Publications by authors named "Lin Miao"

312 Publications

Establishment and validation of a computer-assisted colonic polyp localization system based on deep learning.

World J Gastroenterol 2021 Aug;27(31):5232-5246

Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai 200433, China.

Background: Artificial intelligence in colonoscopy is an emerging field, and its application may help colonoscopists improve inspection quality and reduce the rate of missed polyps and adenomas. Several deep learning-based computer-assisted detection (CADe) techniques were established from small single-center datasets, and unrepresentative learning materials might confine their application and generalization in wide practice. Although CADes have been reported to identify polyps in colonoscopic images and videos in real time, their diagnostic performance deserves to be further validated in clinical practice.

Aim: To train and test a CADe based on multicenter high-quality images of polyps and preliminarily validate it in clinical colonoscopies.

Methods: With high-quality screening and labeling from 55 qualified colonoscopists, a dataset consisting of over 71000 images from 20 centers was used to train and test a deep learning-based CADe. In addition, the real-time diagnostic performance of CADe was tested frame by frame in 47 unaltered full-ranged videos that contained 86 histologically confirmed polyps. Finally, we conducted a self-controlled observational study to validate the diagnostic performance of CADe in real-world colonoscopy with the main outcome measure of polyps per colonoscopy in Changhai Hospital.

Results: The CADe was able to identify polyps in the test dataset with 95.0% sensitivity and 99.1% specificity. For colonoscopy videos, all 86 polyps were detected with 92.2% sensitivity and 93.6% specificity in frame-by-frame analysis. In the prospective validation, the sensitivity of CAD in identifying polyps was 98.4% (185/188). Folds, reflections of light and fecal fluid were the main causes of false positives in both the test dataset and clinical colonoscopies. Colonoscopists can detect more polyps (0.90 0.82, < 0.001) and adenomas (0.32 0.30, = 0.045) with the aid of CADe, particularly polyps < 5 mm and flat polyps (0.65 0.57, < 0.001; 0.74 0.67, = 0.001, respectively). However, high efficacy is not realized in colonoscopies with inadequate bowel preparation and withdrawal time ( = 0.32; = 0.16, respectively).

Conclusion: CADe is feasible in the clinical setting and might help endoscopists detect more polyps and adenomas, and further confirmation is warranted.
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http://dx.doi.org/10.3748/wjg.v27.i31.5232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384745PMC
August 2021

Effect of Tea Tree Oil on the Expression of Genes Involved in the Innate Immune System in Goat Rumen Epithelial Cells.

Animals (Basel) 2021 Aug 21;11(8). Epub 2021 Aug 21.

College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.

In subacute rumen acidosis (SARA), the rumen epithelium is frequently attacked by endotoxin (LPS), which is caused by the lysis of dead Gram-negative bacteria. However, the rumen epithelium innate immune system can actively respond to the infection. Previous studies have demonstrated that tea tree oil (TTO) has good bactericidal and anti-inflammatory effects. Therefore, the aim of this study was to investigate the effect of TTO on the expression of genes involved in the inflammatory cytokines in goat rumen epithelial cells (GRECs) triggered by LPS. Our study shows that rumen epithelial cells isolated from goat rumen tissue can be cultured in vitro in 0.25% trypsin for a long time. These cells were identified as epithelial cells by the expression of cytokeratin 18, monocarboxylate transporter 4 (MCT4), Na[+]/H[+] hydrogen exchanger 1 (NHE1), putative anion transporter 1 (PAT1), vH ATPase B subunit (vH ATPase), and anion exchanger 2 (AE2). The mRNA expression of IL-1β, IL-6, TNF-α, TLR-2, NF-κB, CXCL6 and CXCL8 genes was significantly increased when LPS was used compared to untreated controls. In addition, mRNA expression of IL-1β, IL-6, TNF-α, TLR-2, NF-κB, CXCL8, CXCL6 and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) genes was also significantly higher in the LPS group compared to the 0.05% TTO group. However, the expression of IL-1β, IL-6, TNF-α, TLR-2, CXCL6 and IFIT3 genes was significantly lower in the LPS and 0.05% TTO group compared to the 1 μg/mL LPS group. These results suggest that TTO can inhibit LPS-induced inflammatory cytokines expression in GRECs.
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http://dx.doi.org/10.3390/ani11082460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388664PMC
August 2021

Effects of 1259 on Growth Performance, Nutrient Digestibility, Rumen Fermentation, and Blood Biochemical Parameters in Holstein Bull Calves.

Animals (Basel) 2021 Aug 12;11(8). Epub 2021 Aug 12.

College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.

is an ideal microecologics in the feed industry. BM1259 was already isolated from chicken manure and the whole-genome sequencing was also analyzed in our previous study. However, few studies concentrated on dietary supplementation with BM1259 in young ruminants and especially its effect on Holstein bull calves have not been reported. Hence, this experiment was conducted with the aim to evaluate the effects of BM1259 on growth performance, nutrient digestibility, rumen fermentation, and blood biochemical parameters in Holstein bull calves. Twenty-four healthy Holstein bull calves with the initial age of 90 days old and a similar body weight (115 ± 6.5 kg) were selected and randomly allocated into two groups with one Holstein bull calf in each pen (2.5 m × 2.2 m). Holstein bull calves in the control group (COG) were fed a basal total mixed ration (TMR), while experimental treatments (BMG) were fed with the TMR diet supplemented with 12 g/head/day of BM1259 powder (1 × 10 cfu/g) separately. Results showed that (1) the average daily gain and dry matter intake of the BMG were significantly higher than those of the COG ( < 0.01), increased by 12.5% and 8.79%, respectively, during the 4-8 weeks after the addition of 12 g/head/day of BM1259; from 0 to 8 weeks, ADG ( < 0.05) and DMI ( < 0.05) in the BMG were significantly higher than those in the COG, increased by 14.9% and 6.04%, respectively. (2) At the end of the fourth week, the apparent digestibility of crude protein and neutral detergent fiber in the BMG was significantly higher than that in the COG ( < 0.05), increased by 5.97% and 6.70%, respectively; at the end of the eighth week, the apparent digestibility of crude protein and neutral detergent fiber was significantly higher than that of the COG ( < 0.01), increased by 5.88% and 10.26%, respectively. (3) At the end of the eighth week, the rumen fluid pH ( < 0.05), MCP ( < 0.05), and acetate ( < 0.05) in the BMG were significantly higher than those in the COG, increased by 9.03%, 19.68%, and 12.74%, respectively; at the end of the fourth and eighth week, NH-N concentration in the BMG was significantly lower than that in the COG, with a decrease of 21.81% and 16.40%, respectively. (4) At the end of the fourth ( < 0.05) and eighth week ( < 0.05), the glutamate content of the rumen fluid of the Holstein bull calves in the BMG was significantly higher than that in the COG, increased by 13.21% and 14.32%, respectively; at the end of the fourth week, the contents of glutamate in the serum ( < 0.05), urine ( < 0.05), and feces ( < 0.05) of the Holstein bull calves in the BMG were significantly lower than those in the COG, decreased by 25.76%, 33.87%, and 9.23%, respectively; at the end of the eighth week, the contents of glutamate in the serum, urine, and feces of the Holstein bull calves in the BMG were significantly lower than those in the COG ( < 0.01), decreased by 26.69%, 27.94%, and 11.11%, respectively. (5) After adding 12 g/head/day of BM1259, the urine ammonia-nitrogen content of the BMG was extremely significantly lower than that of the COG at the end of the fourth and eighth week ( < 0.01), decreased by 54.60% and 40.31%, respectively. (6) After adding 12 g/head/day of BM1259, there was no significant effect on the level of blood biochemical parameters of the Holstein bull calves. This study demonstrates that BM1259 can be applied as a potential microecologics to improve growth performance, nutrient digestibility, rumen fermentation, and nitrogen utilization in Holstein bull calves.
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http://dx.doi.org/10.3390/ani11082379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388779PMC
August 2021

Sevoflurane-Remifentanil Versus Propofol-Remifentanil Anesthesia During Noncardiac Surgery for Patients with Coronary Artery Disease - A Prospective Study Between 2016 and 2017 at a Single Center.

Med Sci Monit 2021 Aug 21;27:e929835. Epub 2021 Aug 21.

Department of Anesthesiology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China (mainland).

BACKGROUND Volatile anesthesia possesses cardioprotective properties, and it is widely used in patients undergoing coronary artery bypass surgery, but no randomized controlled trials (RCTs) are available on the use of sevoflurane-remifentanil versus propofol-remifentanil anesthesia for patients with coronary artery disease (CAD) during noncardiac surgery. This study was designed to compare the 2 different types of general anesthesia in patients with CAD undergoing noncardiac surgery at a single center. MATERIAL AND METHODS Patients with CAD undergoing noncardiac surgery were enrolled in an RCT conducted between March 2016 and December 2017. The participants were randomized to receive either sevoflurane-remifentanil or propofol-remifentanil anesthesia. The primary endpoint was occurrence of in-hospital cardiovascular events. The secondary endpoints included delirium, postoperative nausea and vomiting (PONV), Intensive Care Unit (ICU) length of stay (LOS), in-hospital morbidity and mortality, and hospital LOS. RESULTS A total of 164 participants completed the study (sevoflurane: 81; propofol: 83). The occurrence of in-hospital cardiovascular events did not differ between the 2 groups (42.6% vs 39.4%, P=0.86). The occurrence of delirium did not differ between the 2 groups after the operation. PONV had a higher frequency after sevoflurane anesthesia at 48 h compared with propofol. In-hospital morbidity and mortality, ICU LOS, and hospital LOS were similar between the 2 groups (all P>0.05). At 30 days after surgery, no between-group differences in cardiac morbidity and mortality were observed. CONCLUSIONS In this study, anesthesia using sevoflurane-remifentanil did not provide additional postoperative cardioprotection in comparison with propofol-remifentanil in patients with CAD undergoing noncardiac surgery.
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http://dx.doi.org/10.12659/MSM.929835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386244PMC
August 2021

miR-378-3p Knockdown Recapitulates Many of the Features of Myelodysplastic Syndromes.

Am J Pathol 2021 Aug 6. Epub 2021 Aug 6.

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

Myelodysplastic syndromes (MDSs) are clonal neoplasms of the hematopoietic stem cell that result in aberrant differentiation of hematopoietic lineages caused by a wide range of underlying genetic, epigenetic, and other causes. Despite the myriad origins, there is a recognizable MDS phenotype that has been associated with miRNA aberrant expression. A model of aberrant myeloid maturation that mimics MDSs that is seen in MDSs has been created using a stable knockdown of miR-378-3p. This model exhibited a transcriptional profile that indicates aberrant maturation and function, immunophenotypic and morphologic dysplasia, and aberrant growth and function that characterizes MDSs. Moreover, aberrant signal transduction in response to stimulation was found that is specific to the stage of myeloid maturation and mimics that seen in samples from patients with MDS using mass cytometry. The aberrant signaling, immunophenotypic changes, cellular growth, and colony formation ability seen in this myeloid model could be reversed with azacytidine, albeit without significant improvement of neutrophil function.
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http://dx.doi.org/10.1016/j.ajpath.2021.07.006DOI Listing
August 2021

Parsonage-Turner syndrome post-infection by SARS-CoV-2: a case report.

Neurologia (Engl Ed) 2021 Sep 22;36(7):568-571. Epub 2021 Jul 22.

Servicio de Medicina Física y Rehabilitación, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.nrleng.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295025PMC
September 2021

An Aspergillus nidulans endo-β-1,3-glucanase exhibited specific catalytic features and was used to prepare 3-O-β-cellobiosyl-d-glucose and 3-O-β-gentiobiosyl-d-glucose with high antioxidant activity from barley β-glucan and laminarin, respectively.

Int J Biol Macromol 2021 Sep 9;186:424-432. Epub 2021 Jul 9.

Jiangsu Key Laboratory for Microbes and Microbial Functional Genomics, Jiangsu Engineering and Technology Research Center for Industrialization of Microbial Resources, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing, Jiangsu 210023, PR China. Electronic address:

An endo-β-1,3(4)-glucanase AnENG16A from Aspergillus nidulans shows distinctive catalytic features for hydrolysis of β-glucans. AnENG16A hydrolyzed Eisenia bicyclis laminarin to mainly generate 3-O-β-gentiobiosyl-d-glucose and hydrolyzed barley β-glucan to mainly produce 3-O-β-cellobiosyl-d-glucose. Using molecular exclusion chromatography, we isolated and purified 3-O-β-cellobiosyl-d-glucose and 3-O-β-gentiobiosyl-d-glucose, respectively, from AnENG16A-hydrolysate of barley β-glucan and E. bicyclis laminarin. Further study reveals that 3-O-β-cellobiosyl-d-glucose had 8.99-fold higher antioxidant activity than barley β-glucan and 3-O-β-gentiobiosyl-d-glucose exhibited 43.0% higher antioxidant activity than E. bicyclis laminarin. Notably, 3-O-β-cellobiosyl-d-glucose and 3-O-β-gentiobiosyl-d-glucose exhibited 148.9% and 116.0% higher antioxidant activity than laminaritriose, respectively, indicating that β-1,4-linkage or -1,6-linkage at non-reducing end of β-glucotrioses had enhancing effect on antioxidant activity compared to β-1,3-linkage. Furthermore, 3-O-β-cellobiosyl-d-glucose showed 237.9% higher antioxidant activity than cellotriose, and laminarin showed 5.06-fold higher antioxidant activity than barley β-glucan, indicating that β-1,4-linkage at reducing end of β-glucans or oligosaccharides resulted in decrease of antioxidant activity compared to β-1,3-linkage.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.07.053DOI Listing
September 2021

Dissecting the single-cell transcriptome network underlying esophagus non-malignant tissues and esophageal squamous cell carcinoma.

EBioMedicine 2021 Jul 27;69:103459. Epub 2021 Jun 27.

Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, China.

Background: Esophageal squamous cell carcinoma (ESCC) is among the most prevalent causes of cancer-related death in adults. Tumor microenvironment (TME) has been associated with therapeutic failure and lethal outcomes for patients. However, published reports on the heterogeneity and TME in ESCC are scanty.

Methods: Five tumor samples and five corresponding non-malignant samples were subjected to scRNA-seq analysis. Bulk RNA sequencing data were retrieved in publicly available databases.

Findings: From the scRNA-seq data, a total of 128,688 cells were enrolled for subsequent analyses. Gene expression and CNV status exhibited high heterogeneity of tumor cells. We further identified a list of tumor-specific genes and four malignant signatures, which are potential new markers for ESCC. Metabolic analysis revealed that energy supply-related pathways are pivotal in cancer metabolic reprogramming. Moreover, significant differences were found in stromal and immune cells between the esophagus normal and tumor tissues, which promoted carcinogenesis at both cellular and molecular levels in ESCC. Immune checkpoints, regarded as potential targets for immunotherapy in ESCC were significantly highly expressed in ESCC, including LAG3 and HAVCR2. Eventually, we constructed a cell-to-cell communication atlas based on cancer cells and immune cells and performed the flow cytometry, qRT-PCR, immunofluorescence, and immunohistochemistry analyses to validate the results.

Interpretation: This study demonstrates a widespread reprogramming across multiple cellular elements within the TME in ESCC, particularly in transcriptional states, cellular functions, and cell-to-cell interactions. The findings offer an insight into the exploration of TME and heterogeneity in the ESCC and provide new therapeutic targets for its clinical management in the future.

Funding: The work was supported by the Shanghai Pujiang Program (2020PJD009) and Research Development Fund of Zhongshan Hospital, Fudan University (2019ZSFZ002 and 2019ZSFZ19).
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http://dx.doi.org/10.1016/j.ebiom.2021.103459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253912PMC
July 2021

Leveraging 16S rRNA Microbiome Sequencing Data to Identify Bacterial Signatures for Irritable Bowel Syndrome.

Front Cell Infect Microbiol 2021 11;11:645951. Epub 2021 Jun 11.

State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain or discomfort. Previous studies have illustrated that the gut microbiota might play a critical role in IBS, but the conclusions of these studies, based on various methods, were almost impossible to compare, and reproducible microorganism signatures were still in question. To cope with this problem, previously published 16S rRNA gene sequencing data from 439 fecal samples, including 253 IBS samples and 186 control samples, were collected and processed with a uniform bioinformatic pipeline. Although we found no significant differences in community structures between IBS and healthy controls at the amplicon sequence variants (ASV) level, machine learning (ML) approaches enabled us to discriminate IBS from healthy controls at genus level. Linear discriminant analysis effect size (LEfSe) analysis was subsequently used to seek out 97 biomarkers across all studies. Then, we quantified the standardized mean difference (SMDs) for all significant genera identified by LEfSe and ML approaches. Pooled results showed that the SMDs of nine genera had statistical significance, in which the abundance of , and in IBS were higher, while the dominant abundance genera of healthy controls were Ruminococcaceae , , , and . In summary, based on six published studies, this study identified nine new microbiome biomarkers of IBS, which might be a basis for understanding the key gut microbes associated with IBS, and could be used as potential targets for microbiome-based diagnostics and therapeutics.
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http://dx.doi.org/10.3389/fcimb.2021.645951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231010PMC
July 2021

The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma.

Cell Oncol (Dordr) 2021 Aug 25;44(4):907-916. Epub 2021 Jun 25.

Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 211166, China.

Purpose: Cholangiocarcinoma (CCA) is the second most malignant tumor of the hepatobiliary system. Due to its cumbersome early diagnosis and rapid progression, chemotherapy has become the main treatment option. Primary drug resistance is a major cause of the poor efficacy of chemotherapeutic drugs. Therefore, it is considered urgent to explore new drugs to overcome primary drug resistance of CCA.

Methods: Western blot and qRT-PCR assays were used to assess the expression of myotrophin (MTPN) and microRNA-885-5p (miR-885-5p) in CCA tissues and cells. The viability of CCA cells treated with arsenic trioxide (ATO), 5-fluorouracil (5-Fu) and cisplatin (CDDP) was analyzed using a CCK-8 assay. A luciferase reporter assay was used to assess the interaction between miR-885-5p and MTPN. Kaplan-Meier analyses were used for survival assessments.

Result: We found that ATO can reduce the resistance of CCA cells to 5-Fu and CDDP and promote the killing effect of 5-Fu and CDDP. Low-dose ATO showed an anti-drug-resistance effect through up-regulation of the expression of miR-885-5p. Combined with sequencing results and database predictions, we found that MTPN may serve as a direct target of miR-885-5p. After MTPN knockdown, the sensitivity of CCA cells to 5-FU and CDDP was increased. Finally, we found that ATO can reverse chemotherapy resistance induced by overexpression of MTPN.

Conclusion: Our data indicate that the ATO/miR-885-5p/MTPN axis may serve as a target for improving the sensitivity of CCA cells to chemotherapy.
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http://dx.doi.org/10.1007/s13402-021-00610-3DOI Listing
August 2021

Phrenic nerve block during nonintubated video-assisted thoracoscopic surgery: a single-centre, double-blind, randomized controlled trial.

Sci Rep 2021 Jun 22;11(1):13056. Epub 2021 Jun 22.

Department of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China.

There has been interest in the use of nonintubated techniques for video-assisted thoracoscopic surgery (VATS) in both awake and sedated patients. The authors' centre developed a nonintubated technique with spontaneous ventilation for use in a patient under general anaesthesia using a phrenic nerve block. This treatment was compared with a case-matched control group. The authors believe that this technique is beneficial for optimizing anaesthesia for patients undergoing VATS. The patients were randomly allocated (1:1) to the phrenic nerve block (PNB) group and the control group. Both groups of patients received a laryngeal mask airway (LMA) that was inserted after anaesthetic induction, which permitted spontaneous ventilation and local anaesthesia in the forms of a paravertebral nerve block, a PNB and a vagal nerve block. However, the patients in the PNB group underwent procedures with 2% lidocaine, whereas saline was used in the control group. The primary outcome included the propofol doses. Secondary outcomes included the number of propofol boluses, systolic blood pressure (SBP), pH values of arterial blood gas and lactate (LAC), length of LMA pulled out, length of hospital stay (length of time from the operation to the time of discharge) and complications after 1 month. Intraoperatively, there were increases in lactate (F = 12.31, P = 0.001) in the PNB group. There was less propofol (49.20 ± 8.73 vs. 57.20 ± 4.12, P = 0.000), fewer propofol boluses (P = 0.002), a lower pH of arterial blood gas (F = 7.98, P = 0.006) and shorter hospital stays (4.10 ± 1.39 vs. 5.40 ± 1.22, P = 0.000) in the PNB group. There were no statistically significant differences in the length of the LMA pulled out, SBP or complications after 1 month between the groups. PNB optimizes the anaesthesia of nonintubated VATS.
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http://dx.doi.org/10.1038/s41598-021-92003-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219794PMC
June 2021

Dietary inflammatory index and cardiorenal function in women with diabetes and prediabetes.

Nutr Metab Cardiovasc Dis 2021 07 24;31(8):2319-2327. Epub 2021 May 24.

Department of Endocrinology, Fujian Provincial Hospital, Fujian Academy of Medical Sciences, Fujian Medical University, Fuzhou 350001, China. Electronic address:

Background And Aims: Previous studies had shed a new light on the importance of multiple inflammatory mechanisms in the pathogenesis of arterial stiffness. The dietary inflammatory index (DII®) is a new tool for estimating the overall inflammatory potential of the diet. The aim of this study is to assess the association of the inflammatory potential of diet with peripheral arterial stiffness and renal function in women with diabetes and prediabetes.

Methods And Results: This is an observational cross-sectional study. A total of 2644 females aged 45-75 years were included for the study. Dietary intake in the past 12 months was assessed by a validated China National Nutrition and Health Survey 2002 (CNHS2002) food-frequency questionnaire. Energy-adjusted DII (E-DII) scores were calculated from daily dietary information. In a multivariable linear regression analysis adjusted for potential confounders, E-DII was positively associated with brachial ankle pulse wave velocity (baPWV) in participants with diabetes (β = 12.820; 95% CI = 2.565, 23.076; P = 0.014) and prediabetes (β = 29.025; 95% CI = 1.110, 56.940; P = 0.042), but not in females with normal glucose homeostasis. In addition, per unit increase of E-DII was significantly associated with lower eGFR (β = -1.363; 95% CI = -2.335, -0.392; P = 0.006) in patients with diabetes.

Conclusion: We identified a direct association between E-DII and arterial stiffness, decreasedeGFR in middle-aged and elderly women with diabetes or prediabetes. Future studies are needed to verify and clarify the role of E-DII as an intervention target for cardiorenal complications of chronic hyperglycemia.
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http://dx.doi.org/10.1016/j.numecd.2021.05.011DOI Listing
July 2021

PPARγ mediates the anti-pulmonary fibrosis effect of icaritin.

Toxicol Lett 2021 Oct 18;350:81-90. Epub 2021 Jun 18.

Xiangya Nursing School, Central South University, Changsha, Hunan, China. Electronic address:

Background: Pulmonary fibrosis is a fatal lung disease with limited treatment options. Icaritin is the active ingredient derived from the traditional Chinese medical plant Epimedium and possesses many biomedical activities. This study aimed to investigate the effects and molecular mechanisms of icaritin on bleomycin-induced pulmonary fibrosis in mice.

Methods: To assess its preventative effects, bleomycin treated mice received 0, 0.04, 0.2, and 1 mg/kg of icaritin from day 1 onwards. To assess its therapeutic effects, bleomycin treated mice received 0 and 1 mg/kg of icaritin from day 15 onwards. Mice were sacrificed on day 21 and lung tissues were collected, stained with HE, Masson and immunohistochemistry. Q-PCR was used to measure Collagen I and Collagen III expression, western blotting was used to quantify α-SMA, Collagen I expression. Hydroxyproline content was measured using a biochemical method. NIH3T3 and HLF-1 cells were treated with TGF-β1with or without icaritin, and α-SMA, Collagen I were tested. PPARγ antagonist GW9662 and PPARγ-targeted siRNA were used to investigate the mechanism of icaritin in inhibiting myofibroblast differentiation.

Results: Both preventative and therapeutic administration of icaritin improved the histopathological changes, decreased Collagen and α-SMA, lowered hydroxyproline content in bleomycin-treated lung tissues. Icaritin decreased α-SMA and Collagen I expression in TGF-β1-stimulated NIH3T3 and HLF-1 cells. However, its effect in reducing α-SMA and Collagen I expression was suppressed when expression or activity of PPARγ was inhibited.

Conclusions: Icaritin has therapeutic potential against pulmonary fibrosis via the inhibition of myofibroblast differentiation, which may be mediated by PPARγ.
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http://dx.doi.org/10.1016/j.toxlet.2021.06.014DOI Listing
October 2021

Kaempferol inhibits benign prostatic hyperplasia by resisting the action of androgen.

Eur J Pharmacol 2021 Sep 12;907:174251. Epub 2021 Jun 12.

Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Poyang Lake Road 10, Tianjin, 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Poyang Lake Road 10, Tianjin, 301617, China; Laboratory of Pharmacology of TCM Formulae Co-Constructed By the Province-Ministry, Tianjin University of TCM, Poyang Lake Road 10, Tianjin, 301617, China. Electronic address:

Kaempferol is a natural compound that inhibits tumor development in androgenic related prostate cancer. However, it is still not clear about its phyto-androgenic activity and whether it suppresses testosterone-induced benign prostatic hyperplasia (BPH) development. In this study, molecular docking, cellular immunofluorescence staining, chromatin immunoprecipitation and dual luciferase reporter assay were performed to investigate the androgenic activity of kaempferol. Dihydrotestosterone-induced gene expression and cell proliferation were further analyzed upon treatment with kaempferol. Testosterone-induced BPH was established in rats and the effect and mechanism of action of kaempferol on BPH development was then assessed. Docking data showed that kaempferol could bind to ASN705 and THR877 residues of androgen receptor which were also the binding sites of dihydrotestosterone. The nuclear translocation of androgen receptor was promoted directly by kaempferol in androgen-dependent prostate cancer LNCaP cells. In addition, the in vivo interaction of androgen receptor with PSA promoter region and the transcriptional activity of androgen receptor were both significantly enhanced after kaempferol stimulation. However, kaempferol pretreatment suppressed dihydrotestosterone-induced effects including the transcriptional activity of androgen receptor, the expressions of PSA and AR genes and cell proliferation of LNCaP, BPH-1 and WPMY-1 cells. Consistently, kaempferol declined the prostate index and improved the pathological properties in BPH rats, and the up-regulated T level in serum from BPH rats was highly decreased after kaempferol administration. Kaempferol exhibited its androgenic-like activity and served as a selective androgen receptor modulator that contributes to androgen-related BPH development.
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http://dx.doi.org/10.1016/j.ejphar.2021.174251DOI Listing
September 2021

Integrative Analysis of Genome, 3D Genome, and Transcriptome Alterations of Clinical Lung Cancer Samples.

Genomics Proteomics Bioinformatics 2021 Jun 8. Epub 2021 Jun 8.

Center for Bioinformatics, School of Life Sciences, Center for Statistical Science, Peking University, Beijing 100871, China. Electronic address:

Genomic studies of cancer cell alterations, such as mutations, copy number variations (CNVs), and translocations, greatly promote our understanding of the genesis and development of cancer. However, the 3D genome architecture of cancers remains less studied due to the complexity of cancer genomes and technical difficulties. To explore the 3D genome structure in clinical lung cancer, we performed Hi-C experiments using paired normal and tumor cells harvested from patients with lung cancer, combining with RNA-seq analysis. We demonstrated the feasibility of studying 3D genome of clinical lung cancer samples with a small number of cells (1 × 10), compared the genome architecture between clinical samples and cell lines of lung cancer, and identified conserved and changed spatial chromatin structures between normal and cancer samples. We also showed that Hi-C data can be used to infer CNVs and point mutations in cancer. By integrating those different types of cancer alterations, we showed significant associations between CNVs, 3D genome, and gene expression. We propose that 3D genome mediates the effects of cancer genomic alterations on gene expression through altering regulatory chromatin structures. Our study highlights the importance of analyzing 3D genomes of clinical cancer samples in addition to cancer cell lines and provides an integrative genomic analysis pipeline for future larger-scale studies in lung cancer and other cancers.
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http://dx.doi.org/10.1016/j.gpb.2020.05.007DOI Listing
June 2021

The Severity of CVB3-Induced Myocarditis Can Be Improved by Blocking the Orchestration of NLRP3 and Th17 in Balb/c Mice.

Mediators Inflamm 2021 12;2021:5551578. Epub 2021 May 12.

Internal Medicine-Cardiovascular Department, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545005, China.

Background: The functional characteristics of NLRP3 in the pathogenesis of coxsackievirus B3- (CVB3-) induced viral myocarditis (VMC) have not been fully elucidated, and the targeted therapeutic effect of NLRP3 or its related pathway in VMC has not been reported.

Method: In this work, the change patterns of NLRP3- and Th17-related factors were detected during the pathological process of CVB3-induced VMC in Balb/c mice. The correlation between NLRP3 and Th17 cells during the VMC process was analyzed by Spearman test. The coculture system of spleen CD4 T and bone marrow CD11c DC cells was set to explore the orchestration of NLRP3 and Th17 in the pathological development of VMC in vitro. Anti-IL-1 antibody or NLRP3 Balb/c were used to block the NLRP3 pathway indirectly and directly to analyze the NLRP3-targeting therapeutic value.

Results: The change patterns of NLRP3- and Th17-related molecules in the whole pathological process of mouse CVB3-induced VMC were described. Through Spearman correlation analysis, it was confirmed that there was a close correlation between NLRP3 and Th17 cells in the whole pathological process of VMC. And the interaction mode between NLRP3 and Th17 was preliminarily explored in the cell experiment in vitro. Under the intervention of an anti-IL-1 antibody or NLRP3 knockout, the survival rate of the intervention group was significantly improved, the degree of myocardial inflammation and fibrosis was significantly alleviated, and the content of myocardial IL-17 and spleen Th17 was also significantly decreased.

Conclusion: Our findings demonstrated a key role of the NLRP3 inflammasome and its close relationship with Th17 in the pathological progression of CVB3-induced VMC and suggested a possible positive feedback-like mutual regulation mechanism between the NLRP3 inflammasome and Th17 in vitro and in the early stage of CVB3 infection. Taking NLRP3 as a new starting point, it provides a new target and idea for the prevention and treatment of CVB3-induced VMC.
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http://dx.doi.org/10.1155/2021/5551578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139334PMC
May 2021

Parsonage-Turner syndrome post-infection by SARS-CoV-2: A case report.

Neurologia 2021 Apr 27. Epub 2021 Apr 27.

Servicio de Medicina Física y Rehabilitación, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, España.

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http://dx.doi.org/10.1016/j.nrl.2021.04.008DOI Listing
April 2021

Mitochondrial localization and moderated activity are key to murine erythroid enucleation.

Blood Adv 2021 05;5(10):2490-2504

Department of Cell, Developmental and Regenerative Biology.

Mammalian red blood cells (RBCs), which primarily contain hemoglobin, exemplify an elaborate maturation process, with the terminal steps of RBC generation involving extensive cellular remodeling. This encompasses alterations of cellular content through distinct stages of erythroblast maturation that result in the expulsion of the nucleus (enucleation) followed by the loss of mitochondria and all other organelles and a transition to anaerobic glycolysis. Whether there is any link between erythroid removal of the nucleus and the function of any other organelle, including mitochondria, remains unknown. Here we demonstrate that mitochondria are key to nuclear clearance. Using live and confocal microscopy and high-throughput single-cell imaging, we show that before nuclear polarization, mitochondria progressively move toward one side of maturing erythroblasts and aggregate near the nucleus as it extrudes from the cell, a prerequisite for enucleation to proceed. Although we found active mitochondrial respiration is required for nuclear expulsion, levels of mitochondrial activity identify distinct functional subpopulations, because terminally maturing erythroblasts with low relative to high mitochondrial membrane potential are at a later stage of maturation, contain greatly condensed nuclei with reduced open chromatin-associated acetylation histone marks, and exhibit higher enucleation rates. Lastly, to our surprise, we found that late-stage erythroblasts sustain mitochondrial metabolism and subsequent enucleation, primarily through pyruvate but independent of in situ glycolysis. These findings demonstrate the critical but unanticipated functions of mitochondria during the erythroblast enucleation process. They are also relevant to the in vitro production of RBCs as well as to disorders of the erythroid lineage.
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http://dx.doi.org/10.1182/bloodadvances.2021004259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152511PMC
May 2021

[Parsonage-Turner syndrome post-infection by SARS-CoV-2: A case report].

Neurologia 2021 09 27;36(7):568-571. Epub 2021 Apr 27.

Servicio de Medicina Física y Rehabilitación, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, España.

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http://dx.doi.org/10.1016/j.nrl.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078912PMC
September 2021

Endoscopic and surgical treatment of T1N0M0 colorectal neuroendocrine tumors: a population-based comparative study.

Surg Endosc 2021 May 13. Epub 2021 May 13.

Medical Centre for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.

Background: With the rapid advances in endoscopic technology, endoscopic therapy (ET) is increasingly applied to the treatment of small (≤ 20 mm) colorectal neuroendocrine tumors (NETs). However, long-term data comparing ET and surgery for management of T1N0M0 colorectal NETs are lacking. The purpose of this work was to compare overall survival (OS) and cancer-specific survival (CSS) of such patients with ET or surgery.

Methods: Patients with T1N0M0 colorectal NETs were identified within the Surveillance Epidemiology and End Results (SEER) database (2004-2016). Demographics, tumor characteristics, therapeutic methods, and survival were compared. Propensity score matching (PSM) was used 1:3 and among this cohort, Cox proportional hazards regression models were performed to evaluate correlation between treatment and outcomes.

Results: Of 4487 patients with T1N0M0 colorectal NETs, 1125 were identified in the matched cohort, among whom 819 (72.8%) underwent ET and 306 (27.2%) underwent surgery. There was no difference in the 5-year and 10-year OS and CSS rates between the 2 treatment modalities. Likewise, analyses stratified by tumor size and site showed that patients did not benefit more from surgery compared with ET. Moreover, multivariate analyses found no significant differences in OS [Hazard Ratio (HR) = 0.857, 95% Confidence Interval (CI): 0.513-1.431, P = 0.555] and CSS (HR = 0.925, 95% CI: 0.282-3.040, P = 0.898) between the 2 groups. Similar results were observed when comparisons were limited to patients with different tumor size and site.

Conclusions: In this population-based study, patients with lesions < 10 mm treated endoscopically had comparable long-term survival compared with those treated surgically, which demonstrates ET as an alternative to surgery in T1N0M0 colorectal NETs of < 10 mm. Further high-quality prospective studies are warranted to comprehensively evaluate the role of ET in patients with tumors 10 to 20 mm.
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http://dx.doi.org/10.1007/s00464-021-08535-6DOI Listing
May 2021

Describing Treatment Patterns for Elderly Patients with Intrahepatic Cholangiocarcinoma and Predicting Prognosis by a Validated Model: A Population-Based Study.

J Cancer 2021 30;12(11):3114-3125. Epub 2021 Mar 30.

Medical Centre for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China.

Elderly patients with Intrahepatic Cholangiocarcinoma (ICC) are frequently under-represented in clinical trials, which leads to the unclear management of ICC in elderly patients. This study aimed to describe treatment patterns and establish a reliable nomogram in elderly ICC patients. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we conducted a retrospective analysis of 1651 elderly patients (≥65 years) diagnosed with ICC between 2004 and 2016. For the whole study population, 29.3% received only chemotherapy, 26.7% no tumor-directed therapy, 19.1% surgery alone, 17.5% radiotherapy, and 7.4% surgery plus chemotherapy. Compared with the age group of 65-74 years, patients aged ≥75 years were less likely to accept treatment. Among patients 66-74 years of age, surgery alone resulted in a median overall survival (OS) of 30 months, surgery combined with chemotherapy 26 months, radiotherapy 17 months, chemotherapy alone 10 months and no therapy 3 months; while among patients ≥75 years of age, the median OS was 21, 25, 14, 9 and 4, respectively. Moreover, independent prognostic indicators including age, gender, grade, tumor size, T stage, N stage, M stage, and treatment were incorporated to construct a nomogram. The C-indexes of the OS nomogram were 0.725 and 0.724 for the training and validation cohorts, respectively. Importantly, the predictive model harbored a better discriminative power than the American Joint Committee on Cancer TNM staging system. Active treatment should not be abandoned among all the elderly patients with ICC. The validated nomogram provided an effective and practical tool to accurately evaluate prognosis and to guide personalized treatment for elderly ICC patients.
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http://dx.doi.org/10.7150/jca.53978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100797PMC
March 2021

Size-Resolved Single Entity Collision Biosensing for Dual Quantification of MicroRNAs in a Single Run.

ACS Appl Mater Interfaces 2021 May 9;13(19):22254-22261. Epub 2021 May 9.

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, People's Republic of China.

Limited to the accuracy of size resolution, single entity collision biosensing (SECBS) for multiplex immunoassays remains challenging, because it is difficult to get the true value of nanoparticle (NP) sizes based on the current intensity due to the complex movement of NPs on the electrode surface. Considering that the size-dependent movement of NPs meanwhile will generate a characteristic current shape, in this work, the huge difference in the current rise time of 5 and 15 nm Pt NPs colliding on an Au ultramicroelectrode ( = 30 μm) was originally used to develop a size-resolved SECBS for multiplex immunoassays of miRNAs. The limit concentration that can be detected was 0.5 fM. Compared with conventional electrochemical biosensors for multiplex immunoassays, for the size-resolved SECBS, one does not need to worry about potential overlapping. Therefore, the proposed method demonstrates a promising potential for the application of SECBS in multiplex immunoassays.
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http://dx.doi.org/10.1021/acsami.1c04747DOI Listing
May 2021

Divergent On-DNA Transformations from DNA-Linked Piperidones.

J Org Chem 2021 May 7. Epub 2021 May 7.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, P. R. China.

A group of highly efficient and divergent transformations for constructing multiple DNA-linked chemotypes based on a piperidone core were successfully developed. We reported the first procedure for the synthesis of a DNA-conjugated piperidine intermediate under basic conditions. Subsequently, this substructure was subjected to additional reactions to generate several privileged scaffolds, including 4-aminopiperidine, fused [1,2,4]triazolo[1,5-]pyrimidine, and a quinoline derivative. These transformations paved the way for constructing focused scaffold-based DNA-encoded libraries with druglike properties.
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http://dx.doi.org/10.1021/acs.joc.1c00670DOI Listing
May 2021

Lipoprotein proteome profile: novel insight into hyperlipidemia.

Clin Transl Med 2021 04;11(4):e361

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.

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http://dx.doi.org/10.1002/ctm2.361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032137PMC
April 2021

Robust Surface States and Coherence Phenomena in Magnetically Alloyed SmB_{6}.

Phys Rev Lett 2021 Apr;126(13):136401

Department of Physics, New York University, New York, New York 10003, USA.

Samarium hexaboride is a candidate for the topological Kondo insulator state, in which Kondo coherence is predicted to give rise to an insulating gap spanned by topological surface states. Here we investigate the surface and bulk electronic properties of magnetically alloyed Sm_{1-x}M_{x}B_{6} (M=Ce, Eu), using angle-resolved photoemission spectroscopy and complementary characterization techniques. Remarkably, topologically nontrivial bulk and surface band structures are found to persist in highly modified samples with up to 30% Sm substitution and with an antiferromagnetic ground state in the case of Eu doping. The results are interpreted in terms of a hierarchy of energy scales, in which surface state emergence is linked to the formation of a direct Kondo gap, while low-temperature transport trends depend on the indirect gap.
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http://dx.doi.org/10.1103/PhysRevLett.126.136401DOI Listing
April 2021

Circadian rhythm-associated clinical relevance and Tumor Microenvironment of Non-small Cell Lung Cancer.

J Cancer 2021 5;12(9):2582-2597. Epub 2021 Mar 5.

Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.

We aimed to explore the prognostic implication for non-small cell lung cancer (NSCLC) based on the expression profiles of circadian clock-related genes (CCRGs), and describe the changes of immune infiltration and cell functions of related to the circadian rhythm. Univariate and multivariate Cox proportional hazard regression were performed to determine a CCRGs risk-score significantly correlated with overall survival (OS) of the training set and validation set. GO, KEGG, and GSVA indicated discrepant changes in cellular processes and signaling pathways associated with these CCRGs. Immune cell infiltration and mutation rates were investigated by the online analysis platform and the algorithm provided by works of literature. The signature-based on ten-gene signatures could independently predict the OS both in TCGA lung adenocarcinoma ( < 0.001, HR: 1.228, 95% CI: 1.158 to 1.302) and lung squamous cell carcinoma ( < 0.001, HR: 2.501, 95% CI: 2.010 to 3.117), respectively. The circadian oscillations driven by CCRGs could disturb the metabolism and cellular functions of cancer cells. The infiltration level of critical cells in specific anti-tumor immunity process was suppressed apparently. In contrast, the infiltrating of inflammatory cells and immune cells with negative regulatory effects were promoted in the high-risk group. CCRGs were evolutionarily conserved with low mutation rates, which brought difficulties to explore therapeutic targets. We identified and validated a circadian rhythm signature to described clinical relevance and tumor microenvironment of NSCLC, which revealed that circadian rhythms might play an influential role in the NSCLC.
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http://dx.doi.org/10.7150/jca.52454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040717PMC
March 2021

Associations of vitamin D status with colorectal cancer risk and survival.

Int J Cancer 2021 08 9;149(3):606-614. Epub 2021 Apr 9.

Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Biological evidence suggests that vitamin D has numerous anticancer functions, but the associations between vitamin D status and colorectal cancer (CRC) risk and survival remain inconclusive. Based on UK Biobank, we prospectively evaluated the associations of season-standardized 25-hydroxyvitamin D (25(OH)D) concentrations with CRC risk among 360 061 participants, and with survival among 2509 CRC cases. We observed an inverse linear relationship between 25(OH)D concentrations and CRC risk (P for linearity = .01; HR per 1-SD increment, 0.95; 95% CI, 0.91-0.99). Compared to the lowest quartile of 25(OH)D, the highest quartile was associated with a 13% (HR, 0.87; 95% CI, 0.77-0.98) lower risk of CRC. For CRC survival, compared to those in the lowest quartile of 25(OH)D, cases in the highest quartile had a 20% (HR, 0.80; 95% CI, 0.65-0.99) lower risk for overall death. Our findings indicate that higher concentrations of serum 25(OH)D are associated with lower incidence and improved survival of CRC, suggesting a role of vitamin D in the pathogenesis of CRC.
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http://dx.doi.org/10.1002/ijc.33580DOI Listing
August 2021

Propensity score-matched analysis for comparing transpancreatic sphincterotomy and needle-knife precut in difficult biliary cannulation.

Sci Rep 2021 03 15;11(1):6059. Epub 2021 Mar 15.

Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China.

Transpancreatic sphincterotomy (TPS) can be an alternative approach of difficult biliary access in endoscopic retrograde cholangiopancreatography (ERCP). We aimed to evaluate the efficacy and safety of TPS compared to needle-knife precut (NKP), considering the early and late outcomes of both techniques. The prospectively collected clinical data, ERCP procedure findings, and outcomes of patients who underwent ERCP with difficult biliary access in our hospital from July 2016 to January 2018 were retrospectively analyzed. The patients were divided into two groups according to the applied secondary cannulation techniques. The propensity score matching (PSM) was applied to reduce the potential selection bias and unify the preventive measures of post-ERCP pancreatitis (PEP) in both groups. A total of 125 patients were enrolled in this study, with 54.4% male and a mean age of 63.29 ± 16.33 years. NKP group included 82 patients, and 43 patients received TPS. Prophylactic pancreatic stents were placed in all patients with TPS and 58.5% of patients with NKP. After applying PSM, the cohort was comprised to 86 patients with 43 patients in each TPS and NKP groups. Successful selective cannulation was achieved by 95.3% using TPS and by 93% using NKP. The mean procedure time was shorter in the TPS group without significant difference. Compared to NKP, using TPS did not affect the rate of PEP. Moreover, TPS was associated with less frequent post-ERCP bleeding and perforation, but without significant differences (all p > 0.05). Patients who received TPS or NKP had no symptoms related to papillary stenosis or chronic pancreatitis during the follow-up period. In conclusion, using TPS in difficult cannulation cases was useful to achieve success cannulation with an acceptable PEP rate and less frequent post-ERCP bleeding and perforation compared to NKP. There were no symptoms related to papillary stenosis or chronic pancreatitis during the follow-up period.
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http://dx.doi.org/10.1038/s41598-021-84655-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961145PMC
March 2021

Simultaneous Improvement of Limonene Production and Tolerance in through Tolerance Engineering and Evolutionary Engineering.

ACS Synth Biol 2021 04 15;10(4):884-896. Epub 2021 Mar 15.

State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, No. 29 13th Street TEDA, Tianjin 300457, PR China.

Limonene is an important plant natural product widely used in food and cosmetics production as well as in the pharmaceutical and chemical industries. However, low efficiency of plant extraction and high energy consumption in chemical synthesis limit the sustainability of industrial limonene production. Recently, the advancement of metabolic engineering and synthetic biology has facilitated the engineering of microbes into microbial cell factories for producing limonene. However, the deleterious effects on cellular activity by the toxicity of limonene is the major obstacle in achieving high-titer production of limonene in engineered microbes. In this study, by using transcriptomics, we identified 82 genes from the nonconventional yeast that were up-regulated when exposed to limonene. When overexpressed, 8 of the gene candidates improved tolerance of this yeast to exogenously added limonene. To determine whether overexpression of these genes could also improve limonene production, we individually coexpressed the tolerance-enhancing genes with a limonene synthase gene. Indeed, expression of 5 of the 8 candidate genes enhanced limonene production in . Particularly, overexpressing YALI0F19492p led to an 8-fold improvement in product titer. Furthermore, through short-term adaptive laboratory evolution strategy, in combination with morphological and cytoplasmic membrane integrity analysis, we shed light on the underlying mechanism of limonene cytotoxicity to . This study demonstrated an effective strategy for improving limonene tolerance of and limonene titer in the host strain through the combinatorial use of tolerance engineering and evolutionary engineering.
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http://dx.doi.org/10.1021/acssynbio.1c00052DOI Listing
April 2021

Using mitochondrial activity to select for potent human hematopoietic stem cells.

Blood Adv 2021 03;5(6):1605-1616

Department of Cell, Developmental & Regenerative Biology.

Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38-CD45RA-CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38-CD45RA-CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.
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http://dx.doi.org/10.1182/bloodadvances.2020003658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993096PMC
March 2021
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