Publications by authors named "Yan Zhou"

2,721 Publications

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One-step Derivation of Functional Mesenchymal Stem Cells from Human Pluripotent Stem Cells.

Bio Protoc 2018 Nov 20;8(22):e3080. Epub 2018 Nov 20.

Department of Biomedicine, Aarhus University, Aarhus C, Denmark.

Mesenchymal stem cells (MSCs) are invaluable cell sources for understanding stem cell biology and potential application in tissue engineering and regenerative medicine. The current issues of MSCs that demand to be further addressed are limited donors, tissue sources and limited capacity of expansion. Here, we describe a simple and easy protocol for generating functional mesenchymal stem cells from human pluripotent stem cells (hPSCs) via one-step low glucose medium switch strategy in feeder-free culture system. In this protocol, human induced pluripotent stem cells (hiPSCs) and H9 human embryonic stem cells (hESCs) were successfully differentiated into MSCs, named hiPSC-MSCs and hESC-MSCs, respectively. The derived hiPSC-MSCs and hESC-MSCs exhibited common MSC characteristics as MSCs derived from human bone marrow (hBM-MSCs), including expressing MSC surface markers and possessing capability of tri-lineage differentiation (adipogenesis, osteogenesis and chondrogenesis). As compared with other available protocols, our protocol can be applied to generate a large number of MSCs from hPSCs with high efficiency, low-cost manner, moreover, not involving embryoid body, mouse feeder-cell, flow sorting, and pathway inhibitors (such as SB203580 and SB431542). We believe that this protocol could provide a robust platform to reach the future demand for producing the industrial scale of MSC from hPSCs for autologous cell-based therapy.
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http://dx.doi.org/10.21769/BioProtoc.3080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342083PMC
November 2018

Supplementation of Kiwifruit Polyphenol Extract Attenuates High Fat Diet Induced Intestinal Barrier Damage and Inflammation via Reshaping Gut Microbiome.

Front Nutr 2021 30;8:702157. Epub 2021 Aug 30.

School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China.

Impaired intestinal integrity and barrier function is associated with various diseases, including inflammatory bowel disease and metabolic syndrome. In recent years, plant-derived polyphenols have attracted much attention on regulating intestinal barrier function. Kiwifruit was recorded as a traditional Chinese medicine which can treat gastrointestinal diseases, but the mechanism was still unclear. In this study we investigated the effects of kiwifruit polyphenol extracts (KPE) on high fat diet induced intestinal permeability and its possible mechanism. Dietary supplementation of KPE with 50 or 100 mg/kg bw could inhibit the increase of intestinal permeability caused by HFD and promote the expression of tight junction protein (Claudin-1, Occludin and ZO-1). From microbial diversity and RT-PCR, KPE administration reshaping gut microbiome, the relative abundance of and were increased, and the relative abundance of and were decreased. The changes in microbe may influence intestinal inflammatory status. Then the expression of TLRs and cytokines were detected. KPE supplementation showed anti-inflammatory effect, the expression of IL-10 was increased and the expression of TLR-2, TLR-4, TNF-α and IL-1β were decreased. Correlation analysis indicated that the expression of tight junction protein was negative correlation with TLR-2, TLR-4, TNF-α and IL-1β expression, but positively correlated with and IL-10 expression; the expression of and were negative correlation with TLR4, TNF-α, and IL-1β expression. KPE treatment relieve the intestinal damage caused by HFD, which was related to the regulation of , and expression and inhibit intestinal inflammation. KPE could be a functional component for preventing gut damage and its related disease.
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http://dx.doi.org/10.3389/fnut.2021.702157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435571PMC
August 2021

Clinical value of an electromagnetic navigation system for CT-guided percutaneous lung biopsy of peripheral lung lesions.

J Thorac Dis 2021 Aug;13(8):4885-4893

Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: The purpose of this study was to retrospectively evaluate the clinical value of an electromagnetic navigation system for CT-guided percutaneous lung biopsy of peripheral lung lesions.

Methods: This was a retrospective study. Patients with peripheral lung lesions in our institution between January 2019 and December 2020, who underwent lung biopsy assisted by the electromagnetic navigation system were included in Group A, and those who underwent lung biopsy using conventional CT-guided percutaneous lung biopsy were included in Group B. The general features and clinical and technical information of each patient were collected and evaluated in both groups.

Results: A total of 141 patients were included in Group A (78 males and 63 females; median age, 65 years; range, 32-79 years), and 96 patients were included in group B (57 males and 39 females; median age, 65 years; range, 34-80 years). The technical success rate was 100% in both groups. The technical efficacy rate was 92.9% and 90.6% in Groups A and B (P=0.525), respectively. There was no significant difference in surgical time and the number of CT scans between the two groups, and only grade 1-2 complications occurred in the patients.

Conclusions: The electromagnetic navigation system is an effective and safe auxiliary tool for CT-guided percutaneous lung biopsy of peripheral lung lesions.
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http://dx.doi.org/10.21037/jtd-21-395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411150PMC
August 2021

Protects against Diabetes-Associated Endothelial Dysfunction: Comparison between Ethanolic Extract and Total Saponin.

Oxid Med Cell Longev 2021 4;2021:4722797. Epub 2021 Sep 4.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.

Previous studies revealed a cardioprotective potential of to relieve acute myocardial infarction and focal cerebral ischemia-reperfusion. However, whether protects endothelial function in diabetes and the underlying mechanisms remain to be explored. contains several chemical components including saponins, which are commonly believed as the major bioactive ingredients. The present study was aimed to examine and compare the vaso-protective effects of the ethanolic extract of (PNE) and total saponin (PNS). Both aortas and carotid arteries were isolated from male C57BL/6J mice for treatment with risk factors (high glucose or tunicamycin) with and without the presence of PNS and PNE. Diabetic model was established by feeding the mice with a high-fat diet (45% kcal% fat) for 12 weeks, while PNS and PNE were administrated by oral gavage at 20 mg/kg/day for another 4 weeks. exposure to high glucose impaired acetylcholine-induced endothelium-dependent relaxations in mouse aortas, decreased phosphorylation of AMPK and eNOS, and induced endoplasmic reticulum (ER) stress and oxidative stress. These effects were reversed by cotreatment of PNS and PNE with PNS being more potent. Furthermore, the vaso-protective effects were abolished by Compound C (AMPK inhibitor). Chronic treatment with PNS and PNE improved endothelium-dependent relaxations and alleviated ER stress and oxidative stress in aortas from high-fat diet-induced obese mice. PNE was more effective to improve glucose sensitivity and normalize blood pressure in diabetic mice. The present results showed that PNS and PNE reduced ER stress and oxidative stress and, subsequently, improved endothelial function in diabetes through AMPK activation. This study provides new inspiration on the therapeutic potential of extract against vascular diseases associated with metabolic disorders.
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http://dx.doi.org/10.1155/2021/4722797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437594PMC
September 2021

Sequential cleavage and blastocyst embryo transfer and IVF outcomes: a systematic review.

Reprod Biol Endocrinol 2021 Sep 14;19(1):142. Epub 2021 Sep 14.

Reproductive Endocrinology Center, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, 310000, China.

Background: Sequential embryo transfer has been proposed as a way to improve embryo implantation in women for in vitro fertilization (IVF), but the effect on pregnancy outcomes remains ambiguous. This systematic review was conducted to investigate the efficacy of sequential embryo transfer on IVF outcomes.

Methods: A literature search was performed in the PubMed, Web of Science, Cochrane Library, ScienceDirect and Wanfang databases. Data were pooled using a random- or fixed-effects model according to study heterogeneity. The results are expressed as relative risks (RRs) with 95% confidence intervals (CIs). Heterogeneity was evaluated by the I statistic. The study protocol was registered prospectively on INPLASY, ID: INPLASY202180019.

Results: Ten eligible studies with 2658 participants compared sequential embryo transfer and cleavage transfer, while four studies with 513 participants compared sequential embryo transfer and blastocyst transfer. The synthesis results showed that the clinical pregnancy rate was higher in the sequential embryo transfer group than in the cleavage embryo transfer group (RR 1.42, 95% CI 1.26-1.60, P< 0.01) for both women who did experience repeated implantation failure (RIF) (RR 1.58, 95% CI 1.17-2.13, P< 0.01) and did not experience RIF (Non-RIF) (RR 1.44, 95% CI 1.20-1.66, P< 0.01). However, sequential embryo transfer showed no significant benefit over blastocyst embryo transfer.

Conclusion: The current systematic review demonstrates that sequential cleavage and blastocyst embryo transfer improve the clinical pregnancy rate over conventional cleavage embryo transfer. For women with adequate embryos, sequential transfer could be attempted following careful consideration. More high-grade evidence from prospective randomized studies is warranted.
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http://dx.doi.org/10.1186/s12958-021-00824-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439041PMC
September 2021

Dietary exposure assessment of paralytic shellfish toxins through shellfish consumption in Shenzhen population, China.

Environ Sci Pollut Res Int 2021 Sep 13. Epub 2021 Sep 13.

Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, No. 8 Longyuan Road, Nanshan District, Shenzhen, Guangdong, 518055, People's Republic of China.

Paralytic shellfish toxins (PSTs) produced by certain marine dinoflagellates accumulate in filter-feeding marine bivalves. We used LC-MS/MS to detect and quantify 13 PSTs in 188 shellfish samples of 14 species collected from Shenzhen city's Buji seafood wholesale market from March 2019 to February 2020. Twenty-six of 188 shellfish samples (13.8%) were PSTs detectable. Within 14 species, 10 out of 34 noble clam Chlamys nobilis samples contain detectable PSTs with the highest detection rate 29.4%. Seven out of 17 samples from Nan'ao island contained detectable PSTs with the highest detection rate 41.2% among 11 origins. Samples containing PSTs were concentrated in spring and winter, with the highest levels in March>December>January. Among PSTs detected, C1 was dominant. Acute dietary exposure assessment for Shenzhen residents were based on mean adult body weight, 99 percentile daily shellfish consumption of Shenzhen food consumption survey 2008 and maximum PSTs concentration for each shellfish species. The outcome for Chlamys nobilis was 2.4~3.7-fold higher than recommended ARfDs. Mean PSTs concentration, P, and mean shellfish consumption were used to assess chronic dietary exposure. The results were lower than recommended ARfDs. In conclusion, residents in Shenzhen are at risk for acute PSTs poisoning, while relatively safe from chronic PSTs exposure.
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http://dx.doi.org/10.1007/s11356-021-16249-4DOI Listing
September 2021

Early Fever Is Associated With Clinical Outcomes in Patients With Coronavirus Disease.

Front Public Health 2021 26;9:712190. Epub 2021 Aug 26.

Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Fever is one of the typical symptoms of coronavirus disease (COVID-19). We aimed to investigate the association between early fever (EF) and clinical outcomes in COVID-19 patients. A total of 1,014 COVID-19 patients at the Leishenshan Hospital were enrolled and classified into the EF and non-EF groups based on whether they had fever within 5 days of symptom onset. Risk factors for clinical outcomes in patients with different levels of disease severity were analyzed using multivariable analyses. Time from symptom onset to symptom alleviation, CT image improvement, and discharge were longer for patients with moderate and severe disease in the EF group than in the non-EF group. Multivariable analysis showed that sex, EF, eosinophil number, C-reactive protein, and IL-6 levels were positively correlated with the time from symptom onset to hospital discharge in moderate cases. The EF patients showed no significant differences in the development of acute respiratory distress syndrome, compared with the non-EF patients. The Kaplan-Meier curve showed no obvious differences in survival between the EF and non-EF patients. However, EF patients with increased temperature showed markedly lower survival than the non-EF patients with increased temperature. EF had no significant impact on the survival of critically ill patients, while an increase in temperature was identified as an independent risk factor. EF appears to be a predictor of longer recovery time in moderate/severe COVID-19 infections. However, its value in predicting mortality needs to be considered for critically ill patients with EF showing increasing temperature.
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http://dx.doi.org/10.3389/fpubh.2021.712190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427156PMC
September 2021

Is There a Regular Pattern in the Recovery of Parathyroid Function After Thyroid Cancer Surgery?

Cancer Manag Res 2021 3;13:6891-6899. Epub 2021 Sep 3.

Department of Head and Neck Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, People's Republic of China.

Purpose: To investigate whether there is a pattern of recovery of parathyroid function after thyroid cancer surgery.

Patients And Methods: The study included 183 patients with papillary thyroid cancer (PTC) who underwent "total thyroidectomy (TT)" plus "unilateral central lymph node dissection (UCLND)" or "bilateral central lymph node dissection (BCLND)". The intact parathyroid hormone (iPTH) and serum calcium (sCa) were analyzed several times within 1 month after surgery to explore the recovery pattern of parathyroid gland function. Then, these 183 cases were divided into group A (97 cases) with UCLND and group B (86 cases) with BCLND to analyze whether the impairment and recovery of parathyroid function were different between the two subgroups.

Results: Postoperative hypoparathyroidism was seen in 115 out of 183 cases. iPTH values decreased significantly on postoperative day (POD) 1 compared with preoperative values, dropped to the lowest point on POD 3, showed an increasing trend on POD 5 and 14, and increased to 85.0% of preoperative values at POD30, whereas changes in sCa differ from changes in iPTH, which showed the lowest sCa value on POD1, and rebounded on the POD3 with the intervention of calcium supplementation, and continued to rise on the POD5 and POD14, and the sCa value reached 96.6% of the preoperative level at POD30. Subgroup analysis showed that temporary hypoparathyroidism was more pronounced in group B than in group A. SCa and iPTH levels in both subgroups showed the same trend of first decrease and then increase.

Conclusion: The recovery of hypocalcemia and hypo-iPTHemia in the first month after thyroid cancer surgery shows a trend of decreasing and then increasing, and knowing the recovery of parathyroid function at different time points is of great value to surgeons and patients alike.
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http://dx.doi.org/10.2147/CMAR.S326705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423411PMC
September 2021

The Role of the VEGF Family in Coronary Heart Disease.

Front Cardiovasc Med 2021 24;8:738325. Epub 2021 Aug 24.

Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.
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http://dx.doi.org/10.3389/fcvm.2021.738325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421775PMC
August 2021

PDK4 decrease neuronal apoptosis via inhibiting ROS-ASK1/p38 pathway in early brain injury after subarachnoid hemorrhage.

Antioxid Redox Signal 2021 Sep 9. Epub 2021 Sep 9.

Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, 66506, #321, Zhongshan Road, Nanjing 210008, China, Nanjing, China, 210008;

Aims: Metabolic disorders may play key roles in oxidative stress and neuronal apoptosis in response to early brain injury (EBI) after subarachnoid hemorrhage (SAH). Pyruvate dehydrogenase (PDH) is related to oxidative stress in EBI, and its activity obviously decreases after SAH. We discovered that only pyruvate dehydrogenase kinase 4 (PDK4) expression was obviously increased among the four PDK isozymes after SAH in preliminary experiments. Therefore, we attempted to investigate the effects and corresponding mechanisms of PDK4 on oxidative stress after SAH.

Results: First, we confirmed that PDK4 overexpression promoted PDH phosphorylation, inhibited PDH activity and changed cell metabolism after SAH. An siRNA targeting PDK4, a lentiviral PDK4 overexpression vector and dichloroacetic acid (DCA) were used to regulate the expression and activity of PDK4. The siRNA decreased PDH phosphorylation, promoted reactive oxygen species (ROS) production, activated the apoptosis signal-regulating kinase 1 (ASK1)/p38 pathway and induced neuronal apoptosis. The lentivirus further attenuated PDH activity, oxidative stress and neuronal apoptosis. DCA inhibited the activity of PDK4 but increased the expression of PDK4 due to a feedback mechanism. Inactivated PDK4 did not effectively suppress PDH activity, which increased ROS production, activated the ASK1/p38 pathway and led to neuronal apoptosis.

Innovation: This study provides new insights into the potential antioxidant and antiapoptotic effects of the PDK4-PDH axis on EBI after SAH.

Conclusions: The early overexpression of PDK4 after SAH may attenuate neuronal apoptosis by reducing oxidative stress via the ROS/ASK1/p38 pathway. PDK4 may be a new potential therapeutic target to ameliorate EBI after SAH.
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http://dx.doi.org/10.1089/ars.2021.0083DOI Listing
September 2021

Relation between elevated first SBP from baseline (delta SBP) and postoperative outcome.

J Hypertens 2021 Oct;39(10):1982-1990

Department of Laboratory, Peking University First Hospital, Beijing, China.

Background: Hypertension is associated with increased postoperative risk. However, no consensus was accepted whether elevated blood pressure in the operating room with normal blood pressure at rest related to additional cardiovascular risk.

Methods: This was a single-center retrospective cohort study based on patients who underwent elective noncardiac surgery from 1 January 2012, to 31 December 2018. We evaluated the relationship between the delta SBP (the difference between first operating room blood pressure and baseline blood pressure) and the development of postoperative major adverse cardiac events (MACEs) in patients with normal baseline blood pressure. Multivariate logistic regression before and after propensity score weighting was performed to adjust for perioperative variables, and the minimum P value approach was used to identify the possible threshold of delta SBP that independently indicated the risk of MACE.

Results: Of the 55 563 surgeries, in 4.1%, postoperative MACE occurred. The threshold for the delta SBP was 49 mmHg. The adjusted odds ratio for MACE before and after propensity score weighting for the delta SBP threshold was 1.35 (95% CI, 1.11--1.59); P less than 0.001 and 1.28 (1.03-1.60); P = 0.028, respectively.

Conclusion: Delta SBP contributed to the elevated risk over and beyond the SBP at rest in patients who underwent elective noncardiac surgery. A rise of SBP of more than 49 mmHg from baseline in the operating room was significantly associated with an increased risk of postoperative MACE.
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http://dx.doi.org/10.1097/HJH.0000000000002872DOI Listing
October 2021

Ascorbic Acid-Induced Photosynthetic Adaptability of Processing Tomatoes to Salt Stress Probed by Fast OJIP Fluorescence Rise.

Front Plant Sci 2021 16;12:594400. Epub 2021 Aug 16.

Department of Horticulture, Agricultural College, Shihezi University, Shihezi, China.

In this study, the protective role of exogenous ascorbic acid (AsA) on salt-induced inhibition of photosynthesis in the seedlings of processing tomatoes under salt stress has been investigated. Plants under salt stress (NaCl, 100 mmol/L) were foliar-sprayed with AsA (0.5 mmol/L), lycorine (LYC, 0.25 mmol/L, an inhibitor of key AsA synthesis enzyme l-galactono-γ-lactone dehydrogenase activity), or AsA plus LYC. The effects of AsA on fast OJIP fluorescence rise curve and JIP parameters were then examined. Our results demonstrated that applying exogenous AsA significantly changed the composition of O-J-I-P fluorescence transients in plants subjected to salt stress both with and without LYC. An increase in basal fluorescence ( ) and a decrease in maximum fluorescence ( ) were observed. Lower K- and L-bands and higher I-band were detected on the OJIP transient curves compared, respectively, with salt-stressed plants with and without LYC. AsA application also significantly increased the values of normalized total complementary area (S), relative variable fluorescence intensity at the I-step (V), absorbed light energy (ABS/CS), excitation energy (TR/CS), and reduction energy entering the electron transfer chain beyond Q (ET/CS) per reaction centre (RC) and electron transport flux per active RC (ET/RC), while decreasing some others like the approximated initial slope of the fluorescence transient (M), relative variable fluorescence intensity at the K-step (V), average absorption (ABS/RC), trapping (TR/RC), heat dissipation (DI/RC) per active RC, and heat dissipation per active RC (DI/CS) in the presence or absence of LYC. These results suggested that exogenous AsA counteracted salt-induced photoinhibition mainly by modulating the endogenous AsA level and redox state in the chloroplast to promote chlorophyll synthesis and alleviate the damage of oxidative stress to photosynthetic apparatus. AsA can also raise the efficiency of light utilization as well as excitation energy dissipation within the photosystem II (PSII) antennae, thus increasing the stability of PSII and promoting the movement of electrons among PS1 and PSII in tomato seedling leaves subjected to salt stress.
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http://dx.doi.org/10.3389/fpls.2021.594400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415309PMC
August 2021

Use of bioinformatic database analysis and specimen verification to identify novel biomarkers predicting gastric cancer metastasis.

J Cancer 2021 13;12(19):5967-5976. Epub 2021 Aug 13.

Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yangzhou University, Jiangsu, China.

Gastric cancer (GC) is a common gastrointestinal tumor, and its metastasis has led to a significant increase in the death rate. The mechanisms of GC metastasis remain unclear. The differentially expressed genes (DmRs) and lncRNAs (DlncRs) of GC were selected from The Cancer Genome Atlas (TCGA) database. We applied the weighted gene co-expression network analysis (WGCNA) to construct co-expression modules related with GC metastasis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) method analyzed the functional regions and signal pathways of genes in vital modules. DmRs-DlncRs co-expression network were drawn for finding out hub nodes. Survival analyses of significant biomarkers were analyzed by Kaplan-Meier (KM) method. Finally, the expressions of selected biomarkers were validated in cell lines and caner tissues by quantitative real-time PCR (qRT-PCR), in GC tissue microarray by Fluorescence hybridization (FISH). 4776 DmRs and 213 DlncRs were involved the construction of WGCNA network, and MEyellow module was identified to have more significant correlation with GC metastasis. DmRs and DlncRs of MEyellow module were proved to be involved in the processes of cancer pathogenesis by GO and KEGG pathway analysis. Through the DmRs-DlncRs co-expression network, 7 DmRs and 1 DlncRs were considered as hub nodes. Besides, the high expression of TIMD4, CETP, KRT27, PTGDS, FAM30A was worse than low expression in GC patients survival, respectively; However, LRRC26 was opposite trend. FAM30A and TIMD4 were all significant biomarkers of GC survival and hub genes. Simultaneously, TIMD4, CETP, KRT27, PTGDS, FAM30A were increased in GC cell lines and tissues compared with GES-1 and normal tissues, respectively; the expression of LRRC26 was reduced in GC cell lines and tissues. This study identified 6 genes as new biomarkers affecting the metastasis of GC. Especially, FAM30A and TIMD4 might be an effective marker for predicting the prognosis and a potential-therapeutic target in GC.
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http://dx.doi.org/10.7150/jca.58768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408128PMC
August 2021

Effect of Vitamin D Deficiency and Supplementation in Lactation and Early Life on Allergic Airway Inflammation and the Expression of Autophagy-Related Genes in an Ovalbumin Mouse Model.

J Inflamm Res 2021 24;14:4125-4141. Epub 2021 Aug 24.

Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200081, People's Republic of China.

Background And Objective: Vitamin D is involved in various physiological and pathological processes, including inflammation and autophagy. We aimed to investigate the effects of dietary vitamin D deficiency or supplementation initiated in lactation and early life on inflammation and autophagy in an ovalbumin (OVA) mouse model.

Methods: Female BALB/c were fed with vitamin D-deficient, sufficient or supplemented diets throughout lactation and their offspring followed the same diet after weaning. Offspring were then sensitized and challenged with OVA, airway resistance (R) was measured, and their serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected. Alveolar macrophages (AMs) were isolated from lung tissue and cultured with different concentrations of 1,25(OH)D. The expressions of autophagy-related (ATG) proteins including light-chain 3 (LC3), Beclin-1, and ATG5, and NF-κB p65 in lung tissue and AMs were measured.

Results: OVA sensitization and challenge induced dramatic allergic airway inflammation and higher R in the vitamin D-deficient group compared with vitamin D-sufficient or the supplemented group. The expression of ATGs including LC3, Beclin-1, and ATG5, and NF-κB p65 in lung tissue in the vitamin D-deficient OVA-mediated group was increased compared with vitamin D-supplemented OVA-mediated group. There was correlation between the expression of LC3 mRNA and inflammatory cell numbers and cytokines in BALF. In vitro, 1,25(OH)D also regulated the expression of LC3, Beclin-1, ATG5, and NF-κB p65 mRNA in AMs in a time- and dose-dependent manner.

Conclusion: Deficiency of vitamin D in early life may aggravate allergic airway inflammation, and maintaining sufficient vitamin D during early life is necessary for lung health. Vitamin D may modulate autophagy in lungs of OVA sensitized/challenged mice, thus playing a protective role in OVA-induced allergic airway inflammation.
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http://dx.doi.org/10.2147/JIR.S321642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403027PMC
August 2021

Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma.

Cancer Biomark 2021 Aug 20. Epub 2021 Aug 20.

Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Background And Objective: Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients.

Methods: One hundred and twenty-eight serum and tissue samples of GAC 20 serum and tissue samples of gastritis patients and 77 serum, 5 tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson's Chi-square test.

Results: Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r= 0.2801, P= 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r= 0.3251, P= 0.002) while not in stromal cells (r= 0.07676, P= 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with Infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P= 0.0020) or with Infiltration depth T1/T2 (P= 0.0169) or with no lymph node metastasis (P= 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P= 0.0150) or with no lymph node metastasis (P= 0.182).

Conclusions: Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients.
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http://dx.doi.org/10.3233/CBM-210178DOI Listing
August 2021

Curcumin in Combination With Omacetaxine Suppress Lymphoma Cell Growth, Migration, Invasion, and Angiogenesis Inhibition of VEGF/Akt Signaling Pathway.

Front Oncol 2021 11;11:656045. Epub 2021 Aug 11.

Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Background: Both omacetaxine (HHT) and curcumin were shown to exhibit anti-proliferative effect on lymphoma cells. However, the role of combination of HHT with curcumin (HHT/curcumin combination) on lymphoma cells remains unclear. Thus, this study aimed to investigate the effect of HHT/curcumin combination on the proliferation, migration, and angiogenesis of lymphoma cells.

Methods: Cell counting kit-8 (CCK-8), Ki67 immunofluorescence and transwell assays were used to assess the viability, proliferation and migration of U937 and Raji cells respectively. In addition, tube formation assay was used to determine the effects of HHT/curcumin combination on angiogenesis in human umbilical vein endothelial cells (HUVECs).

Results: In this study, we found that HHT/curcumin combination significantly inhibited the proliferation, migration and invasion in U937 and Raji cells (all P < 0.01). In addition, combination treatment markedly inhibited the secreted levels of vascular endothelial growth factor (VEGF)-(A-D) (all P < 0.01) in Raji cells. Moreover, combination treatment exhibited anti-tumor effects in Raji cells, as shown by the decreased signals of phosphorylated VEGF receptor 2 (p-VEGFR2) and phosphorylated protein kinase B (p-Akt) (all P < 0.01). Meanwhile, combination treatment inhibited VEGFA levels (P < 0.01) in exosomes derived from Raji cells. Application of exosomes with downregulated VEGF to HUVECs notably inhibited proliferation, migration and tube formation of HUVECs, evidenced by the decreased signals of p-Akt, angiogenin-1, matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) (all P < 0.01).

Conclusion: Our findings indicated that combination of HHT and curcumin could inhibit lymphoma cell growth and angiogenesis inhibition of VEGF/Akt signaling pathway. These results suggested that HHT combined with curcumin might be regarded as a promising therapeutic approach for the treatment of lymphoma.
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http://dx.doi.org/10.3389/fonc.2021.656045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386016PMC
August 2021

Pancreatic Safety of Once-Weekly Dulaglutide in Chinese Patients with Type 2 Diabetes Mellitus: Subgroup Analysis by Potential Influencing Factors.

Diabetes Ther 2021 Aug 28. Epub 2021 Aug 28.

Endocrinology Department of the First Affiliated Hospital (Xijing Hospital) of Air Force Medical University, 127 Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi Province, China.

Introduction: In the randomized, open-label, parallel-arm, active-controlled phase III AWARD-CHN2 trial, once-weekly dulaglutide plus concomitant oral antihyperglycemic medications (OAMs) improved HbA1c over 26 weeks compared with once-daily insulin glargine in patients with type 2 diabetes mellitus (T2DM). This post-hoc subgroup analysis of AWARD-CHN2 investigated the pancreatic safety of dulaglutide in Chinese patients with T2DM, stratified by potential influencing factors.

Methods: Changes in pancreatic enzyme (pancreatic amylase, total amylase, and lipase) levels over 26 weeks were assessed and stratified by patient age (< 60, ≥ 60 years), sex (female, male), duration of diabetes (< 10, ≥ 10 years), baseline weight (< 70, ≥ 70 kg), BMI (< 25, ≥ 25 kg/m), HbA1c (< 8.5, ≥ 8.5%), triglycerides (< 2.3, ≥ 2.3 mmol/L), and concomitant OAMs (metformin, sulfonylurea, metformin plus sulfonylurea).

Results: A total of 203 Chinese patients with T2DM were included in this post-hoc analysis. Pancreatic enzyme levels increased within the normal range from baseline to Week 26, and no pancreatitis events were confirmed by independent adjudication. Least-squares mean increase in pancreatic amylase (U/L) from baseline to Week 26 was comparable across all subgroups with no statistically (all P-values > 0.05) or clinically significant between-group differences for age (< 60 years: 5.34; ≥ 60 years: 6.71), sex (female: 5.85; male: 5.66), duration of diabetes (< 10 years: 6.15; ≥ 10 years: 4.85), weight (< 70 kg: 6.19; ≥ 70 kg: 5.39), BMI (< 25 kg/m: 5.92; ≥ 25 kg/m: 5.61), HbA1c (< 8.5%: 6.82; ≥ 8.5%: 4.08), triglycerides (< 2.3 mmol/L: 4.94; ≥ 2.3 mmol/L: 8.04), and concomitant OAMs (metformin: 5.68; sulfonylurea: 5.44; metformin plus sulfonylurea: 5.87). Similar results were observed for total amylase and lipase.

Conclusion: In Chinese patients with T2DM receiving dulaglutide 1.5 mg in AWARD-CHN2, elevations of pancreatic enzymes over 26 weeks were within the normal range and were neither associated with pancreatitis nor baseline factors, which suggests the clinical use of dulaglutide in Chinese patients with T2DM is not associated with pancreatic safety issues.

Clinical Trial Registration: NCT01648582.
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http://dx.doi.org/10.1007/s13300-021-01139-2DOI Listing
August 2021

In(III) Metal-Organic Framework Incorporated with Enzyme-Mimicking Nickel Bis(dithiolene) Ligand for Highly Selective CO Electroreduction.

J Am Chem Soc 2021 Sep 27;143(35):14071-14076. Epub 2021 Aug 27.

State Key Laboratory of Coordination Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210023, P. R. China.

Inspired by the exciting physical/chemical properties in metal-organic frameworks (MOFs) of the redox-active tetrathiafulvalene (TTF) ligands, nickel bis(dithiolene-dibenzoic acid), [Ni(CS(CHCOOH))], has been designed and developed as an inorganic analogue of the corresponding TTF-type donors (such as tetrathiafulvalene-tetrabenzoate, TTFTB), where a metal site (Ni) replaces the central C═C bond. In this work, [Ni(CS(CHCOOH))] and In have been successfully assembled into a three-dimensional MOF, (MeNH){In-[Ni(CS(CHCOO))]}·3DMF·1.5HO (, DMF = -dimethylformamide), with satisfying chemical and thermal stabilities. With the combination of reversible redox activity and unsaturated metal sites originated from [Ni(CS(CHCOOH))], showed a significantly enhanced performance in electrocatalytic CO reduction compared with the isomorphic MOF, (MeNH)[In-(TTFTB)]·0.7CHOH·DMF (, with TTFTB ligand). More importantly, by mimicking the active [NiS] sites of formate dehydrogenase and CO-dehydrogenase, a prominently higher conversion rate and Faradaic efficiency (FE), with FE increasing from 54.7% to 89.6% (at -1.3 V vs RHE, = 36.0 mA cm), were achieved in . Mechanistic investigations further confirm that [NiS] can serve as a CO binding site and efficient catalytic center. This unprecedented effect of redox-active nickel dithiolene-based MOF catalysts on the performance of electroreduction of CO provides an important strategy for designing stable and efficient crystalline enzyme-mimicking catalysts for the conversion of CO into high-value chemical stocks.
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http://dx.doi.org/10.1021/jacs.1c06797DOI Listing
September 2021

Research Status and Prospect of Additive Manufactured Nickel-Titanium Shape Memory Alloys.

Materials (Basel) 2021 Aug 11;14(16). Epub 2021 Aug 11.

State Key Laboratory of Material Processing and Die & Mold Technology, School of Materials Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074, China.

Nickel-titanium alloys have been widely used in biomedical, aerospace and other fields due to their shape memory effect, superelastic effect, as well as biocompatible and elasto-thermal properties. Additive manufacturing (AM) technology can form complex and fine structures, which greatly expands the application range of Ni-Ti alloy. In this study, the development trend of additive manufactured Ni-Ti alloy was analyzed. Subsequently, the most widely used selective laser melting (SLM) process for forming Ni-Ti alloy was summarized. Especially, the relationship between Ni-Ti alloy materials, SLM processing parameters, microstructure and properties of Ni-Ti alloy formed by SLM was revealed. The research status of Ni-Ti alloy formed by wire arc additive manufacturing (WAAM), electron beam melting (EBM), directional energy dedication (DED), selective laser sintering (SLS) and other AM processes was briefly described, and its mechanical properties were emphatically expounded. Finally, several suggestions concerning Ni-Ti alloy material preparation, structure design, forming technology and forming equipment in the future were put forward in order to accelerate the engineering application process of additive manufactured Ni-Ti alloy. This study provides a useful reference for scientific research and engineering application of additive manufactured Ni-Ti alloys.
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http://dx.doi.org/10.3390/ma14164496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401032PMC
August 2021

Enhanced Expression of Thaumatin-like Protein Gene () Endows Resistance to in .

Life (Basel) 2021 Aug 23;11(8). Epub 2021 Aug 23.

Institute of Applied Mycology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

(shiitake mushrooms) is heavily affected by the infection of , causing yield loss and decreases quality in shiitake mushrooms. The selection and breeding of fungal-resistant species are an important approach to protecting from infection. Herein, a highly resistant strain (Y3334) and a susceptible strain (Y55) were obtained by using a resistance evaluation test. Transcriptome analyses and qRT-PCR detection showed that the expression level of () was strongly induced in response to infection in the resistant Y3334. Then, silenced and -overexpression transformants were obtained. Overexpression of resulted in resistance to . Compared with the parent strain Y3334, silenced transformants had reduced resistance relative to Additionally, the TLP1 protein (Y3334) exhibited significant antifungal activity against . These findings suggest that overexpression of is a major mechanism for the resistance of to The molecular basis provides a theoretical basis for the breeding of resistant strains and can eventually contribute to the mushroom cultivation industry and human health.
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http://dx.doi.org/10.3390/life11080863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398078PMC
August 2021

Roles and Therapeutic Implications of Endoplasmic Reticulum Stress and Oxidative Stress in Cardiovascular Diseases.

Antioxidants (Basel) 2021 Jul 22;10(8). Epub 2021 Jul 22.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.

In different pathological states that cause endoplasmic reticulum (ER) calcium depletion, altered glycosylation, nutrient deprivation, oxidative stress, DNA damage or energy perturbation/fluctuations, the protein folding process is disrupted and the ER becomes stressed. Studies in the past decade have demonstrated that ER stress is closely associated with pathogenesis of obesity, insulin resistance and type 2 diabetes. Excess nutrients and inflammatory cytokines associated with metabolic diseases can trigger or worsen ER stress. ER stress plays a critical role in the induction of endothelial dysfunction and atherosclerosis. Signaling pathways including AMP-activated protein kinase and peroxisome proliferator-activated receptor have been identified to regulate ER stress, whilst ER stress contributes to the imbalanced production between nitric oxide (NO) and reactive oxygen species (ROS) causing oxidative stress. Several drugs or herbs have been proved to protect against cardiovascular diseases (CVD) through inhibition of ER stress and oxidative stress. The present article reviews the involvement of ER stress and oxidative stress in cardiovascular dysfunction and the potential therapeutic implications.
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http://dx.doi.org/10.3390/antiox10081167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388996PMC
July 2021

Exosomes derived from induced pluripotent stem cells suppresses M2-type macrophages during pulmonary fibrosis via miR-302a-3p/TET1 axis.

Int Immunopharmacol 2021 Oct 17;99:108075. Epub 2021 Aug 17.

Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People's Republic of China. Electronic address:

Idiopathic pulmonary fibrosis (PF) is a type of chronic lung disease. Here, we investigated the effect of induced pluripotent stem cell (iPSC)-derived exosomes (iPSC-exosomes) on M2-type macrophages which play a critical role in pulmonary fibrosis. Exosomes were purified from the conditioned medium of iPSCs. Mice models of pulmonary fibrosis were established by intratracheal instillation with 5 mg/kg bleomycin. Thereafter, the histopathological changes and collagen deposition were detected by HE and masson staining. Meanwhile the level of M2-type macrophages was elevated by immunofluorescence staining with F4/80 and Arg-1. Luciferase reporter assay was conducted to verify the binding of miR-302a-3p to ten-eleven translocation 1 (TET1). Our results showed that, after treatment with iPSC-exosomes, the pulmonary fibrosis induced by bleomycin was relieved, with less collagen deposition. In addition, the increased M2-type macrophages in PF mice were reduced upon treatment with iPSC-exosomes. Moreover, we found that the iPSC-exosomes showed higher level of miR-302a-3p. Interestingly, the level of miR-302a-3p in the lungs of PF mice was increased upon treatment with iPSC-exosomes. Furthermore, we verified that TET1 was a direct target of miR-302a-3p. Up-regulation of miR-302a-3p or TET1 silencing repressed M2-type macrophages. Down-regulation of miR-302a-3p abolished the beneficial effects of iPSC-exosomes on pulmonary fibrosis. Collectively, our study revealed that iPSC-exosomes delivered miR-302a-3p to suppress the M2-type macrophages via targeting TET1, thus mitigating pulmonary fibrosis. This study indicates that iPSC-exosomes may become a potential therapeutic agent for pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.intimp.2021.108075DOI Listing
October 2021

Structural insights into ligand recognition and activation of the melanocortin-4 receptor.

Cell Res 2021 Aug 25. Epub 2021 Aug 25.

Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G protein stimulated by the endogenous peptide ligand α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.
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http://dx.doi.org/10.1038/s41422-021-00552-3DOI Listing
August 2021

The integration of bevacizumab improves tumor response and survival in patients with refractory cervical cancer treated with radical chemoradiotherapy.

Ann Transl Med 2021 Jul;9(14):1184

Department of Radiation Oncology, First Affiliated Hospital of Air Force Medical University, Xi'an, China.

Background: Management of refractory cervical cancers (CC) is a debated question and rises dilemma in clinical practice. This study aimed to assess the safety and effectiveness of bevacizumab combined with concurrent chemoradiotherapy in the treatment of refractory CC.

Methods: A total of 129 patients with refractory CC who received radical concurrent chemoradiotherapy (CCRT) were included in this study. Among the patients, 64 received combination treatment with bevacizumab, while the 65 remaining patients did not receive bevacizumab. Treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumorsversion1.1. The Cox proportional-hazards model was applied to determine prognostic factors associated with overall survival and the tumor response during treatment was analyzed for patients treated with bevacizumab.

Results: Bevacizumab was an independent prognostic factor (P=0.017). Therefore, we only analyzed 64 patients who received combination treatment with bevacizumab. In the 64 patients treated with bevacizumab, the 3-year OS, locoregional relapse-free survival, and distant metastasis-free survival rates were 87.2%, 98.1%, and 81%, respectively. Complete clinical response rates were 37.8% (17/45) for patients with neoadjuvant chemotherapy and chemoradiotherapy after neoadjuvant chemotherapy (NACT), complete clinical response rates were 62.5% (40/64), 73.3% (33/45) and 52.6% (10/19) before brachytherapy (BT), respectively for the entire cohort, patients with NACT and chemoradiotherapy and patients with chemoradiotherapy only. The 2-year OS rate was higher for patients who achieved a complete clinical response BT than for patients who did not, 94.6% 73.2%, P=0.03. Among the 64 patients who received it, 28 (43.8%) experienced hematological toxicities of grade 3 or 4, and 3 (4.7%) experienced grade 3 gastrointestinal toxicities.

Conclusions: Bevacizumab combined with radical chemoradiotherapy is a safe and tolerable treatment option for refractory CC, with quicker tumor regression and high OS, locoregional relapse-free survival, and distant metastasis-free survival rates.
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http://dx.doi.org/10.21037/atm-21-3521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350679PMC
July 2021

Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.

Ann Transl Med 2021 Jul;9(14):1150

Pulmonary and Critical Care Medicine Department, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor () gene respond dramatically to tyrosine kinase inhibitors (TKIs). However, these patients inevitably develop acquired resistance to -TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism.

Methods: We used a 639 cancer-relevant gene panel to detect genetic differences in tissues before and after -TKIs resistance caused by SCLC transformation. experiments were conducted to study the role of ETS variant transcription factor 1 () on SCLC transformation and -TKIs resistance.

Results: We present two -mutant lung adenocarcinoma (LUAD) patients. One patient, with exon 19 deletion (Ex19del), accepted first-line gefitinib treatment and then received osimertinib treatment due to acquisition of an -T790M mutation. A novel mutation (p.P159S) was detected in the SCLC tissue after osimertinib resistance when not coexisting with T790M. The other patient harbored an exon 21 mutation (p.L858R), and had a long-lasting response to first-line gefitinib, and then transformed to SCLC after TKI resistance. A previously unreported mutation (p.E462Q) was detected in the SCLC tissue. , p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of achaete-scute homolog 1 (ASCL1) and promoting the proliferation of H69 cells. p.E462Q and p.P159S mutations were also resistant to gefitinib and osimertinib after introduction into H358 cells.

Conclusions: Novel p.E462Q and p.P159S mutations were found in the SCLC tissues of TKIs-resistant LUAD patients, providing a new understanding of involvement in acquired resistance to -TKIs via SCLC transformation.
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http://dx.doi.org/10.21037/atm-21-2625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350694PMC
July 2021

The Contribution of White Matter Diffusion and Cortical Perfusion Pathology to Vascular Cognitive Impairment: A Multimode Imaging-Based Machine Learning Study.

Front Aging Neurosci 2021 6;13:687001. Epub 2021 Aug 6.

Department of Radiology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Widespread impairments in white matter and cerebrovascular integrity have been consistently implicated in the pathophysiology of patients with small vessel disease (SVD). However, the neural circuit mechanisms that underlie the developing progress of clinical cognitive symptoms remain largely elusive. Here, we conducted cross-modal MRI scanning including diffusion tensor imaging and arterial spin labeling in a cohort of 113 patients with SVD, which included 74 patients with vascular mild cognitive impairment (vMCI) and 39 patients without vMCI symptoms, and hence developed multimode imaging-based machine learning models to identify markers that discriminated SVD subtypes. Diffusion and perfusion features, respectively, extracted from individual white matter and gray matter regions were used to train three sets of classifiers in a nested 10-fold fashion: diffusion-based, perfusion-based, and combined diffusion-perfusion-based classifiers. We found that the diffusion-perfusion combined classifier achieved the highest accuracy of 72.57% with leave-one-out cross-validation, with the diffusion features largely spanning the capsular lateral pathway of the cholinergic tracts, and the perfusion features mainly distributed in the frontal-subcortical-limbic areas. Furthermore, diffusion-based features within vMCI group were associated with performance on executive function tests. We demonstrated the superior accuracy of using diffusion-perfusion combined multimode imaging features for classifying vMCI subtype out of a cohort of patients with SVD. Disruption of white matter integrity might play a critical role in the progression of cognitive impairment in patients with SVD, while malregulation of coritcal perfusion needs further study.
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http://dx.doi.org/10.3389/fnagi.2021.687001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379092PMC
August 2021

Optimization, extraction, and purification of three bioactive compounds from Entada phaseoloides by high-speed countercurrent chromatography.

Biomed Chromatogr 2021 Aug 23:e5232. Epub 2021 Aug 23.

College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, P. R. China.

The objective of this paper was to develop a preparative method for the separation and purification of phaseoloidin, entadamide A, and entadamide A-β-D-glucopyranoside from the crude extract of Entada phaseoloides by high-speed countercurrent chromatography (HSCCC) for the first time. Optimized by orthogonal experiments, the extraction conditions were extraction temperature of 65°C, solid-to-liquid ratio of 1:15 (g/mL), ethanol concentration of 40%, and extraction time of 2.5 h. Using n-butanol-acetic acid-water (4:1:5, v/v/v) as the two-phase solvent system, 38.79 mg phaseoloidin (the purity was 99.3% with a recovery of 98.1%), 34.85 mg entadamide A (the purity was 96.4% with a recovery of 98.5%), and 33.97 mg entadamide A-β-D-glucopyranoside (the purity was 98.6% with a recovery of 97.7%) were obtained from 500 mg crude extract by HSCCC in head-to-tail elution mode. The retention ratio of stationary phase was 51.0%. According to the antioxidant activity assays, phaseoloidin, entadamide A, and entadamide A-β-D-glucopyranoside had certain scavenging abilities on 1,1-diphenyl-2-picrylhydrazyl free radicals and hydroxyl free radicals.
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http://dx.doi.org/10.1002/bmc.5232DOI Listing
August 2021

BCL9 regulates CD226 and CD96 checkpoints in CD8 T cells to improve PD-1 response in cancer.

Signal Transduct Target Ther 2021 Aug 20;6(1):313. Epub 2021 Aug 20.

Department of Pharmacology, School of Basic Medical Sciences and School of Pharmacy, Fudan University, Shanghai, China.

To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8 T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9's role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8 T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8 T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints.
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http://dx.doi.org/10.1038/s41392-021-00730-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379253PMC
August 2021

Challenges of THP-AD centrate treatment using partial nitritation-anammox (PN/A) - inhibition, biomass washout, low alkalinity, recalcitrant and more.

Water Res 2021 Sep 13;203:117555. Epub 2021 Aug 13.

Advanced Environmental Biotechnology Centre, Nanyang Environment and Water Research Institute, Nanyang Technological University, 1 Cleantech Loop, Singapore 637141, Singapore; School of Civil and Environmental Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore. Electronic address:

The centrate produced from a thermal hydrolysis pretreatment coupled anaerobic digestion (THP-AD) system is generally characterized by high concentrations of ammonium and recalcitrant organics. In this study, a cost-effective partial nitritation-anammox (PN/A) process was developed to evaluate the potential challenges in THP-AD centrate treatment. The results show ammonium oxidizing bacteria (AOB) and anammox bacteria were seriously inhibited by THP-AD centrate, while long-term acclimation together with aeration optimization can mitigate such inhibition. A nitrogen removal rate (NRR) of 0.55 kg N/m/d was obtained and maintained with 60% THP-AD centrate as feed. However, 100% THP-AD centrate caused sludge wash-out from PN reactor due to excessive polymer and high solids in influent. The alkalinity deficit also reduced the AOB activity. Moreover, anammox activity and overall NRR also declined (to 0.37 kg N/m/d). The organics transformation mainly occurred in PN reactor with very low removal efficiency due to their recalcitrant characteristics. The humic acid-like, fulvic acid-like substances and building blocks were revealed as the major organic compounds in THP-AD centrate (51.5-53.8% TOC), which likely contributed to the recalcitrant. Nitrosomonas and Candidatus Brocadia were the major AOB and anammox bacteria in the PN and anammox reactors respectively. With the increased THP-AD centrate proportion in the feed, the abundance of both population declined. Interestingly, Denitratisoma, being the major denitrifying bacteria in anammox reactor, had relatively stable abundance (7.0-7.9%) when THP-AD centrate was improved from 3 and 100%, suggesting the inhibition on anammox bacteria was not due to the overgrowth of denitrifying microorganism despite the high organics loading rate. Overall, this study provides a guide to develop the energy-saving PN/A process for THP-AD centrate treatment by pointing out potential challenges and mitigating strategies.
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http://dx.doi.org/10.1016/j.watres.2021.117555DOI Listing
September 2021

Knockout of the Cannabinoid Receptor 2 Gene Promotes Inflammation and Hepatic Stellate Cell Activation by Promoting A20/Nuclear Factor-κB (NF-κB) Expression in Mice with Carbon Tetrachloride-Induced Liver Fibrosis.

Med Sci Monit 2021 Aug 20;27:e931236. Epub 2021 Aug 20.

Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China (mainland).

BACKGROUND This study aimed to investigate the effect of deleting the cannabinoid receptor 2 (CB2) gene on the development of hepatic fibrosis induced by carbon tetrachloride (CCl₄) in mice via regulating inflammation. MATERIAL AND METHODS The DNA was extracted from the tails of mice to identify whether the cannabinoid receptor 2 gene was successfully knocked out. A liver fibrosis model was established by an intraperitoneal injection of CCl₄ into mice. Hepatic damage and hepatic fibrosis were evaluated by detecting serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and staining paraffin sections of liver tissue with hematoxylin-eosin (HE). The secretion and distribution of collagen in liver tissue were observed by Masson staining. Western blot analysis was performed to detect the expression of a-smooth muscle actin (alpha-SMA), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor alpha-induced protein 3 (A20), phosphorylated nuclear factor-kB p65 (p-NF-kappaB p65), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) in liver tissue. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of IL-6 and TNF-alpha mRNA in liver tissue. RESULTS Compared with the control mice, the mice with CB2 knockout that were exposed to CCl₄ exhibited increased liver damage, liver fibrosis, and upregulated alpha-SMA, TGF-ß1, A20, and p-NF-kappaB p65 protein levels. IL-6 and TNF-alpha protein levels and mRNA levels were upregulated. CONCLUSIONS The deletion of the CB2 gene promoted the activation of hepatic stellate cells in mice with liver fibrosis and aggravated liver fibrosis by up-regulating the protein expression of A20 and p-NF-kappaB p65 and inducing inflammatory response, potentially providing new insight into the treatment of liver fibrosis.
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http://dx.doi.org/10.12659/MSM.931236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409143PMC
August 2021
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