Publications by authors named "Yi Zhao"

1,816 Publications

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High Expression of circ_0001821 Promoted Colorectal Cancer Progression Through miR-600/ISOC1 Axis.

Biochem Genet 2022 Aug 9. Epub 2022 Aug 9.

Department of Radiotherapy, Shaanxi Provincial People's Hospital, No. 256 Youyi West Rd, Xi'an, 710068, Shaanxi, China.

It has been reported that circRNAs play an important regulatory role in the progression of colorectal cancer (CRC). However, the molecular role of circ_0001821 in CRC development is unclear. In this study, we aimed to investigate the regulatory role and molecular mechanisms of circ_0001821 in CRC. Reverse transcription-quantitative PCR and western blot assays were used to detect the expression of circ_0001821, miR-600 and isochorismatase domain containing 1 (ISOC1) in CRC tissues as well as its cell lines. Colony formation assay and EDU assay were used to detect the proliferative capacity of cells. Transwell assay was used to assess cell migration and invasion ability. Flow cytometry was used to analyze cell apoptosis. ELISA was used to measure the glycolytic capacity of cells. Dual-luciferase reporter assay and RNA pull-down assay were used to analyze the relationships between circ_0001821, miR-600 and ISOC1. Animal experimentation was used to validate the functional study of circ_0001821 in vivo. Immunohistochemistry (IHC) of Ki67 staining analysis was conducted to assess tumor growth. Circ_0001821 and ISOC1 were significantly increased in CRC tissues and its cell lines, and miR-600 was significantly decreased in CRC tissues and its cell lines. Silencing circ_0001821 inhibited cell proliferation, migration, invasion and glycolytic capacity, while inducing apoptosis. And it could inhibit tumor growth in vivo. Circ_0001821 could act as a sponge for miR-600 to regulate CRC processes. ISOC1 was identified as a downstream regulator of miR-600, also miR-600 could regulate the expression of ISOC1. In addition, circ_0001821 could regulate ISOC1 expression changes through miR-600. Mechanistically, either miR-600 inhibitor or overexpression of ISOC1 could reverse the effects of knockdown of circ_0001821 on cell biological properties. Circ_0001821 regulated the developmental process of CRC through miR-600/ISOC1 axis.
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http://dx.doi.org/10.1007/s10528-022-10262-zDOI Listing
August 2022

CD133, but Not CD44, May Serve as a Novel Biomarker for Differential Diagnosis Between Basal Cell Carcinoma and Trichoblastomas.

Clin Cosmet Investig Dermatol 2022 2;15:1517-1526. Epub 2022 Aug 2.

Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People's Republic of China.

Purpose: To investigate the clinical value of CD133 and CD44 as putative cancer stem cell markers in distinguishing between basal cell carcinoma (BCC) and trichoblastomas (TB).

Patients And Methods: Tumor samples from 24 BCC and 23 TB patients were retrospectively retrieved for immunohistochemical staining of CD133 and CD44. The results were interpreted using a semiquantitative scoring system (H score). A receiver operating characteristic (ROC) curve was developed to identify an optimal cutoff value for differentiating between BCC and TB.

Results: Expression of CD133 was significantly higher in BCC patients than in TB patients (median H score: 30 [IQR: 12.5-56.3] vs 0 [IQR: 0-2], < 0.001). However, there was no significant difference in CD44 expression between the two groups (median H score: 105 [IQR: 63.8-155.0] vs 60 [IQR: 30-120], = 0.095). The ROC analysis of CD133 immunostaining yielded an area under the curve (AUC) of 0.881 (95% CI: 0.756-1.000) for differentiating between BCC and TB by using a H score of 7 as the cut-off value (98.5% sensitivity and 87.0% specificity). By contrast, immunostaining of CD44 showed a lower diagnostic value, with an AUC of 0.642 (95% CI: 0.476-0.808) at the optimal cut-off value of 85 (62.5% sensitivity and 73.9% specificity). The positive and negative predictive values were 88.5% and 95.2% for CD133 and 71.4% and 65.4% for CD44, respectively. Additionally, CD133 expression was significantly associated with mitotic activity in BCC patients ( = 0.549, = 0.005).

Conclusion: Our study expanded upon previous studies of CD133 and CD44 expressions in skin tumors, suggesting that CD133, but not CD44, may serve as a novel biomarker for differential diagnosis of BCC, although future studies using a larger number of patients are needed to justify it further.
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http://dx.doi.org/10.2147/CCID.S373331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356750PMC
August 2022

Lycopene alleviates di(2-ethylhexyl) phthalate-induced splenic injury by activating P62-Keap1-NRF2 signaling.

Food Chem Toxicol 2022 Jul 31;168:113324. Epub 2022 Jul 31.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant. It has been determined that DEHP is involved in multiple health disorders. Lycopene (Lyc) is a natural carotenoid pigment, with anti-inflammatory and antioxidant properties. However, it is not clear whether Lyc can protect the spleen from DEHP-induced oxidative damage. A total of 140 mice were randomly divided into seven groups (n = 20) and continuously gavaged with corn oil, distilled water, DEHP (500 or 1000 mg/kg BW/day) and/or Lyc (5 mg/kg BW/day) for 28 days. Histopathological and ultrastructural results showed a DEHP-induced inflammatory response and mitochondrial injuries. Moreover, DEHP exposure induced redox imbalance, which resulted in the up-regulation of ROS activity and MDA content, and the down-regulation of T-AOC, T-SOD and CAT in the DEHP groups. Simultaneously, our results also demonstrated that DEHP-induced kelch-like ECH-associated protein 1 (Keap1) expression was downregulated, and the expression levels of P62, nuclear factor erythroid 2-related factor (NRF2) and their downstream target genes were up-regulated. However, the supplementary Lyc reverted these changes to normal levels. Together, Lyc prevented DEHP-induced splenic injuries by regulating the P62-Keap1-NRF2 signaling pathway. Hence, the protective effects of Lyc might be a therapeutic strategy to ameliorate DEHP-induced splenic damage.
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http://dx.doi.org/10.1016/j.fct.2022.113324DOI Listing
July 2022

HIF signaling: A new propellant in bone regeneration.

Biomater Adv 2022 Jul 18;138:212874. Epub 2022 May 18.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.

Bone tissue destruction leads to severe pain, physical flaws, and loss of motility. Bone repair using biocompatible and osteo-inductive scaffolds is regarded as a viable and potential therapeutic approach. However, for large-scale bone regeneration, oxygen and nutrient supply have become limiting factors. Further, a considerable need exists for recruited cell activities and blood vessel growth. Hypoxia-inducible factor (HIF) signaling pathways induced by hypoxia are involved in angiogenesis and osteogenesis. As an important transcription factor, HIF-1 functions by modulating vital genes, such as VEGF, PDK1, and EPO, and is a crucial regulator that influences the final fate of bone regeneration. Collectively, to achieve better osteogenesis results, the in-depth molecular mechanisms that underpin the links between materials, cells, and HIF signaling pathways must be determined. This review aimed to provide an in-depth insight into recent progress in HIF-regulated bone regeneration. Hypoxia and cellular oxygen-sensing mechanisms and their correlations with osteogenesis were determined, and recent studies on hypoxia-inducing and hypoxia-mimicking strategies were briefly described. Finally, the potential applications of HIF signaling in bone regeneration were highlighted. This review provides theoretical support for establishing a novel and viable bone repair strategy in the clinic by harnessing HIF signaling.
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http://dx.doi.org/10.1016/j.bioadv.2022.212874DOI Listing
July 2022

Three-dimensional electroconductive carbon nanotube-based hydrogel scaffolds enhance neural differentiation of stem cells from apical papilla.

Biomater Adv 2022 Jul 16;138:212868. Epub 2022 May 16.

Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, Guangdong, China.. Electronic address:

The radical treatment of neurological impairments remains a major clinical challenge. Stem cells with high neural differentiation ability delivered by electroconductive hydrogel scaffolds have demonstrated promising applications in neural tissue regeneration. However, there are still challenges in designing bioactive scaffolds with good biocompatibility, appropriate electrical conductivity, and neurogenic niche. Herein, a three-dimensional (3D) electroconductive gelatin methacryloyl-multi-walled carbon nanotube/cobalt (GelMA-MWCNTs/Co) hydrogel scaffold was fabricated by incorporating MWCNTs/Co composites into a GelMA hydrogel matrix. The surface morphology, pore size, elastic modulus, swelling ratio, and conductivity of the hydrogels were measured. GelMA-MWCNTs/Co exhibited higher electrical conductivity than GelMA-MWCNTs. Live/dead and CCK8 assays demonstrated the good biocompatibility of the hydrogel for stem cells from apical papilla (SCAP) growth and differentiation. The cells encapsulated in the GelMA-MWCNTs and GelMA-MWCNTs/Co hydrogel scaffolds exhibited significant neuronal cell-like changes and a notable level of neuronal-specific marker expression after the electrical stimulation (ES) for 7 days, compared to that in the hydrogels without ES. Notably, the neurite spreading and Tuj1 fluorescent intensity of the SCAP in the electrically conductive GelMA-MWCNTs/Co hydrogel were more prominent compared to those of the other two groups. In addition, the 3D conductive hydrogel scaffolds advanced the neural differentiation of SCAP to an earlier time point. Considering these aspects, the novel electroconductive GelMA-MWCNTs/Co hydrogel synergized with ES greatly promotes SCAP neuronal differentiation.
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http://dx.doi.org/10.1016/j.bioadv.2022.212868DOI Listing
July 2022

Exogenous proline enhances susceptibility of NSCLC to cisplatin metabolic reprogramming and PLK1-mediated cell cycle arrest.

Front Pharmacol 2022 14;13:942261. Epub 2022 Jul 14.

Department of Translational Medical Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

The occurrence of cisplatin resistance is still the main factor limiting the therapeutic effect of non-small cell lung cancer (NSCLC). It is urgent to elucidate the resistance mechanism and develop novel treatment strategies. Targeted metabolomics was first performed to detect amino acids' content in cisplatin-resistant cancer cells considering the relationship between tumour metabolic rearrangement and chemotherapy resistance and chemotherapy resistance. We discovered that levels of most amino acids were significantly downregulated, whereas exogenous supplementation of proline could enhance the sensitivity of NSCLC cells to cisplatin, evidenced by inhibited cell viability and tumour growth and xenograft models. In addition, the combined treatment of proline and cisplatin suppressed ATP production through disruption of the TCA cycle and oxidative phosphorylation. Furthermore, transcriptomic analysis identified the cell cycle as the top enriched pathway in co-therapy cells, accompanied by significant down-regulation of PLK1, a serine/threonine-protein kinase. Mechanistic studies revealed that PLK1 inhibitor (BI2536) and CDDP have synergistic inhibitory effects on NSCLC cells, and cells transfected with lentivirus expressing shPLK1 showed significantly increased toxicity to cisplatin. Inhibition of PLK1 inactivated AMPK, a primary regulator of cellular energy homeostasis, ultimately leading to cell cycle arrest via FOXO3A-FOXM1 axis mediated transcriptional inhibition in cisplatin-resistant cells. In conclusion, our study demonstrates that exogenous proline exerts an adjuvant therapeutic effect on cisplatin resistance, and PLK1 may be considered an attractive target for the clinical treatment of cisplatin resistance in NSCLC.
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http://dx.doi.org/10.3389/fphar.2022.942261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330219PMC
July 2022

Increased expression of ST2 on regulatory T cells is associated with cancer associated fibroblast-derived IL-33 in laryngeal cancer.

Pathol Res Pract 2022 Jul 13;237:154023. Epub 2022 Jul 13.

Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address:

Interleukin (IL)- 33 plays an essential role in regulatory T cell (Treg)-mediated immunosuppression in cancers and underlies the crosstalk between Tregs and the tumor microenvironment. However, the phenotypic characteristics of subset Tregs modulated by IL-33 and its association with the tumor microenvironment are not fully understood. This study aimed to examine the expression of ST2, the receptor of IL-33, on Tregs in tumors and to evaluate their association with cancer associated fibroblasts (CAFs) and reciprocal influences on the prognosis of laryngeal cancer. Our results showed that increased numbers of Tregs were found in laryngeal tumor tissues. Tregs in stromal IL-33-positive tumor tissues demonstrated significantly higher expression of ST2 than those in IL-33 or adjacent nontumor tissues. ST2-expressing Tregs exhibited upregulation of Ki67 and CTLA4 compared with their ST2 negative counterparts. Furthermore, IL-33 in the tumor microenvironment was mainly derived from fibroblasts. ST2 expression on Tregs was correlated with the number of IL-33-positive CAFs. High ST2 expression on Tregs, combined high ST2 on Tregs and the presence of IL-33 expressing CAFs was associated with worse survival outcomes in laryngeal cancer. This study indicated that increased expression of ST2 on Tregs is associated with microenvironmental IL-33 signaling derived from CAFs in laryngeal cancer, unraveling the special role of Tregs and fibroblasts in modulating IL-33/ST2 involved immune-evasive tumor microenvironment.
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http://dx.doi.org/10.1016/j.prp.2022.154023DOI Listing
July 2022

Glioblastoma-educated mesenchymal stem-like cells promote glioblastoma infiltration via extracellular matrix remodelling in the tumour microenvironment.

Clin Transl Med 2022 Aug;12(8):e997

Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.

Background: The biological function of mesenchymal stem-like cells (MSLCs), a type of stromal cells, in the regulation of the tumour microenvironment is unclear. Here, we investigated the molecular mechanisms underlying extracellular matrix (ECM) remodelling and crosstalk between MSLCs and glioblastomas (GBMs) in tumour progression.

Methods: In vitro and in vivo co-culture systems were used to analyze ECM remodelling and GBM infiltration. In addition, clinical databases, samples from patients with GBM and a xenografted mouse model of GBM were used.

Results: Previous studies have shown that the survival of patients with GBM from whom MSLCs could be isolated is substantially shorter than that of patients from whom MSLCs could not be isolated. Therefore, we determined the correlation between changes in ECM-related gene expression in MSLC-isolatable patients with that in MSLC non-isolatable patients using gene set enrichment analysis (GSEA). We found that lysyl oxidase (LOX) and COL1A1 expressions increased in MSLCs via GBM-derived clusters of differentiation 40 ligand (CD40L). Mechanistically, MSLCs are reprogrammed by the CD40L/CD40/NFκB2 signalling axis to build a tumour infiltrative microenvironment involving collagen crosslinking. Importantly, blocking of CD40L by a neutralizing antibody-suppressed LOX expression and ECM remodelling, decreasing GBM infiltration in mouse xenograft models. Clinically, high expression of CD40L, clusters of differentiation 40 (CD40) and LOX correlated with poor survival in patients with glioma. This indicated that GBM-educated MSLCs promote GBM infiltration via ECM remodelling in the tumour microenvironment.

Conclusion: Our findings provide mechanistic insights into the pro-infiltrative tumour microenvironment produced by GBM-educated MSLCs and highlight a potential therapeutic target that can be used for suppressing GBM infiltration.
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http://dx.doi.org/10.1002/ctm2.997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339241PMC
August 2022

Automated synthesis of [Ga]Ga-FAPI-46 without pre-purification of the generator eluate on three common synthesis modules and two generator types.

EJNMMI Radiopharm Chem 2022 Jul 29;7(1):20. Epub 2022 Jul 29.

Department of Nuclear Medicine, Molecular Diagnostic Imaging and Therapy, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Karl Lennert Cancer Center North, Feld-Str. 21 (Haus L), 24105, Kiel, Germany.

Background: The recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge. Our aim was to simplify the synthesis and shorten the automated synthesis of [Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community.

Results: We developed and evaluated the GMP compliant automatic synthesis of [Ga]Ga-FAPI-46 using two different Ge/Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing.

Conclusions: Independent of the synthesis modules or the generators employed we were able to complete the synthesis of [Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia.
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http://dx.doi.org/10.1186/s41181-022-00172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338183PMC
July 2022

Comparison of Multiparametric Magnetic Resonance Imaging with Prostate-Specific Membrane Antigen Positron-Emission Tomography Imaging in Primary Prostate Cancer Diagnosis: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2022 Jul 19;14(14). Epub 2022 Jul 19.

UCL Division of Surgery & Interventional Science, University College London, London WC1E 6BT, UK.

Multiparametric magnetic-resonance imaging (mpMRI) has proven utility in diagnosing primary prostate cancer. However, the diagnostic potential of prostate-specific membrane antigen positron-emission tomography (PSMA PET) has yet to be established. This study aims to systematically review the current literature comparing the diagnostic performance of mpMRI and PSMA PET imaging to diagnose primary prostate cancer. A systematic literature search was performed up to December 2021. Quality analyses were conducted using the QUADAS-2 tool. The reference standard was whole-mount prostatectomy or prostate biopsy. Statistical analysis involved the pooling of the reported diagnostic performances of each modality, and differences in per-patient and per-lesion analysis were compared using a Fisher's exact test. Ten articles were included in the meta-analysis. At a per-patient level, the pooled values of sensitivity, specificity, and area under the curve (AUC) for mpMRI and PSMA PET/CT were 0.87 (95% CI: 0.83-0.91) vs. 0.93 (95% CI: 0.90-0.96, < 0.01); 0.47 (95% CI: 0.23-0.71) vs. 0.54 (95% CI: 0.23-0.84, > 0.05); and 0.84 vs. 0.91, respectively. At a per-lesion level, the pooled sensitivity, specificity, and AUC value for mpMRI and PSMA PET/CT were lower, at 0.63 (95% CI: 0.52-0.74) vs. 0.79 (95% CI: 0.62-0.92, < 0.001); 0.88 (95% CI: 0.81-0.95) vs. 0.71 (95% CI: 0.47-0.90, < 0.05); and 0.83 vs. 0.84, respectively. High heterogeneity was observed between studies. PSMA PET/CT may better confirm the presence of prostate cancer than mpMRI. However, both modalities appear comparable in determining the localisation of the lesions.
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http://dx.doi.org/10.3390/cancers14143497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323375PMC
July 2022

Interleukin-32γ promotes macrophage-mediated chemoresistance by inducing CSF1-dependent M2 macrophage polarization in multiple myeloma.

Cancer Immunol Immunother 2022 Jul 26. Epub 2022 Jul 26.

College of Medicine, Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, Qingchun Road 79, Hangzhou, China.

Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206 M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy.
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http://dx.doi.org/10.1007/s00262-022-03241-1DOI Listing
July 2022

MRG Chip: A High-Throughput qPCR-Based Tool for Assessment of the Heavy Metal(loid) Resistome.

Environ Sci Technol 2022 Aug 25;56(15):10656-10667. Epub 2022 Jul 25.

State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.

Bacterial metal detoxification mechanisms have been well studied for centuries in pure culture systems. However, profiling metal resistance determinants at the community level is still a challenge due to the lack of comprehensive and reliable quantification tools. Here, a novel high-throughput quantitative polymerase chain reaction (HT-qPCR) chip, termed the metal resistance gene (MRG) chip, has been developed for the quantification of genes involved in the homeostasis of 9 metals. The MRG chip contains 77 newly designed degenerate primer sets and 9 published primer sets covering 56 metal resistance genes. Computational evaluation of the taxonomic coverage indicated that the MRG chip had a broad coverage matching 2 kingdoms, 29 phyla, 64 classes, 130 orders, 226 families, and 382 genera. Temperature gradient PCR and HT-qPCR verified that 57 °C was the optimal annealing temperature, with amplification efficiencies of over 94% primer sets achieving 80-110%, with > 0.993. Both computational evaluation and the melting curve analysis of HT-qPCR validated a high specificity. The MRG chip has been successfully applied to characterize the distribution of diverse metal resistance determinants in natural and human-related environments, confirming its wide scope of application. Collectively, the MRG chip is a powerful and efficient high-throughput quantification tool for exploring the microbial metal resistome.
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http://dx.doi.org/10.1021/acs.est.2c00488DOI Listing
August 2022

Tricyclic Aza-Andrographolide Derivatives from Late-Stage Hydroamination and Their Anti-human Coronavirus (Anti-HCoV) Activity.

ACS Omega 2022 Jul 7;7(28):24824-24837. Epub 2022 Jul 7.

BayRay Innovative Center, Shenzhen Bay Laboratory, Shenzhen 518032, China.

A late-stage functionalization (LSF) of the natural product andrographolide for the efficient assembly of a range of structurally interesting and diverse tricyclic-aza derivatives was developed. The key to the diversification is a photo-catalyzed intramolecular hydroamination reaction, and acridinium derivatives were demonstrated to be the optimal catalysts. Additionally, the synthesized tricyclic aza-andrographolide derivatives were found to inhibit human coronavirus with high potency.
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http://dx.doi.org/10.1021/acsomega.2c02979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301648PMC
July 2022

Characterization of heterotrophic nitrification by a thermotolerant Brevibacillus Agri N2 isolated from sewage sludge composting.

Environ Res 2022 Jul 19;214(Pt 2):113903. Epub 2022 Jul 19.

School of Environment, Harbin Institute of Technology, Harbin, 150090, China.

A thermotolerant strain isolated from sewage sludge (SS) composting was identified as Brevibacillus Agri N2, which showed the efficient capability for heterotrophic nitrification under high-temperature conditions. Incubation at 60 °C, strain N2 could utilize 45.47% of ammonium nitrogen (99.64 mg/L), 68.89% of hydroxylamine nitrogen (51.14 mg/L) and 76.77% of nitrite nitrogen (55.20 mg/L), with a minor part of nitrogen loss for 1.64%, 2.82% and 5.01%, respectively. The successful detection of ammonia monooxygenase, hydroxylamine oxidase, and nitrate oxidoreductase and PCR amplification of amoA, hao and nxrA genes provided evidence of nitrification ability by strain N2. Furthermore, single-factor experiments indicated that the optimal conditions for efficient nitrification performance by strain N2 were succinate as carbon source, 50 °C, C/N 12, pH 8 and 200 r/min. Strain N2 could perform the complete nitrification process, with minimal nitrogen loss at high temperature conditions, which indicated it had the potential for practical application for reducing nitrogen loss of SS composting.
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http://dx.doi.org/10.1016/j.envres.2022.113903DOI Listing
July 2022

Cyclometalated Platinum(II) Metallomesogens Based on Half-Disc-Shaped β-Diketonate Ligands with Hexacatenar: Crystal Structures, Mesophase Properties, and Semiconductor Devices.

Inorg Chem 2022 Aug 18;61(30):11702-11714. Epub 2022 Jul 18.

College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China.

A series of new half-disc-shaped platinum(II) complexes [Pt(ppy)(AL-6OCH)] (, [Pt(ppyF)(AL-6OCH)] (, and [Pt(ppyCF)(AL-6OCH)] ( (AL-6OCH = 1,3-bis(3,4,5-trialkoxyphenyl)propane-1,3-dionato; = 1, 6, 12) with concise structures have been designed and synthesized, in which 2-phenylpyridine (ppy) derivatives were used as cyclometalated ligands and hexacatenar β-diketonate derivatives AL-6OCH as auxiliary ligands. The single-crystal data of the methoxy diketonate analogues , , and indicate that they all display excellent square planarity. These platinum(II) complexes show a certain emission tunability (ranging from λ = 506-535 nm) by the introduction of fluorine or trifluoromethyl into ppy. Thermal studies reveal that the fluorine-substituted complexes are liquid crystals but the trifluoromethyl-substituted complexes are not. The platinum(II) complexes , , and can form a hexagonal columnar mesophase via intermolecular π-π interactions. In addition, compared to the reported platinum(II) metallomesogens, and exhibit improved ambipolar carrier mobility behaviors in semiconductor devices at the liquid crystal states.
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http://dx.doi.org/10.1021/acs.inorgchem.2c01327DOI Listing
August 2022

Subcutaneous Adipose Tissue Accumulation Is an Independent Risk Factor of Urinary Stone in Young People.

Front Endocrinol (Lausanne) 2022 30;13:865930. Epub 2022 Jun 30.

Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.

Background: Urinary stones usually start at a young age and tend to recur. Therefore, preventing stone occurrence and recurrence in young people is crucial. We aimed to investigate the association between subcutaneous adipose tissue, visceral adipose tissue, and stone episodes in young people.

Methods: We retrospectively studied patients aged below 40 years with kidney or ureteral stones. Data on demographic and metabolic characteristics, urolithiasis history, subcutaneous fat area (SFA), and visceral fat area (VFA) were collected. We evaluated the association between SFA or VFA and the occurrence or recurrence of stone episodes using binary logistic regression and Poisson regression analyses.

Results: In total, 120 patients were included. Abdominal obesity, overweight or obesity, dyslipidemia, metabolic syndrome, SFA, and VFA increased with the number of stone episodes (all p < 0.05). The increase in SFA was independently associated with episode occurrence (p = 0.015). Patients with an SFA > 97 cm had a higher risk of episode occurrence. SFA and VFA accumulation were independently associated with episode recurrence (all p < 0.05), and SFA had a stronger association than VFA did.

Conclusions: In young people, SFA accumulation is an independent and early risk factor for the occurrence and recurrence of stone episodes. Subcutaneous fat could be a convenient and effective indicator to assess the risk of stone episodes before the development of metabolic disorders.
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http://dx.doi.org/10.3389/fendo.2022.865930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280630PMC
June 2022

Silver nanoparticles reduce the tolerance of Cronobacter sakazakii to environmental stress by inhibiting expression of related genes.

J Dairy Sci 2022 Aug 13;105(8):6469-6482. Epub 2022 Jul 13.

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China. Electronic address:

Cronobacter sakazakii is a food-borne pathogen that is resistant to a variety of environmental stress conditions. It can survive in harsh environments. We studied the effects of silver nanoparticles (AgNP) on the environmental tolerance and biofilm formation of C. sakazakii. First, we determined the minimum inhibitory concentration (MIC) of AgNP to C. sakazakii and determined the growth curve of C. sakazakii treated with different concentrations of AgNP by using the plate counting method. After determining the sub-inhibition concentrations (SIC) of AgNP on C. sakazakii, we studied the effects of AgNP on the resistance of C. sakazakii to heat, desiccation, osmotic pressure, and acid. The antibiofilm activity of AgNP was also studied. Finally, real-time quantitative PCR was used to analyze the transcription levels of 16 genes related to the environmental tolerance of C. sakazakii. The SIC of AgNP significantly reduced the survival rate of C. sakazakii under various environmental stress conditions. The results showed that AgNP at 0.625 and 1.25 μg/mL significantly inhibited the formation of C. sakazakii biofilms. The expression levels of most genes were significantly downregulated in C. sakazakii cells treated with 0.625 and 1.25 μg/mL AgNP. Therefore, AgNP may reduce the environmental tolerance of C. sakazakii by inhibiting the expression of genes related to stress tolerance. Moreover, AgNP inhibited the production of ATP in C. sakazakii cells and the formation of C. sakazakii biofilms. Our research provides a theoretical basis for the application of AgNP in food packaging, bactericidal coatings, and other fields.
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http://dx.doi.org/10.3168/jds.2022-21833DOI Listing
August 2022

Truncated analog Brevinin2-CE-N26V5K: Revelation the Augmentation of Antimicrobial Activity.

World J Microbiol Biotechnol 2022 Jul 14;38(9):162. Epub 2022 Jul 14.

College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, P. R. China.

Brevinin2-CE (B2CE), a natural peptide containing 37 amino acids, was first isolated from the skin secretions of the Chinese forest frog Rana chensinensis. B2CE shows good antibacterial activity. In this study, a series of B2CE analogs with differences in cationicity, α-helicity, hydrophobicity and amphipathic properties were designed through chain-length deletion and amino acid substitution. The most potent, nontoxic analog, B2CE-N26V5K, was identified by examination of its antibacterial activity, hemolytic activity, and stability under physiological conditions. The increased cationicity, hydrophobicity and more obvious hydrophilic and hydrophobic surface of B2CE-N26-N16WA18KG23K did not improve the antibacterial activity but increased the hemolytic activity of this modified peptide. The helicity might promote antibacterial activity for brevinin-2 peptides, as the 15-aa analogs with lower helicity show decreased potency against different test bacteria (approximately 2- to 72-fold) compared to B2CE-N26V5K. Additionally, the results indicated that the "Rana box" does not affect the antimicrobial activity of brevinin-2 peptides, as B2CE, B2CE-nonDS and B2CE-C31-37 S have similar strong inhibitory effects on both gram-positive and gram-negative bacteria. However, the "Rana box" does affect the hemolytic activity, as the HC values of the 3 peptides range from 25 ~ 130 µM. Furthermore, B2CE-N26V5K caused obvious morphological alterations of the bacterial surfaces, as shown by atomic force microscopy. Additionally, B2CE-N26V5K exhibited strong membrane-disrupting activity when examined using the LIVE/DEAD Bac Light Bacterial Viability Kit. Thus, the antibacterial effect of B2CE-N26V5K on gram-negative and gram-positive bacteria may be caused by cell membrane attack. In conclusion, the excellent candidate B2CE-N26V5K was obtained and has application prospects as a novel anti-infective agent.
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http://dx.doi.org/10.1007/s11274-022-03333-1DOI Listing
July 2022

Message in hand: the application of CRISPRi, RNAi, and LncRNA in adenocarcinoma.

Med Oncol 2022 Jul 14;39(10):148. Epub 2022 Jul 14.

Cancer Research Institute, Guangdong Medical University, Dongguan, 523808, China.

Gene editing interference technology has been flourishing for more than 30 years. It has always been a common means to interfere with the expression of particular genes. Today it has shown a broad application prospect in clinical treatment, especially in adenocarcinoma treatment. In just a few years, the CRISPRi technology has attracted much z attention with its precise targeting and convenient operability significantly promoted the transformation from bench to bedside, and won the Nobel Prize in Chemistry 2020. In recent years, the importance of non-coding RNA has led LncRNA research to the center. At the same time, it also recalls the surprises obtained in laboratory and clinic research by RNAi technologies such as microRNA, siRNA, and shRNA at the beginning of the century. Therefore, this article focuses on CRISPRi, RNAi, and LncRNA to review their gene interference mechanisms currently expected to be translational research. Their applications and differences in adenocarcinoma research will also be described powerfully. It will provide a helpful reference for scientists to understand better and apply several RNA interference technologies.
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http://dx.doi.org/10.1007/s12032-022-01727-7DOI Listing
July 2022

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer.

J Enzyme Inhib Med Chem 2022 Dec;37(1):1995-2003

Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.

A series of 1,2,3-triazole analogues as novel fat mass and obesity-associated protein (FTO) inhibitors were synthesised in this study. Among all 1,2,3-triazoles, compound exhibited the most robust inhibition of FTO with an IC value of 780 nM. It displayed the potent antiproliferative activity against KYSE-150, KYSE-270, TE-1, KYSE-510, and EC109 cell lines with IC value of 2.17, 1.35, 0.95, 4.15, and 0.83 μM, respectively. In addition, arrested the cell cycle at G2 phase against TE-1 and EC109 cells in a concentration-dependent manner. Analysis of cellular mechanisms demonstrated that concentration-dependently regulated epithelial mesenchymal transition (EMT) pathway and PI3K/AKT pathway against TE-1 and EC109 cells. Molecular docking studies that formed important hydrogen-bond interaction with Lys107, Asn110, Tyr108, and Leu109 of FTO. These findings suggested that as a novel FTO inhibitor and orally antitumor agent deserves further investigation to treat esophageal cancer.
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http://dx.doi.org/10.1080/14756366.2022.2098954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291647PMC
December 2022

Pathway Lasso: Pathway Estimation and Selection with High-Dimensional Mediators.

Authors:
Yi Zhao Xi Luo

Stat Interface 2022 11;15(1):39-50. Epub 2021 Aug 11.

Department of Biostatistics and Data Science, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, TX USA.

In many scientific studies, it becomes increasingly important to delineate the pathways through a large number of mediators, such as genetic and brain mediators. Structural equation modeling (SEM) is a popular technique to estimate the pathway effects, commonly expressed as the product of coefficients. However, it becomes unstable and computationally challenging to fit such models with high-dimensional mediators. This paper proposes a sparse mediation model using a regularized SEM approach, where sparsity means that a small number of mediators have a nonzero mediation effect between a treatment and an outcome. To address the model selection challenge, we innovate by introducing a new penalty called . This penalty function is a convex relaxation of the non-convex product function for the mediation effects, and it enables a computationally tractable optimization criterion to estimate and select pathway effects simultaneously. We develop a fast ADMM-type algorithm to compute the model parameters, and we show that the iterative updates can be expressed in closed form. We also prove the asymptotic consistency of our Pathway Lasso estimator for the mediation effect. On both simulated data and an fMRI data set, the proposed approach yields higher pathway selection accuracy and lower estimation bias than competing methods.
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http://dx.doi.org/10.4310/21-sii673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269990PMC
August 2021

Bandpass Filter Integrated Metalens Based on Electromagnetically Induced Transparency.

Nanomaterials (Basel) 2022 Jul 2;12(13). Epub 2022 Jul 2.

Key Laboratory of Optical System Advanced Manufacturing Technology, Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun 130033, China.

A bandpass filter integrated metalens based on electromagnetically induced transparency (EIT) for long-wavelength infrared (LWIR) imaging is designed in this paper. The bandwidth of the metalens, which is a diffractive optical element, decreases significantly with the increase of the aperture size to a fixed f-number, which leads to the decline of imaging performance. The same material composition and preparation process of the metalens and the EIT metasurface in the long-wavelength infrared make it feasible that the abilities of focusing imaging and filtering are integrated into a metasurface device. With the purpose of validating the feasibility of this design method, we have designed a 300-μm-diameter integrated metalens whose f-number is 0.8 and the simulation was carried out. The introduction of EIT metasurface does not affect the focusing near the diffraction limit at the target wavelength, and greatly reduces the influence of stray light caused by non-target wavelength incident light. This bandpass filter integrated metalens design method may have a great potential in the field of LWIR compact optical systems.
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http://dx.doi.org/10.3390/nano12132282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268714PMC
July 2022

Evaluation of the sequence-dependent relative activity of APE1 for optimal biosensing design.

Biosens Bioelectron 2022 Oct 4;214:114539. Epub 2022 Jul 4.

Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Analytical & Testing Center, Sichuan University, Chengdu, 610064, China. Electronic address:

Apurinic/apyrimidinic endonuclease 1 (APE1) can selectively incise the AP site of DNA, thus is universal for various DNA substrates for flexible endonuclease-assisted signal amplification. However, the substrate preference of APE1 has never been systematically investigated. Therefore in this work, the detailed sequence-dependent relative activity of APE1 was determined. It turned out that the APE1 activity did vary with the change of the adjacent and opposite bases, and over 10-fold relative activity difference was observed for different sequence combinations. Such difference is appreciable enough to induce evident impact on APE1-involved biosensing. With an APE1 probe designed for cycled signal amplification, the sensitivities followed exactly with the above activity order. Compared with Nb.BbvCl, the sensitivity of the APE1 probe varied between higher and lower than the Nb.BbvCl probe (with varied substrates), demonstrating the importance of the sequence-dependent relative activity of APE1 for optimal biosensor development. Moreover, the above APE1 probe design was harvested and engineered for sensitive biosensing of uracil-DNA glycosylase (UDG). Through theoretical analysis of the interaction between APE1 and the substrates, the accuracy of the determined sequence-dependent relative activity of APE1 was partially confirmed.
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http://dx.doi.org/10.1016/j.bios.2022.114539DOI Listing
October 2022

Alpha-1 antitrypsin in autoimmune diseases: Roles and therapeutic prospects.

Int Immunopharmacol 2022 Jul 6;110:109001. Epub 2022 Jul 6.

Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China; Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address:

Alpha-1 antitrypsin (A1AT) is a protease inhibitor in the serum. Its primary function is to inhibit the activity of a series of proteases, including proteinase 3, neutrophil elastase, metalloproteases, and cysteine-aspartate proteases. In addition, A1AT also has anti-inflammatory, anti-apoptotic, anti-oxidative stress, anti-viral, and anti-bacterial activities and plays essential roles in the regulation of tissue repair and lymphocyte differentiation and activation. The overactivation of the immune system characterizes the pathogenesis of autoimmune diseases. A1AT treatment shows beneficial effects on patients and animal models with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. This review summarizes the functions and therapeutic prospects of A1AT in autoimmune diseases.
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http://dx.doi.org/10.1016/j.intimp.2022.109001DOI Listing
July 2022

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria.

Pathog Immun 2022 23;7(1):60-80. Epub 2022 Jun 23.

Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway.

Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193).

Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up.

Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.
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http://dx.doi.org/10.20411/pai.v7i1.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254869PMC
June 2022

Liver Transplantation for Giant Hemangioma Complicated by Kasabach-Merritt Syndrome: A Case Report and Literature Review.

Am J Case Rep 2022 May 23;23:e936042. Epub 2022 May 23.

Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, TX, USA.

BACKGROUND Liver hemangiomas are the most common benign liver tumor. Giant hepatic hemangiomas are hemangiomas that are greater than 4 cm in diameter. While asymptomatic giant hepatic hemangioma patients can be monitored without intervention, patients that experience complications can be managed by trans-arterial embolization, radiofrequency ablation, surgical resection, or enucleation. Although there is no consensus on definite medical treatment or optimal timing of surgery, liver transplantation is rarely indicated. Among giant hepatic hemangioma patients who received liver transplantation, Kasabach-Merritt syndrome (KMS), a consumptive coagulopathy associated with hemangiomas, is one of the most common indications. We present a case of giant hepatic hemangioma complicated by Kasabach-Merritt syndrome, which was successfully treated by orthotopic liver transplantation. CASE REPORT The patient was a 39-year-old woman with a known history of multiple giant hepatic hemangiomas who presented with abdominal pain and distension. She had life-threatening intra-abdominal hemorrhages caused by benign endometriomas due to hepatic hemangiomas complicated by Kasabach-Merritt syndrome. Despite interventional radiology embolization of a bleeding uterine artery and aggressive resuscitation with fluid and blood products, the patient's status continued to decline. Emergent orthotopic liver transplantation was applied with subsequent resolution of the consumptive coagulopathy. She remained well at 2-month follow-up, with normal liver enzyme levels and intact liver allograft function. CONCLUSIONS Liver transplantation is indicated for selected patients with giant hepatic hemangioma complicated by KMS; despite the high surgical risk, outcomes seem favorable.
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http://dx.doi.org/10.12659/AJCR.936042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136188PMC
May 2022

Location and Effect of Bone Cement in Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures.

Biomed Res Int 2022 26;2022:6127620. Epub 2022 Jun 26.

Department of Orthopedic Surgery, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai 200940, China.

In this study, the effectiveness and use of bone cement are thoroughly elaborated, and the role of bone cement on percutaneous vertebroplasty (PVP) fixed joints and its distribution on PVP are also elucidated. The aim of this study was to investigate the effect of unilateral and bilateral bone cement distribution on the clinical efficacy of PVP in the treatment of osteoporotic vertebral compression fractures (OVCF) of the thoracolumbar spine. A total of 60 patients with thoracolumbar OVCF (T11-L2) hospitalized in our hospital from January 2020 to January 2021 were studied. All patients had thoracolumbar OVCF. Under the guidance of the C-arm machine, unilateral PVP was performed. According to the distribution of bone cement across the midline, the patients were divided into two groups: the unilateral group (37 cases): bone cement was distributed on one side of the midline of the vertebral body, and the bilateral group (23 cases): bone cement was distributed on both sides of the midline. Visual analogue scale (VAS), vertebral height recovery values, and preoperative and postoperative Cobb's angle were recorded at 3 days, 1 month, 3 months, and 6 months. The differences between the two groups were compared and analyzed to evaluate the clinical efficacy. There was a statistically significant difference in VAS scores between the two groups before and after surgery ( < 0.05), but there was no statistically significant difference in VAS scores between the two groups at 3 days, 1 month, 3 months, and 6 months after surgery ( > 0.05). There were statistically significant differences in vertebral height recovery value and Cobb's angle between the two groups before and after surgery ( < 0.05).
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http://dx.doi.org/10.1155/2022/6127620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251087PMC
July 2022

Microwave-Induced Deep Catalytic Oxidation of NO Using Molecular-Sieve-Supported Oxygen-Vacancy-Enriched Fe-Mn Bimetal Oxides.

Environ Sci Technol 2022 07 6;56(14):10423-10432. Epub 2022 Jul 6.

Hebei Key Lab of Power Plant Flue Gas Multi-Pollutants Control, Department of Environmental Science and Engineering, North China Electric Power University, Baoding 071003, P. R. China.

A novel microwave (MW) catalytic oxidation denitrification method was developed, which can deeply oxidize NO into nitrate/nitrite with little NO yield. A molecular-sieve-supported oxygen-vacancy-enriched FeO-MnO catalyst ([email protected]) was fabricated. Physicochemical properties of the catalyst were revealed by various characterization methods. MW irradiation was superior to the conventional heating method in NO oxidation (90.5 vs 70.6%), and MW empowered the catalyst with excellent low-temperature activity (100-200 °C) and good resistance to HO and SO. Ion chromatography analysis demonstrated that the amount of nitrate/nitrite accounted for over 90.0% of the N products, but the main product gradually varied from nitrate to nitrite as the reaction proceeded because of the switching of the main reaction path of NO removal. Mechanism analyses clarified that NO oxidation was a non-radical catalytic reaction: (i) the chemisorbed NO on ≡Mn(IV) reacted with O* to produce nitrate and (ii) the excited NO* due to MW irradiation reacted with the active O* generated from Ov···O to form nitrite. Density functional theory calculations combined with electron paramagnetic resonance tests revealed the promotional effects of FeO in (i) boosting the Ov's quantity; (ii) facilitating O adsorption; (iii) increasing the nitrite formation; and (iv) alleviating the suppression of SO.
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http://dx.doi.org/10.1021/acs.est.2c02851DOI Listing
July 2022

Pre- and intratherapeutic predictors of overall survival in patients with advanced metastasized castration-resistant prostate cancer receiving Lu-177-PSMA-617 radioligand therapy.

BMC Urol 2022 Jul 4;22(1):96. Epub 2022 Jul 4.

Department of Nuclear Medicine, Molecular Diagnostic Imaging and Therapy, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Straße 3, Haus L, 24105, Kiel, Germany.

Background: Systemic Lutetium-177 prostate-specific membrane antigen-617 radioligand therapy (Lu-177-PSMA-617-RLT) is a novel treatment approach in patients suffering from metastasized castration-resistant prostate cancer. Nonetheless, a therapeutic response may fail to appear in a proportion of patients. This study aims to identify routinely obtainable pre- and intratherapeutic parameters to allow a prediction of overall survival in patients receiving Lu-177-PSMA-617 radioligand therapy.

Methods: Between January 2015 and December 2020 52 patients treated with a total of 146 cycles Lu-177-PSMA-617-RLT were retrospectively analysed in a single-center trial. The median overall survival time (OS) was compared to pre-therapeutic serological parameters, the extend of metastatic spread and previously performed therapies using Kaplan-Meier estimators and multivariate Cox-regression. Bonferroni-Holm correction was performed on all statistical tests.

Results: The median OS of all patients was 55.6 weeks. Multivariate Cox-regression revealed significant lower survival for decreased pretherapeutic hemoglobin levels (HR 0.698 per g/dl; 95%-CI 0.560-0.872; p = 0.001), increased lactate dehydrogenase (LDH) levels (HR 1.073 per 25 U/l; 95%-CI 1.024-1.125; p = 0.003) and the presence of hepatic metastasis (HR 6.981; 95%-CI 2.583-18.863; p < 0.001). Increased pretherapeutic c-reactive protein (CRP), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels were also associated with a shorter survival. A prostate-specific antigen decline after one therapy cycle did not significantly correlate with an increased survival. No significant relations were observed between overall survival time and other serological parameters or previously performed therapies.

Conclusion: Pre-therapeutic hemoglobin and LDH levels, as well as the presence of hepatic metastasis are independent predictors of overall survival in patients receiving Lu-177-PSMA-617-RLT. CRP, ALP and GGT levels cloud be utilized as additional decision aids when a Lu-177-PSMA-617-RLT is intended. Trial Registration Not applicable (retrospective observational study).
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http://dx.doi.org/10.1186/s12894-022-01050-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254582PMC
July 2022

Mutational landscape of pan-cancer patients with PIK3CA alterations in Chinese population.

BMC Med Genomics 2022 07 1;15(1):146. Epub 2022 Jul 1.

National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huan-Hu Road, Ti Yuan Bei, Hexi District, Tianjin, 300060, China.

Purpose: To analyze the mutational landscape of pan-cancer patients with PIK3CA mutations in Chinese population in real-world.

Methods: We analyzed PIK3CA mutation status in sequencing data of cell-free DNA from plasma and genomic DNA from matched peripheral blood lymphocyte in 11,904 Chinese pan-cancer patients, and compared them with genomic data from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Besides, concomitant genomic aberrations in PIK3CA-mutated samples were detected to investigate cancer driver genes, as well as their enriched pathways. Meanwhile, the mutations of Alpelisib targeting genes were screened and their co-alterations were analyzed according to OncoKB definition to identify the potential actionable ones.

Results: The proportion of patients with PIK3CA mutations varied among 21 types of cancer, with the top being BRCA, CESC, SCL, and UCEC. The most common PIK3CA mutation hotspots were found to be E545K, E542K and H1047R. The Chinese cohort had significantly lower frequencies of PIK3CA mutations in breast and stomach cancers, but markedly higher PIK3CA mutation frequencies in large intestine, kidney and lung cancers than the COSMIC cohort. Compared with COSMIC cohort, the mutation frequencies of Alpelisib-targeted genes in breast cancer were significantly reduced in the Chinese cohort. All PIK3CA-mutated patients had concomitant genomic aberrations. While the most common concomitant genomic alterations occurred in TP53, EGFR and FAT1, these co-mutated genes were mainly enriched in RTK/RAS pathway, PI3K pathway and P53 pathway. Moreover, 83.6% of patients carrying mutations in Alpelisib-targeted genes had at least one actionable concomitant alteration. Level 1 actionable alteration was identified in LUAD, BRCA, COAD, LUSC, READ, and STAD.

Conclusion: Compared with the Western cohort, the mutation frequency of PIK3CA in breast cancer was reduced in the Chinese cohort. RTK/RAS pathway, PI3K pathway and P53 pathway were identified as the most common co-mutation pathways, suggesting that they may potentially serve as targets for possible Alpelisib-based combination therapy.
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http://dx.doi.org/10.1186/s12920-022-01297-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248192PMC
July 2022
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