVID-19 pandemic on the water ecosystem being the main topics in 2020. Various studies have shown that drinking water is safety whereas wastewater may be a potential risk during this pandemic. From the perspective of the water cycle, the scopes for further research needs are discussed and proposed, which could enhance the important role and value of water science in warning, monitoring, and predicting COVID-19 during epidemic outbreaks.
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http://dx.doi.org/10.1016/j.jece.2021.105357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959687PMC
August 2021

An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors.

Cell Rep 2021 02;34(7):108744

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, MN 55905, USA. Electronic address:

Acquisition of resistance to phosphatidylinositol 3-kinase (PI3K)/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here, we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-coenzyme A (CoA) shortage, and a global decrease in histone acetylation. In addition, PI3K/AKT inhibitors induce drug resistance by selectively augmenting histone H3 lysine 27 acetylation (H3K27ac) and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug-resistant cell growth are vulnerable to both bromodomain and histone deacetylase (HDAC) inhibitors. Little or no occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique acetyl-histone-related vulnerability offers two clinically viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
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http://dx.doi.org/10.1016/j.celrep.2021.108744DOI Listing
February 2021

ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor-activated cancer.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905;

Both gene repressor (Polycomb-dependent) and activator (Polycomb-independent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase () gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer.
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http://dx.doi.org/10.1073/pnas.2019052118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923384PMC
February 2021

PGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors.

Cell Death Differ 2021 Jun 26;28(6):1955-1970. Epub 2021 Jan 26.

Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Hong Kong, China.

Poorly differentiated tumors usually exhibit phenotypes similar to that of their developmental precursor cells. Tumor cells that acquire the lineage progenitor cells feature usually exploit developmental signaling to potentiate cancer progression. However, the underlying molecular events remain elusive. In this study, based on analysis of an in vitro hepatocyte differentiation model, the maternal factor PGC7 (also known as DPPA3, STELLA) was found closely associated with liver development and tumor differentiation in hepatocellular carcinoma (HCC). Expression of PGC7 decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Whole-genome methylation sequencing found that PGC7 could induce promoter demethylation of genes related to development. Pathway-based network analysis indicated that downstream targets of PGC7 might form networks associated with developmental transcription factor activation. Overexpression of PGC7 conferred progenitor-like features of HCC cells both in vitro and in vivo. Mechanism studies revealed that PGC7 could impede nuclear translocation of UHRF1, and thus facilitate promoter demethylation of GLI1 and MYCN, both of which are important regulators of HCC self-renewal and differentiation. Depletion or inhibition of GLI1 effectively downregulated MYCN, abolished the effect of PGC7, and sensitized HCC cells to sorafenib treatment. In addition, we found a significant correlation of PGC7 with GLI1/MYCN and lineage differentiation markers in clinical HCC patients. PGC7 expression might drive HCC toward a "dedifferentiated" progenitor lineage through facilitating promoter demethylation of key developmental transcription factors; further inhibition of PGC7/GLI1/MYCN might reverse poorly differentiated HCCs and provide novel therapeutic strategies.
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http://dx.doi.org/10.1038/s41418-020-00726-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185079PMC
June 2021

An Efficient and Easy-to-Use Network-Based Integrative Method of Multi-Omics Data for Cancer Genes Discovery.

Front Genet 2020 8;11:613033. Epub 2021 Jan 8.

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Identifying personalized driver genes is essential for discovering critical biomarkers and developing effective personalized therapies of cancers. However, few methods consider weights for different types of mutations and efficiently distinguish driver genes over a larger number of passenger genes. We propose MinNetRank (Minimum used for Network-based Ranking), a new method for prioritizing cancer genes that sets weights for different types of mutations, considers the incoming and outgoing degree of interaction network simultaneously, and uses minimum strategy to integrate multi-omics data. MinNetRank prioritizes cancer genes among multi-omics data for each sample. The sample-specific rankings of genes are then integrated into a population-level ranking. When evaluating the accuracy and robustness of prioritizing driver genes, our method almost always significantly outperforms other methods in terms of precision, F1 score, and partial area under the curve (AUC) on six cancer datasets. Importantly, MinNetRank is efficient in discovering novel driver genes. SP1 is selected as a candidate driver gene only by our method (ranked top three), and SP1 RNA and protein differential expression between tumor and normal samples are statistically significant in liver hepatocellular carcinoma. The top seven genes stratify patients into two subtypes exhibiting statistically significant survival differences in five cancer types. These top seven genes are associated with overall survival, as illustrated by previous researchers. MinNetRank can be very useful for identifying cancer driver genes, and these biologically relevant marker genes are associated with clinical outcome. The R package of MinNetRank is available at https://github.com/weitinging/MinNetRank.
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http://dx.doi.org/10.3389/fgene.2020.613033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820902PMC
January 2021

Study of soil microorganisms modified wheat straw and biochar for reducing cadmium leaching potential and bioavailability.

Chemosphere 2021 Jun 13;273:129644. Epub 2021 Jan 13.

School of Environmental Science and Engineering, Shaanxi University of Science & Technology, Xi'an, 710021, PR China; College of Resources and Environment, South China Agricultural University, Guangzhou, 510642, PR China. Electronic address:

The application of crops straw and biochar in trace metals remediation from the contaminated environment attracted more and more attention during the past decade. Although there has been some review work on the mechanism of trace metals stabilization by crops straw, the effects and mechanisms of interaction among soil indigenous-microbes and crops-straw for trace metal adsorption and stabilization is still unclear. In this study, the dynamic effects along with potential mechanisms of wheat-straw (WS), wheat-straw biochar (WBC) and biologically modified wheat-straw (BMWS) were conducted to investigate the adsorption, leaching behaviour, chemical fractions and bioavailability of cadmium (Cd). The results showed that the biosorption capacity (q) was most elevated in the BMWS treatment (14.42 mg g) as compared to WBC (6.28 mg g) and WS (4.20 mg g). The application of BMWS, WBC and WS at the rate of 3% significantly reduced Cd concentration in leachate to 53, 45 and 21% respectively, as compared to control. The addition of BMWS reduced the exchangeable Cd fraction resulted an increase in organic matter and carbonate bound Cd fraction in the soil. The DTPA extractable Cd was significantly decreased by 31.2 and 28.6% with the application of BMWS and WBC at 3% w/w respectively as compared to control. The research results may provide a novel perceptive for the development of functional materials and strategies for eco-friendly and sustainable trace metal remediation in contaminated soil and water by combination of straw and soil-indigenous microorganisms.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129644DOI Listing
June 2021

HDAC5 Loss Impairs RB Repression of Pro-Oncogenic Genes and Confers CDK4/6 Inhibitor Resistance in Cancer.

Cancer Res 2021 03 8;81(6):1486-1499. Epub 2021 Jan 8.

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle-related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells and prostate tumors , but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. SIGNIFICANCE: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2828DOI Listing
March 2021

Vincristine upregulates PD-L1 and increases the efficacy of PD-L1 blockade therapy in diffuse large B-cell lymphoma.

J Cancer Res Clin Oncol 2021 Mar 2;147(3):691-701. Epub 2021 Jan 2.

Department of Hematology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, People's Republic of China.

Background: Some chemotherapy drugs have immunomodulatory effects on specific tumors. The potential of vincristine (VCR) in the R-CHOP regimen to act as both a chemotherapeutic and an immunomodulatory agent via PD-L1 in tumor cells remains unclear.

Methods: In vitro screening VCR showed that the IC50 value of VCR in the DLBCL cell lines was approximately 2 nM. Western blotting and q-PCR were used to detect the expression of PD-L1. The effect of VCR combined with PD-L1 mAb was tested in a co-culture system of LY-OCI-3 cells and peripheral blood mononuclear cells and in DLBCL xenograft mouse model. Flow cytometry was used to determine the proportion of T lymphocyte subsets. The effect of the STAT3 inhibitor nifuroxazide on VCR-induced PD-L1 expression was tested in LY-OCI-3 and SU-DHL-4 cells.

Results: VCR upregulated PD-L1 protein and mRNA expression in various DLBCL cell lines. PD-L1 Ab combined with VCR significantly increased the proportion of CD8 + Granzyme B + , INF-γ + or TNF-α + CD3 + T cells. VCR + PD-L1 Ab inhibited tumor growth more effectively than VCR monotherapy, whereas PD-L1 Ab alone had no significant effect. Survival time did not differ significantly between the PD-L1 Ab group and the control group, whereas it was significantly longer in the VCR monotherapy and combination groups which showed more longer survival compared with the former. Nifuroxazide downregulated p-STAT3 and PD-L1 protein levels.

Conclusions: VCR upregulated PD-L1 expression in DLBCL cells partially by promoting the p-STAT3; VCR combined with PD-L1 Ab activated effector T cells and increased the antitumor immune response in vitro and in vivo.
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http://dx.doi.org/10.1007/s00432-020-03446-wDOI Listing
March 2021

Chitosan/hydroxyapatite composite coatings on porous Ti6Al4V titanium implants: and studies.

J Periodontal Implant Sci 2020 Dec;50(6):392-405

Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University School of Stomatology, Jinan, China.

Purpose: Titanium implants are widely used in the treatment of dentition defects; however, due to problems such as osseointegration failure, peri-implant bone resorption, and peri-implant inflammation, their application is subject to certain restrictions. The surface modification of titanium implants can improve the implant success rate and meet the needs of clinical applications. The goal of this study was to evaluate the effect of the use of porous titanium with a chitosan/hydroxyapatite coating on osseointegration.

Methods: Titanium implants with a dense core and a porous outer structure were prepared using a computer-aided design model and selective laser sintering technology, with a fabricated chitosan/hydroxyapatite composite coating on their surfaces. and experiments were used to assess osteogenesis.

Results: The quasi-elastic gradient and compressive strength of porous titanium implants were observed to decrease as the porosity increased. The experiments demonstrated that, the porous titanium implants had no biological toxicity; additionally, the porous structure was shown to be superior to dense titanium with regard to facilitating the adhesion and proliferation of osteoblast-like MC3T3-E1 cells. The experimental results also showed that the porous structure was beneficial, as bone tissue could grow into the pores, thereby exhibiting good osseointegration.

Conclusions: Porous titanium with a chitosan/hydroxyapatite coating promoted MC3T3-E1 cell proliferation and differentiation, and also improved osseointegration . This study has meaningful implications for research into ways of improving the surface structures of implants and promoting implant osseointegration.
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http://dx.doi.org/10.5051/jpis.1905680284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758299PMC
December 2020

Comparison of gene mutation spectra in younger and older Chinese acute myeloid leukemia patients and its prognostic value.

Gene 2021 Feb 14;770:145344. Epub 2020 Dec 14.

Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China. Electronic address:

Differences in the gene mutation spectra of younger and older Chinese adult AML patients and the prognostic significance of these differentially presented gene mutations are rarely reported. One hundred and thirteen newly diagnosed Chinese adults with AML, divided into groups of younger and older patients, were enrolled in this study. Bone marrow samples from the patients were analyzed using targeted next-generation sequencing with a panel of 141 genes. Ninety-eight mutated genes were detected and the top 10 mutated genes were KMT2D, FLT3, FAT1, ASXL1, NRAS, DNMT3A, RELN, TET2, JAK2, and KRAS. The top five functional groups were the tyrosine kinase pathway, transcription factors, DNA methylation, chromatin modifiers, and the JAK-STAT signaling pathway. Younger patients exhibited higher incidences of KMT2D (33.8% vs 10.4%, P = 0.004) and KRAS (15.4% vs 2.1%, P = 0.042) mutations than older patients; whereas, older patients harbored more SRSF2 (20.8% vs 0%, P = 0.002), transcription factor (85.4% vs 67.7%, P = 0.031), DNA methylation (58.3% vs 36.9%, P = 0.024), and RNA splicing (31.3% vs 12.3%, P = 0.013) mutations than younger patients. Moreover, patients with SRSF2 mutations exhibited a lower rate of overall survival (P < 0.001) and relapse-free survival (P < 0.001) than patients carrying wild-type SRSF2. In conclusion, rarely reported KMT2D, FAT1, and RELN mutations were detected at high frequencies in our cohort. The gene mutation spectrum of older patients was different to that of younger patients. Moreover, older patients harbored more SRSF2 mutations, which predicted lower rates of overall and relapse-free survival.
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http://dx.doi.org/10.1016/j.gene.2020.145344DOI Listing
February 2021

C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism.

Oncogene 2021 02 15;40(6):1147-1161. Epub 2020 Dec 15.

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, Hong Kong.

Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3'-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.
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http://dx.doi.org/10.1038/s41388-020-01593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878188PMC
February 2021
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