Publications by authors named "Linlin Wang"

648 Publications

Correlation among Metabolic Changes in Tea Plant (L.) Shoots, Green Tea Quality and the Application of Cow Manure to Tea Plantation Soils.

Molecules 2021 Oct 13;26(20). Epub 2021 Oct 13.

Tea Research Institute, Qingdao Agricultural University, Qingdao 266109, China.

Traditionally, the supplement of organic manure in tea plantations has been a common approach to improving soil fertility and promoting terroir compounds, as manifested by the coordinated increase in yield and quality for the resulting teas. However, information regarding the effect of organic manure in the metabolome of tea plants is still inadequate. The metabolite profiles of tea shoots applied with cow manure, urea or no fertilizer were studied using gas chromatography-mass spectrometry (GC-MS). In total, 73 metabolites were detected, and the modulated metabolites included mainly amino acids, organic acids and fatty acids. In particular, glutamine, quinic acid and proline accumulated more in tea shoots in soils treated with cow manure, but octadecanoic acid, hexadecanoic acid and eicosanoic acid were drastically reduced. Pearson correlation analysis indicated that organic acids and amino acids in tea shoots were the two major metabolite groups among the three treatments. The analysis of metabolic pathways demonstrated that the cow manure treatment significantly changed the enrichment of pathways related to amino acids, sugars and fatty acids. Sensory evaluation showed that the quality of green teas was higher when the plants used to make the tea were grown in soil treated with cow manure rather than urea during spring and late summer. The results indicated that the application of cow manure in soils changed the metabolic characteristics of tea shoots and improved the qualities of the resulting teas.
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http://dx.doi.org/10.3390/molecules26206180DOI Listing
October 2021

Antihypertensive potential of fermented milk: the contribution of lactic acid bacteria proteolysis system and the resultant angiotensin-converting enzyme inhibitory peptide.

Food Funct 2021 Oct 18. Epub 2021 Oct 18.

School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, P. R. China.

Hypertension has become an increasing health concern given that it is a major risk for cardiovascular disease. Synthetic antihypertensive drugs, including angiotensin-converting enzyme (ACE) inhibitors, effectively control high blood pressure but are associated with unpleasant side effects. Milk fermented by certain lactic acid bacteria (LAB) provides energetic contributions to the management of hypertension, especially the regulation of ACE. LAB are important food-grade microbial organisms that release ACE inhibitory peptides through their unique proteolysis system, which consists of cell-envelope proteinases (CEPs), transporter systems, and intracellular peptidases. Thus, the description of LAB proteolysis system genes and their contributions to ACE inhibitory peptide production is a challenging but promising study. This review provides a survey of LABs with potential ACE inhibitory activity and investigates the research progress of LAB proteolytic systems with an emphasis on the correlation of their components and ACE inhibitory activity. Subsequently, a depiction of the ACE inhibitory peptide action mechanism, structure-activity relationship and bioavailability is presented. The improved functional annotation of LAB proteolytic system genes will provide an excellent framework for future experimental validations of predicted ACE inhibitory activity in fermented milk.
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http://dx.doi.org/10.1039/d1fo02435cDOI Listing
October 2021

Prenatal uranium exposure and risk for fetal neural tube defects: A case-control study in women living in a rural area of northern China.

J Hazard Mater 2021 Oct 7;424(Pt B):127466. Epub 2021 Oct 7.

Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Electronic address:

The adverse effects of uranium exposure on human health are well-known; less is known, however, regarding its association with congenital malformations. We conducted a case-control study to examine the association between prenatal exposure to uranium and risk for fetal neural tube defects (NTDs) using the concentration of uranium in placental tissue as an exposure marker in 408 NTD cases and 593 healthy controls. Uranium concentration was quantified with an inductively coupled plasma mass spectrometer. The odds ratios of NTDs for uranium exposure levels, categorized into quartiles, were estimated using logistic regression. The median concentration of uranium in the NTD group (0.409 ng/g) was significantly higher than that in the control group (0.218 ng/g). The risk for NTDs increased 2.52-fold (95% CI, 1.85-3.45) for concentrations of uranium above the median value for all participants. After adjusting for confounders, the risk for NTDs increased 1.36-fold (95% CI, 1.25-6.17), 1.77-fold (95% CI, 1.09-2.85), and 3.60-fold (95% CI, 2.30-5.64) for the second, third, and fourth quartiles of uranium concentrations compared to the lowest quartile, respectively. Prenatal exposure to uranium is a risk factor for NTDs in this population. Prospective studies are needed to further validate this finding.
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http://dx.doi.org/10.1016/j.jhazmat.2021.127466DOI Listing
October 2021

Development and validation of a prognostic nomogram for malignant esophageal fistula based on radiomics and clinical factors.

Thorac Cancer 2021 Oct 14. Epub 2021 Oct 14.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, China.

Background: The current study aimed to comprehensively analyze the clinical prognostic factors of malignant esophageal fistula (MEF). Furthermore, this study sought to establish and validate prognostic nomograms incorporating radiomics and clinical factors to predict overall survival and median survival after fistula for patients with MEF.

Methods: The records of 76 patients with MEF were retrospectively analyzed. A stepwise Cox proportional hazards regression model was employed to screen independent prognostic factors and develop clinical nomograms. Radiomic features were extracted from prefistula CT images and post fistula CT images. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression algorithm was used to filter radiomic features and avoid overfitting. Radiomic signature was a linear combination of optimal features and corresponding coefficients. The joint prognostic nomograms was constructed by radiomic signatures and clinical features. All models were validated by Harrell's concordance index (C-index), caliberation and bootstrap validation.

Results: For overall survival, age, prealbumin, KPS and interval between diagnosis of esophageal cancer and fistula were identified as independent prognostic factors and incorporated into the clinical nomogram. Age, prealbumin, serum albumin, KPS and neutrophil proportion were selected for the clinical nomogram of post fistula survival. The C-index of overall survival nomogram was 0.719 (95% CI: 0.645-0.793) and that was 0.722 (95% CI: 0.653-0.791) in the post fistula survival nomogram. The radiomic signature developed by radiomic features of prefistula CT showed a significant correlation with both overall survival and post fistula survival. The C-index of joint nomogarm for overall survival and post fistula survival was 0.831 (95% CI: 0.757-0.905) and 0.77 (95% CI: 0.686-0.854), respectively. The calibration curve showed the joint nomograms outperformed the clinical ones.

Conclusions: The study presents nomograms incorporating independent clinical risk factors and radiomic signature to predict the prognosis of MEF. This prognostic classification system has the potential to guide therapeutic decisions for patients with malignant esophageal fistulas.
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http://dx.doi.org/10.1111/1759-7714.14115DOI Listing
October 2021

LOXL2-enriched small extracellular vesicles mediate hypoxia-induced premetastatic niche and indicates poor outcome of head and neck cancer.

Theranostics 2021 3;11(19):9198-9216. Epub 2021 Sep 3.

Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041.

Small extracellular vesicles (sEVs) operate as a signaling platform due to their ability to carry functional molecular cargos. However, the role of sEVs in hypoxic tumor microenvironment-mediated premetastatic niche formation remains poorly understood. : Protein expression profile of sEVs derived from normoxic and hypoxic head and neck squamous cell carcinoma (HNSCC) cells were determined by Isobaric Tagging Technology for Relative Quantitation. In vitro invasion assay and in vivo colonization were performed to evaluate the role of sEV-delivering proteins. : We identified lysyl oxidase like 2 (LOXL2) which had the highest fold increase in hypoxic sEVs compared with normoxic sEVs. Hypoxic cell-derived sEVs delivered high amounts of LOXL2 to non-hypoxic HNSCC cells to elicit epithelial-to-mesenchymal transition (EMT) and induce the invasion of the recipient cancer cells. Moreover, LOXL2-enriched sEVs were incorporated by distant fibroblasts and activate FAK/Src signaling in recipient fibroblasts. Increased production of fibronectin mediated by FAK/Src signaling recruited myeloid-derived suppressor cells to form a premetastatic niche. Serum sEV LOXL2 can reflect a hypoxic and aggressive tumor type and can serve as an alternative to tissue LOXL2 as an independent prognostic factor of overall survival for patients with HNSCC. : sEVs derived from the hypoxic tumor microenvironment of HNSCC can drive local invasion of non-hypoxic HNSCC cells and stimulate premetastatic niche formation by delivering LOXL2 to non-hypoxic HNSCC cells and fibroblasts to induce EMT and fibronectin production, respectively.
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http://dx.doi.org/10.7150/thno.62455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490529PMC
September 2021

Genome-Wide Identification and Characterization of Polygalacturonase Gene Family in Maize ( L.).

Int J Mol Sci 2021 Oct 3;22(19). Epub 2021 Oct 3.

Zhongzhi International Institute of Agricultural Biosciences, Shunde Graduate School, Research Center of Biology and Agriculture, University of Science and Technology Beijing (USTB), Beijing 100024, China.

Polygalacturonase (PG, EC 3.2.1.15) is a crucial enzyme for pectin degradation and is involved in various developmental processes such as fruit ripening, pollen development, cell expansion, and organ abscission. However, information on the gene family in the maize ( L.) genome and the specific members involved in maize anther development are still lacking. In this study, we identified 55 family genes from the maize genome and further characterized their evolutionary relationship and expression patterns. Phylogenetic analysis revealed that are grouped into six Clades, and gene structures of the same Clade are highly conserved, suggesting their functional conservation. The are randomly distributed across maize chromosomes, and collinearity analysis showed that many might be derived from tandem duplications and segmental duplications, and these genes are under purifying selection. Furthermore, gene expression analysis provided insights into possible functional divergence among . Based on the RNA-seq data analysis, we found that many are expressed in various tissues while 18 are highly expressed in maize anther, and their detailed expression profiles in different anther developmental stages were further investigated by using RT-qPCR analysis. These results provide valuable information for further functional characterization and application of the in maize.
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http://dx.doi.org/10.3390/ijms221910722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509529PMC
October 2021

Chromatographic Fingerprinting Based on Column Switching Technology for Quality Evaluation of Tianmeng Oral Liquid.

Int J Anal Chem 2021 29;2021:2514762. Epub 2021 Sep 29.

School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.

Separation power was limited when the conventional high-performance liquid chromatography (HPLC) fingerprinting method based on a single column was used to analyze very complex traditional Chinese medicine (TCM) preparations. In this research, a novel HPLC fingerprinting method based on column switching technology by using a single pump was established for evaluating the quality of Tianmeng oral liquid (TMOL). Twelve batches of TMOL samples were used for constructing HPLC fingerprints. Compared with the 16 common peaks in fingerprinting with a single column, 25 common peaks were achieved with two columns connected through a six-way valve. The similarity analysis combined with bootstrap method was applied to determine the similarity threshold, which was 0.992 to distinguish expired samples and unexpired samples. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) were also applied to classify the TMOL samples, and results revealed that expired and unexpired samples are classified into two categories. The HPLC fingerprinting based on column switching technology with better separation power and higher peak capacity could characterize chemical composition information more comprehensively, providing an effective and alternative method to control and evaluate the quality of TMOL, which would offer a valuable reference for other TCM preparations.
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http://dx.doi.org/10.1155/2021/2514762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494583PMC
September 2021

Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Na 1.5-subunit mutations.

J Biomed Res 2021 Jul;35(5):395-407

Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.

Brugada syndrome (BrS) is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death. Considering that its heterogeneity in clinical manifestations may result from genetic background, the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) may help to reveal cell phenotype characteristics underlying different genetic variations. Here, to verify and compare the pathogenicity of mutations ( c.4213G>A and c.590C>T) identified from two BrS patients, we generated two novel BrS iPS cell lines that carried missense mutations in or compared their structures and electrophysiology, and evaluated the safety of quinidine in patient-specific iPSC-derived CMs. Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration, and varying degrees of decreased , but no structural difference. After applying different concentrations of quinidine, drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration (ETPC). The data presented proved that iPSC-CMs with variants in c.4213G>A or c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.
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http://dx.doi.org/10.7555/JBR.35.20210045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502687PMC
July 2021

XPO1-mutant NSCLC without STK11/KEAP1 mutations may predict better survival to immunotherapy.

J Transl Med 2021 Oct 9;19(1):421. Epub 2021 Oct 9.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

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http://dx.doi.org/10.1186/s12967-021-03098-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502403PMC
October 2021

Saponins from Nigella glandulifera seeds attenuate collagen-induced rheumatoid arthritis in rats via the OPG/RANKL/NF-κB and Ang/Tie-2 pathways.

J Ethnopharmacol 2021 Oct 5;283:114714. Epub 2021 Oct 5.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address:

Ethnopharmacological Relevance: Nigella glandulifera Freyn et Sint. (N. glandulifera) seeds are widely used in traditional Uyghur medicine for a variety of immuno-inflammatory diseases. The total saponins from N. glandulifera seeds (TSNGS) have been shown to have analgesic, antioxidant, and anti-inflammatory effects that can alleviate joint pain and swelling.

Aim Of The Study: Rheumatoid arthritis (RA) is a chronic and progressive, debilitating autoimmune disease for which current treatments are not sufficiently effective and result in unsatisfactory side effects. This study aimed to mechanistically investigate the therapeutic effects of TSNGS on RA.

Materials And Methods: Qualitative analysis of TSNGS was performed using ultra-high-performance liquid chromatography-Q-Orbitrap-high-resolution mass spectrometry. Rats with collagen-induced arthritis (CIA), IL-1β-induced HFLS-RAs, and VEGF-induced HUVECs were analyzed to determine the efficacy and mechanism of TSNGS on RA.

Results: Twenty-one compounds were identified in TSNGS. TSNGS (10, 50, or 250 mg/kg) reduced the severity of arthritis, indicated by a lower arthritis score, reduced paw swelling, and body weight in rats with CIA. TSNGS ameliorated histopathological changes involving inflammatory infiltration, bone degeneration, and angiogenesis in knee and ankle joints. TSNGS improved the immuno-inflammatory response by restoring the levels of the cytokines IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, IL-4, and IL-10, and increasing the number of CD4CD25 Tregs in the peripheral circulation and Foxp3 levels in knee joints in rats with CIA. Furthermore, TSNGS increased the OPG/RANKL ratio and downregulated p-p65 in serum and joint synovia. Inhibition of angiogenesis by TSNGS was associated with recovery of the angiogenesis-related Ang/Tie-2 signaling pathway.

Conclusions: It was established that TSNGS provides a therapeutic effect on RA by alleviating synovitis, bone degeneration, and angiogenesis via the OPG/RANKL/NF-κB and Ang/Tie-2 pathways and may be used for the treatment of RA.
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http://dx.doi.org/10.1016/j.jep.2021.114714DOI Listing
October 2021

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors.

Transl Oncol 2021 Dec 1;14(12):101231. Epub 2021 Oct 1.

State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Chengdu, Sichuan 610041, China. Electronic address:

Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.
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http://dx.doi.org/10.1016/j.tranon.2021.101231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493591PMC
December 2021

Orofacial Clefts in High Prevalence Area of Birth Defects - Five Counties, Shanxi Province, China, 2000-2020.

China CDC Wkly 2021 Sep;3(37):773-777

Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing, China.

What Is Already Known On This Topic?: The prevalence of structural birth defects, especially neural tube defects, decreased after national folic acid (FA) supplementation initiation.

What Is Added By This Report?: The prevalence of orofacial clefts (OFCs) in five counties of Shanxi Province in northern China, including most subtypes except cleft palate, showed a downward trend in the past two decades. In this study, pre-perinatal prevalence increased due to earlier detection.

What Are The Implications For Public Health Practice?: Periconceptional supplementation with FA may contribute to the decline in OFCs prevalence, while the effect on the OFCs subtype needs further investigation. Continuing to advocate for earlier supplementation (3 months before conception) and increased supplementation frequency (daily consumption) could promote further reduction in the prevalence of OFCs. Specific surveillance of this effect in the era of universal three-child policy is warranted.
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http://dx.doi.org/10.46234/ccdcw2021.192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441179PMC
September 2021

Selected Structural Birth Defects - Shanxi Province, China, 2000-2019.

China CDC Wkly 2020 Sep;2(37):718-722

Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, School of Public Health, Peking University, Beijing, China.

To reduce the high prevalence of neural tube defects (NTDs) in rural areas of the country, the Ministry of Health of China (currently known as the National Health Commission) initiated a nationwide folic acid supplementation program in 2009. The prevalence of NTDs have decreased from 118.9/10,000 births to 31.5/10,000 in northern China from 2000 to 2014.



Based on a population-based birth-defect surveillance system, the prevalence of selected structural birth defects in 5 counties in northern China decreased significantly from 182.8/10,000 births to 119.3/10,000 during the past two decades. Perinatal (28 gestational weeks or more) structural birth defects decreased from 83.9% of total birth defects in 2000 to 59.9% in 2019.



Improving the compliance of periconceptional folic acid supplementation, the fortification of staple foods with folic acid, and the health education surrounding early prenatal check-ups should be considered to further reduce the risk of birth defects in the population.
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http://dx.doi.org/10.46234/ccdcw2020.196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392938PMC
September 2020

Mechanically Strong, Autonomous Self-Healing, and Fully Recyclable Silicone Coordination Elastomers with Unique Photoluminescent Properties.

Macromol Rapid Commun 2021 Sep 29:e2100519. Epub 2021 Sep 29.

Key Laboratory of Special Functional Aggregated Materials (Shandong University), Ministry of Education; School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China.

The combination of excellent mechanical performances, high reprocess efficiency, and wide-range tunability for functional dynamic siloxane materials is a challenging subject. Herein, the fabrication of mechanically strong, autonomous self-healing, and fully recyclable silicone elastomers with unique photoluminescent properties by coordination of poly(dimethylsiloxane) (PDMS) containing coordination bonding motifs with Zn ions is reported. Salicylaldimine groups, which are introduced into the polysiloxane backbone via mild Schiff-base reaction, coordinate with zinc ions to form elastomeric networks The obtained supramolecular elastomers have excellent mechanical properties, with the optimized tensile strength up to 10.0 MPa, which is unprecedented among the reported thermoplastic polysiloxane-based elastomers. Both mechanical properties and stress relaxation kinetics are tunable via adjusting the length of PDMS segments or the molar ratio of metal versus salicylaldimine. Furthermore, these elastomers can be conveniently healed and recycled to regain their original mechanical properties and integrity under mild conditions. In addition, this new kind of polysiloxane also exhibits coordination-enhanced fluorescence, showing great promise for preparing photoluminescent elastomers or coatings.
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http://dx.doi.org/10.1002/marc.202100519DOI Listing
September 2021

MustSeq, an alternative approach for multiplexible strand-specific 3' end sequencing of mRNA transcriptome confers high efficiency and practicality.

RNA Biol 2021 Sep 29:1-12. Epub 2021 Sep 29.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong Province, China.

RNA-seq has been widely used to reveal the molecular mechanism of variants of life process. We have developed an alternative method, MustSeq, which generates multiple second strands along a single 1 strand cDNA by random-priming initiation, immediately after reverse transcription for each RNA extract using sample-barcoded poly-dT primers, then 3' ends-enriching PCR is applied to construct the library. Unlike the conventional RNA seq, MustSeq avoids procedures such as mRNA isolation, fragmentation and RNA 5'-end capture, enables early pooling of multiple samples, and requires only one twentieth of sequencing reads of full-length sequencing. We demonstrate the power and features of MustSeq comparing with TruSeq and NEBNext RNA-seq, two conventional full-length methods and QuantSeq, an industrial 3' end method. In cancer cell lines, the reads distribution of CDS-exon as well as genes, lncRNAs and GO terms detected by MustSeq are closer than QuantSeq to TruSeq. In mouse hepatocarcinoma and healthy livers, MustSeq enriches the same pathways as by NEBNext, and reveals the molecular profile of carcinogenesis. Overall MustSeq is a robust and accurate RNA-seq method allowing efficient library construction, sequencing and analysis, particularly valuable for analysis of differentially expressed genes with a large number of samples. MustSeq will greatly accelerate the application of bulk RNA-seq on different fields, and potentially applicable for single cell RNA-seq.
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http://dx.doi.org/10.1080/15476286.2021.1974208DOI Listing
September 2021

Mere15, a novel polypeptide from Meretrix meretrix, inhibits proliferation and metastasis of human non-small cell lung cancer cells through regulating the PI3K/Akt/mTOR signaling pathway.

Neoplasma 2021 Sep 29. Epub 2021 Sep 29.

Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.

Mere15, an anticancer polypeptide with a molecular weight of 15 kDa, is extracted from the marine species Meretrix meretrix. A previous study in our laboratory has confirmed that Mere15 displays a potent antitumor activity. However, the underlying mechanism of Mere15 still remains unclear. The effect of Mere15 on the growth of a variety of tumor cells was measured by the CCK-8 assay. Hoechst33342/PI double staining and flow cytometry assays were used to detect the apoptosis status of cancer cells. Western blotting was used to detect the expression of apoptosis-related proteins, migration and invasion-related protein, and the changes in the PI3K/Akt/mTOR signaling pathway-related proteins. Treatment with Mere15 inhibited cancer cell growth significantly. Scratch wound-healing assay, as well as Transwell experiments, revealed that the polypeptide was able to inhibit the invasion and migration of NSCLC cells significantly. Western blotting analysis confirmed that treatment with Mere15 inhibited the phosphorylation of PI3K, Akt, and mTOR significantly. The effects of Mere15 were also evaluated in the presence of an activator or inhibitor of the PI3K/Akt/mTOR pathway. Downregulated expression of MMP-2, MMP-9, and Snail, and increased expression of E-cadherin were also found in cells treated with Mere15. In vivo study revealed that Mere15 inhibited tumor growth significantly in xenograft nude mice bearing NCI-H460 cancer cells. The study provides evidence that Mere15 has the potential to be developed as a novel antimetastatic agent for the treatment of NSCLC patients. The work also provides further evidence that targeting PI3K/Akt/mTOR pathway is an important strategy for overcoming cancer metastasis.
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http://dx.doi.org/10.4149/neo_2021_210509N628DOI Listing
September 2021

Fucoidan hydrogels induced by κ-carrageenan: Rheological, thermal and structural characterization.

Int J Biol Macromol 2021 Sep 24;191:514-520. Epub 2021 Sep 24.

Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, National & Local Joint Engineering Laboratory for Marine Bioactive Polysaccharide Development and Application, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China. Electronic address:

Fucoidan (FUC) is a non-gelling polysaccharide but could interact with κ-carrageenan (KC) to form a stable gel blend. However, their interaction mechanism is unclear. Herein, FUC and KC blended gels are prepared by mixing FUC (10 and 20 mg/mL) and KC (6, 7 and 8 mg/mL) solutions, and characterized through LF-NMR, rheology, DSC, Cryo-SEM, and FTIR. The FTIR analysis confirms the formation of hydrogen bonds between FUC and KC chains. The KC addition to FUC significantly improves the water retention and frost resistance. The viscoelastic measurements reveal higher gelling nature of the FUC-KC binary mixtures, and the DSC results confirm the higher thermal stability. The Cryo-SEM images clearly reveal the gel network structure. The outcome of this study deemed to further the FUC use in food and non-food applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.111DOI Listing
September 2021

Differentiation of Diffuse Infiltration Pattern in Multiple Myeloma From Hyperplastic Hematopoietic Bone Marrow: Qualitative and Quantitative Analysis Using Whole-Body MRI.

J Magn Reson Imaging 2021 Sep 24. Epub 2021 Sep 24.

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, 1st, Jianshe Dong Road, Zhengzhou, Henan Province, 450052, China.

Background: The visual assessment used for diffuse infiltration of multiple myeloma (MM) is inadequate. It can be difficult to differentiate MM from hyperplastic hematopoietic bone marrow (HHBM) because the MRI signal characteristics overlap.

Purpose: To analyze the bone marrow diffuse signal changes on whole-body MRI caused by MM and HHBM.

Study Type: Retrospective.

Subjects: Thirty Four patients with MM (21 men and 13 women), 22 patients with HHBM (9 men and 13 women), and 15 healthy controls (9 men and 6 women).

Field Strength/sequence: A 3.0 T MRI; diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), modified Dixon T1 fast field echo, and T2 STIR.

Assessment: Three radiologists analyzed the whole-body MRI alone and in combination with apparent diffusion coefficient (ADC) and fat fraction (FF) with qualitative and quantitative analysis. Normalized T1 and T2 signal intensities (nT1 and nT2) and signal-to-noise ratio (SNR) were obtained.

Statistical Tests: Kruskal-Wallis and chi-square tests.

Results: The MM group had significantly higher ADC and significantly lower FF than HHBM and control groups. There was no significant difference in nT1, nT2 or SNR between MM and HHBM (P = 0.932, P = 0.097, and P = 0.110, respectively). Receiver operating characteristic (ROC) analysis using ADC and FF cut-off values of 0.47 × 10  mm /sec and 20.63%, respectively. The AUC was 0.866 for ADC and 0.886 for FF. The quantitative analysis yielded better specificity (observer 1: 81.8% vs. 27.3%; observer 2: 68.2% vs. 22.7%; and observer 3: 72.7% vs. 18.2%) and a higher diagnostic accuracy (observer 1: 82.1% vs. 51.8%; observer 2: 80.4% vs. 50.0%; observer 3: 76.8% vs. 44.6%) than the qualitative analysis.

Data Conclusion: Whole-body MRI combined with DWIBS and mDIXON could be used to differentiate between MM and HHBM. Combining the quantitative ADC and FF with the whole-body MRI improved the specificity and accuracy in differentiating these conditions.

Evidence Level: 3 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27934DOI Listing
September 2021

Role of Extracellular Vesicles on Cancer Lymphangiogenesis and Lymph Node Metastasis.

Front Oncol 2021 7;11:721785. Epub 2021 Sep 7.

State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Lymph node metastasis (LNM) of tumors is an established indicator of poor prognosis in patients. Tumor-associated lymphangiogenesis is a key step in LNM and has gained much attention. However, currently, there is no anti-tumor lymphangiogenesis drug used in clinical practice. Recently, studies on extracellular vesicles (EVs) have shown that different types of cells in the tumor microenvironment can release EVs that encapsulate a variety of molecules, including proteins, nucleic acids, and metabolites. Lymph endothelial cells (LECs) regulate tumor lymphangiogenesis through the uptake of EVs packed with different biologically active contents. In this review, we will discuss the possible mechanisms by which EVs participate in the regulation of tumor-associated lymphangiogenesis and LNM, summarize the potential value of EVs that can be used as biomarkers for the determination of tumor LNM, and indicate the potential anti-tumor lymphangiogenesis therapy.
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http://dx.doi.org/10.3389/fonc.2021.721785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451414PMC
September 2021

Vanadium -mediated ultrafine Co/CoS nanoparticles anchored on Co-N-doped porous carbon enable efficient hydrogen evolution and oxygen reduction reactions.

Nanoscale 2021 Oct 8;13(38):16277-16287. Epub 2021 Oct 8.

School of Materials Science & Engineering, International S&T Cooperation Foundation of Shaanxi Province, Xi'an Key Laboratory of Green Manufacture of Ceramic Materials, Shaanxi Key Laboratory of Green Preparation and Functionalization for Inorganic Materials, Key Laboratory of Auxiliary Chemistry and Technology for Chemical Industry, Ministry of Education, Shaanxi University of Science & Technology, Xi'an Shaanxi, 710021, P.R. China.

Developing cost-effective, highly-active and robust electrocatalysts is of vital importance to supersede noble-metal ones for both hydrogen evolution reactions (HERs) and oxygen reduction reactions (ORRs). Herein, a unique vanadium-mediated space confined strategy is reported to construct a composite structure involving Co/CoS nanoparticles anchored on Co-N-doped porous carbon ([email protected]) as bifunctional electrocatalysts toward HER and ORR. Benefitting from the ultrafine nanostructure, abundant Co-N active sites, large specific surface area and defect-rich carbon framework, the resultant [email protected] exhibits unexceptionable HER catalytic activity, needing extremely low HER overpotentials in pH-universal media (alkaline: 117 mV, acid: 178 mV, neutral: 210 mV) at a current density of 10 mA cm, paralleling at least 100 h catalytic durability. Notably, the [email protected] catalyst delivers high-efficiency ORR performance in alkaline solution, accompanied with a quite high half wave potential of 0.901 V, far overmatching the commercial Pt/C catalyst. Our research opens up novel insight into engineering highly-efficient multifunctional non-precious metal electrocatalysts by a metal-mediated space-confined strategy in energy storage and conversion system.
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http://dx.doi.org/10.1039/d1nr04607aDOI Listing
October 2021

Warming reshaped the microbial hierarchical interactions.

Glob Chang Biol 2021 Sep 20. Epub 2021 Sep 20.

Institute of Marine Science and Technology, Shandong University, Qingdao, China.

Global warming may alter microbially mediated ecosystem functions through reshaping of microbial diversity and modified microbial interactions. Here, we examined the effects of 5-year experimental warming on different microbial hierarchical groups in a coastal nontidal soil ecosystem, including prokaryotes (i.e., bacteria and archaea), fungi, and Cercozoa, which is a widespread phylum of protists. Warming significantly altered the diversity and structure of prokaryotic and fungal communities in soil and additionally decreased the complexity of the prokaryotic network and fragmented the cercozoan network. By using the Inter-Domain Ecological Network approach, the cross-trophic interactions among prokaryotes, fungi, and Cercozoa were further investigated. Under warming, cercozoan-prokaryotic and fungal-prokaryotic bipartite networks were simplified, whereas the cercozoan-fungal network became slightly more complex. Despite simplification of the fungal-prokaryotic network, the strengthened synergistic interactions between saprotrophic fungi and certain prokaryotic groups, such as the Bacteroidetes, retained these phyla within the network under warming. In addition, the interactions within the fungal community were quite stable under warming conditions, which stabilized the interactions between fungi and prokaryotes or protists. Additionally, we found the microbial hierarchical interactions were affected by environmental stress (i.e., salinity and pH) and soil nutrients. Interestingly, the relevant microbial groups could respond to different soil properties under ambient conditions, whereas under warming these two groups tended to respond to similar soil properties, suggesting network hub species responded to certain environmental changes related to warming, and then transferred this response to their partners through trophic interactions. Finally, warming strengthened the network modules' negative association with soil organic matters through some fungal hub species, which might trigger soil carbon loss in this ecosystem. Our study provides new insights into the response and feedback of microbial hierarchical interactions under warming scenario.
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http://dx.doi.org/10.1111/gcb.15891DOI Listing
September 2021

Cancers associated with human gammaherpesviruses.

FEBS J 2021 Sep 18. Epub 2021 Sep 18.

Department of Microbiology & Immunology & Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

Epstein-Barr virus (EBV; human herpesvirus 4; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; human herpesvirus 8; HHV-8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV-8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B-cell lymphoma, post-transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV-positive diffuse large B-cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities.
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http://dx.doi.org/10.1111/febs.16206DOI Listing
September 2021

A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68 Macrophages.

Front Immunol 2021 31;12:711231. Epub 2021 Aug 31.

Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, China.

Women with endometriosis may have a defective immune system. However, evidence of the immune responses of endometriosis patients with a history of endometriosis surgery is lacking, and the association between the location of endometriosis lesions and immune responses is unclear. This retrospective study included 117 females with reproductive failure and a history of endometriosis and 200 females with reproductive failure but without endometriosis to analyze their endometrial and peripheral immune responses. The results show that endometriosis was associated with decreased peripheral natural killer (NK) cytotoxicity and increased uterine macrophages. Peripheral NK cytotoxicity at effector-to-target ratios of 25:1 and 50:1 was significantly reduced in women with a history of endometriosis from that of the control group (26.6% 33.3% and 36.1% 43.3%, respectively, both < 0.001). Furthermore, after further division of patients into three subgroups according to the location of endometriosis lesions, we observed that NK cytotoxicity in the endometriosis subgroups, especially the mixed endometriosis group, was strongly decreased from that of the controls ( = 0.001). The endometrial CD68 macrophage proportion in the mixed endometriosis subgroup was higher than that in the control group (2.8% 2.1%, = 0.043). In addition, the baseline estradiol (E2) level was weakly correlated with the percentage of endometrial macrophages (r = 0.251, = 0.009), indicating a potential association among the endocrine system, endometrial immune environment, and endometriosis. This study indicated that peripheral NK cytotoxicity and endometrial immune cell profiles could be useful for diagnosing and treating endometriosis and endometriosis-related reproductive diseases.
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http://dx.doi.org/10.3389/fimmu.2021.711231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438297PMC
August 2021

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p-CaMKII/ERK/CREB and ox-CaMKII-Dependent MAPK/NF-B Pathways.

Oxid Med Cell Longev 2021 4;2021:6673967. Epub 2021 Sep 4.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-B associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKII siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKII. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.
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http://dx.doi.org/10.1155/2021/6673967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437593PMC
September 2021

Detection of Neoplasms by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid.

JAMA Neurol 2021 Sep 13. Epub 2021 Sep 13.

Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.

Importance: Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis.

Objective: To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm.

Design, Setting, And Participants: Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed.

Main Outcomes And Measures: The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance.

Results: Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%.

Conclusions And Relevance: This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.
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http://dx.doi.org/10.1001/jamaneurol.2021.3088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438621PMC
September 2021

GO-based antibacterial composites: Application and design strategies.

Adv Drug Deliv Rev 2021 Sep 10;178:113967. Epub 2021 Sep 10.

Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Guangzhou 510515, China. Electronic address:

Graphene oxide (GO), for its unique structure with high biocompatibility and designability, is widely used in the antibacterial field. Various strategies have been designed to fabricate GO-based composites with antibacterial properties. This review summarized these strategies, divided them into three types and interpreted their antibacterial mechanisms: (i) "GO*/non-GO" type in which GO acts as the single antibacterial core, (ii) "GO*/non-GO*" type in which GO and non-GO components function synergistically as dual antibacterial cores, (iii) "GO/non-GO*" type in which non-GO acts as the single antibacterial core, while GO component plays a supportive, not a dominant role in antibiosis. Besides, the fields suiting their applications and factors influencing their antibacterial properties were analyzed. Finally, the limitations and prospects in the current researches were discussed. In summary, GO-based composites have revolutionized antibacterial strategies. This review may serve as a reference to inspire further research on GO-based antibacterial composites.
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http://dx.doi.org/10.1016/j.addr.2021.113967DOI Listing
September 2021

Fabrication of CoO-BiO-Ti catalytic membrane for efficient degradation of organic pollutants in water by peroxymonosulfate activation.

J Colloid Interface Sci 2021 Aug 18;607(Pt 1):451-461. Epub 2021 Aug 18.

State Key Laboratory of Separation Membranes and Membrane Processes, School of Environmental Science and Engineering, Tiangong University, Tianjin 300387, China.

In this study, a functionalized CoO-BiO-Ti catalytic membrane (CBO-Ti-M) was prepared and applied for removing organic pollutants via activating peroxymonosulfate (PMS) in the dead-end filtration mode. Characterizations including scanning electron microcopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) showed that the CoO-BiO catalyst was successfully supported on the Ti membrane. The CBO-Ti-M /PMS system could efficiently remove various organic pollutants such as sulfamethoxazole, methyl orange, bisphenol A and methylene blue, achieving removal efficiencies of 98.0%-99.5%. The effects of PMS concentration, flow rate and solution environment on degradation efficiency were investigated in detail. Furthermore, quenching experiments, electron spin resonance (ESR) and in-situ open circuit potential (OCP) tests collectively demonstrated that singlet oxygen as well as the non-radical electron transfer pathway mainly contributed in the reaction mechanism. The synergistic effect of Co and Bi was illustrated according to XPS results, and the possible degradation pathway of MB was proposed based on LC-MS analysis. Reusability test showed that pollutant removal efficiency with the CBO-Ti-M /PMS system remained stable in four runs and limited metal leaching was observed.
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http://dx.doi.org/10.1016/j.jcis.2021.08.086DOI Listing
August 2021

Global Cytopathology-Hematopathology Practice Trends.

Am J Clin Pathol 2021 Sep 11. Epub 2021 Sep 11.

Department of Pathology, Stanford University, Stanford, CA, USA.

Objectives: Small-volume biopsy-fine-needle aspiration biopsy (FNAB) with or without core biopsy-is in increasing use in diagnosis and management of lymphoma patients. Our objective was to survey the current practice in small-volume biopsy diagnosis of lymphoma, focusing on the interaction among hematopathologists and cytopathologists and the integration of FNAB, core biopsy, and flow cytometry studies at sign-out.

Methods: This study used a cross-sectional survey design employing the RedCap database distributed via nine pathology professional society email listservs. The survey consisted of 25 multiple-choice questions and several free text fields. In total, 128 pathologists participated.

Results: Most respondents indicated that FNAB specimens in which lymphoma is a diagnostic consideration (FNAB-L) are seen daily or weekly (68/116; 58.6%). However, most institutions have separate hematopathology and cytopathology services (72/116; 62.1%) with inconsistent communication. When communication occurred, respondents were frequently inclined to reconsider their original diagnoses. Barriers identified included lack of communication, inadequate access to diagnostic studies, no formal subspecialty training, and various opinions regarding FNAB in diagnosing lymphoma.

Conclusions: This survey showed that FNAB-L specimens are common, with a lack of uniformity in how complementary fine-needle aspiration and core biopsy specimens or flow immunophenotyping results are shared across hematopathology and cytopathology services.
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http://dx.doi.org/10.1093/ajcp/aqab111DOI Listing
September 2021

Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response.

J Hematol Oncol 2021 Sep 8;14(1):142. Epub 2021 Sep 8.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb.

Methods: We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2IL-2R-γc-KO (BRG) mice. Depleting antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, was tested for its effect on TIMs.

Results: BsAb-driven T cells recruited myeloid cells into human tumor xenografts. Each TIM targeting therapy depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, and particularly TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and survival in multiple cancer xenograft models. Dexamethasone premedication depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and anti-tumor response with survival benefit.

Conclusion: Reducing TIMs markedly enhanced anti-tumor effects of BsAb-based T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion was more effective than PMN- or M-MDSCs depletion at boosting the anti-tumor response of T cell engaging BsAb.
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http://dx.doi.org/10.1186/s13045-021-01156-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424962PMC
September 2021
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