Publications by authors named "Di Wu"

3,119 Publications

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Does the addition of Braun anastomosis to Billroth II reconstruction on laparoscopic-assisted distal gastrectomy benefit patients?

World J Gastrointest Oncol 2022 Jun;14(6):1141-1147

Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.

Background: Operation is the primary therapeutic option for patients with distal gastrectomy. Braun anastomosis is usually performed after Billroth II reconstruction, which is wildly applied on distal gastrectomy because it is believed to benefit patients. However, studies are needed to confirm that.

Aim: To identify whether the addition of Braun anastomosis to Billroth II reconstruction on laparoscopy-assisted distal gastrectomy benefits patients.

Methods: A total of 143 patients with gastric cancer underwent laparoscopy-assisted distal gastrectomy at Centre 1 of PLA general hospital between January 2015 and December 2019. Clinical data of the patients were collected, and 93 of the 143 patients were followed up. These 93 patients were divided into two groups: Group 1 (Billroth II reconstruction, 33 patients); and Group 2 (Billroth II reconstruction combined with Braun anastomosis, 60 patients). Postoperative complication follow-up data and relevant clinical data were compared between the two groups.

Results: There were no significant differences between Group 1 and Group 2 in postoperative complications (6.1% 6.7%, = 0.679), anal exhaust time or blood loss. The follow-up prevalence of reflux gastritis indicated no significant difference between Group 1 and Group 2 (68.2% 51.7%, = 0.109). The follow-up European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 scores revealed no evident difference between Group 1 and Group 2 as well. Group 1 had a shorter operating time than Group 2 on average (234.6 min 262.0 min, = 0.017).

Conclusion: Combined with Billroth II reconstruction, Braun anastomosis has been applied due to its ability to reduce the prevalence of reflux gastritis. Whereas in this study, the prevalence of reflux gastritis showed no significant difference, leading to a conclusion that under the circumstance of Braun anastomosis costing more time and more money, simple Billroth II reconstruction should be widely applied.
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http://dx.doi.org/10.4251/wjgo.v14.i6.1141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244985PMC
June 2022

Antioxidant Biodegradable Covalent Cyclodextrin Frameworks as Particulate Carriers for Inhalation Therapy against Acute Lung Injury.

ACS Appl Mater Interfaces 2022 Aug 10. Epub 2022 Aug 10.

Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Drug therapies for acute lung injury (ALI) are far from satisfactory, primarily because drugs cannot specifically target the lungs. Direct delivery of drugs to the deep alveolar regions by inhalation administration is crucial for the treatment of ALI. However, conventional inhalable carriers such as lactose and mannitol are generally inactive. Therefore, the use of a novel pharmacologically active carrier for pulmonary delivery may produce synergetic effects in treating ALI. Considering the pathophysiological environment of ALI, which typically featured excessive reactive oxygen species (ROS) and acute inflammation, we synthesized a novel kind of biodegradable and ROS-sensitive cross-linked covalent cyclodextrin frameworks (OC-COF) with uniform inhalable particle size to treat ALI. OC-COF was devised to incorporate HO-scavenging peroxalate ester linkages, which could hydrolyze and eliminate ROS generated in inflammatory sites. Ligustrazine (LIG), an antioxidant and anti-inflammatory natural compound, was loaded into OC-COF and evaluated as a dry powder inhaler ([email protected]) and , showing favorable aerodynamic properties and prominent antioxidant and anti-inflammatory capacities for the synergistic effects of OC-COF and LIG. In ALI rats, inhalation of [email protected] with a one-fifth LIG dose significantly alleviated the inflammation, oxidant stress, and lung damage. Western blot analysis demonstrated that [email protected] protected the lungs by regulating the Nrf2/NF-κB signaling pathway. In summary, this study provides a novel ROS-responsive material as an inhalable particulate carrier for the improved treatment of ALI and other medical conditions.
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http://dx.doi.org/10.1021/acsami.2c05220DOI Listing
August 2022

Polyethylene glycol recombinant human growth hormone in Chinese prepubertal slow-growing short children: doses reported in a multicenter real-world study.

BMC Endocr Disord 2022 Aug 9;22(1):201. Epub 2022 Aug 9.

Department of Endocrine and Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, No.56 Nanlishi Road, Xicheng District, 100045, Beijing, China.

Background: To evaluate the effectiveness of individualized-dose polyethylene glycol recombinant human growth hormone (PEG-rhGH) for short stature.

Methods: This real-world study enrolled children with short stature in 19 hospitals throughout China. They were treated with PEG-rhGH for 6 months. The starting dosage ranged from 0.10 to 0.20 mg/kg/week. The primary outcome was the change in height standard deviation score (ΔHt SDS).

Results: Five hundred and ten patients were included and grouped based on dosage as A (0.10-0.14 mg/kg/week), B (0.15-0.16 mg/kg/week), C (0.17-0.19 mg/kg/week), and D (0.20 mg/kg/week). The mean 6-month ΔHt SDS for the total cohort was 0.49 ± 0.27, and the means differed among the four dose groups (P = 0.002). The ΔHt SDS was lower in group A than in groups B (LSM difference [95%CI], -0.09 [-0.17, -0.01]), C (LSM difference [95%CI], -0.10 [-0.18, -0.02]), and D (LSM difference [95%CI], -0.13 [-0.21, -0.05]) after adjusting baseline covariates. There were no significant differences among groups B, C, and D. When the baseline IGF-1 was < -2 SDS or > 0 SDS, the △Ht SDS was not different among the four groups (P = 0.931 and P = 0.400). In children with baseline IGF-1 SDS of -2 ~ 0 SDS, a higher dosage was associated with a better treatment effect (P = 0.003), and the △Ht SDS was lower in older children than in younger ones (P < 0.001).

Conclusions: PEG-rhGH could effectively increase height in prepubertal short children. When the baseline IGF-1 was < -2 SDS, 0.10 mg/kg/week could be a starting dose. In other IGF-1 statuses, 0.15-0.20 mg/kg/week might be preferred.

Trial Registration: ClinicalTrials.gov: NCT03249480 , retrospectively registered.
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http://dx.doi.org/10.1186/s12902-022-01101-8DOI Listing
August 2022

Dual specificity phosphatase 1 attenuates inflammation-induced cardiomyopathy by improving mitophagy and mitochondrial metabolism.

Mol Metab 2022 Aug 6:101567. Epub 2022 Aug 6.

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address:

Objectives: Dual specificity phosphatase 1 (DUSP1) is regarded as an anti-inflammatory factor in cardiovascular disorders. Mitophagy removes damaged mitochondria and thus promotes mitochondrial regeneration. We investigated whether DUSP1 could attenuate inflammation-induced cardiomyopathy by improving mitophagy.

Methods: Lipopolysaccharide was used to induce septic cardiomyopathy in wild-type (WT) and DUSP1 transgenic (DUSP1) mice.

Results: Echocardiography revealed that lipopolysaccharide impaired heart function by reducing the cardiac systolic and diastolic capacities of WT mice. Freshly isolated single cardiomyocytes from lipopolysaccharide-treated WT mice also exhibited reduced contractile/relaxation parameters. However, DUSP1 overexpression not only maintained the mechanical properties of cardiomyocytes, but also improved heart performance. Lipopolysaccharide upregulated myocardial inflammatory gene transcription and adhesive factor expression, which increased myocardial neutrophil accumulation and cardiomyocyte apoptosis in WT mice. DUSP1 overexpression inhibited the inflammatory response and therefore promoted cardiomyocyte survival. Lipopolysaccharide disrupted mitochondrial respiration and metabolism in WT cardiomyocytes, but DUSP1 overexpression restored mitochondrial metabolism, maintained the mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species production, possibly by increasing FUN14 domain-containing 1 (FUNDC1)-dependent mitophagy. Silencing of FUNDC1 abolished the protective effects of DUSP1 overexpression on cardiomyocytes and their mitochondria following lipopolysaccharide treatment.

Conclusion: These results demonstrated that DUSP1 is a novel anti-inflammatory factor that protects against septic cardiomyopathy by improving FUNDC1-induced mitophagy.
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http://dx.doi.org/10.1016/j.molmet.2022.101567DOI Listing
August 2022

Plasma metabolome and cytokine profile reveal glycylproline modulating antibody fading in convalescent COVID-19 patients.

Proc Natl Acad Sci U S A 2022 Aug 9;119(34):e2117089119. Epub 2022 Aug 9.

State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian 361102, China.

The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the "new normal." The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning-based classification models using 17 features (six cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least six machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2-specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.
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http://dx.doi.org/10.1073/pnas.2117089119DOI Listing
August 2022

Fluorescence energy transfer biosensing platform based on hyperbranched rolling circle amplification and multi-site strand displacement for ultrasensitive detection of miRNA.

Anal Chim Acta 2022 Aug 21;1222:340190. Epub 2022 Jul 21.

Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, 266042, PR China. Electronic address:

A novel fluorescence biosensor based on hyperbranched rolling circle amplication (HRCA) and multi-site strand displacement amplification (SDA) strategy was constructed to realize super-sensitive detection of miRNA-21. The target miRNA-21 was specifically used to trigger HRCA reaction and generated abundant DNA sequences with different lengths. These sequences could initiate the SDA reaction with hairpin HP1 and HP2 to form the fluorescence signal double-stranded bodies (FSDB), and produced the fluorescence resonance energy transfer (FRET) for target assay. The circle template, reverse primer, hairpin HP1 and HP2 were skillfully designed to much improve the assay selectivity. This FRET signal ratio-based strategy not only avoided the false positive signal produced by traditional detection methods, but also minimized the influence of system fluctuation. So the detection limit of the target could reach fM level. In addition, this method could also be applied to the detection of other miRNAs, proteins and biomolecules, and had great potential in biomedical research, environmental detection and clinical diagnostic applications.
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http://dx.doi.org/10.1016/j.aca.2022.340190DOI Listing
August 2022

Zinc oxide nanoparticles (ZnO-NPs) exhibit immune toxicity to crucian carp (Carassius carassius) by neutrophil extracellular traps (NETs) release and oxidative stress.

Fish Shellfish Immunol 2022 Aug 3. Epub 2022 Aug 3.

College of Life Sciences and Engineering, Foshan University, Foshan, 528225, Guangdong Province, PR China; College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin province, PR China. Electronic address:

Zinc oxide nanoparticles (ZnO-NPs) are widely used in sunscreens, cosmetics, paint, construction materials, and other products. ZnO-NPs released into the environment can harm aquatic creatures and pose a health risk to humans through the food chain. ZnO-NPs are toxic to fish, but there are few reports on its immunotoxicity on crucian carp (Carassius carassius). In this study, ZnO-NPs increased the biochemical indexes of the liver in serum, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In histopathological observation, many inflammatory cells were filled in the liver's central vein stimulated by ZnO-NPs. Furthermore, ZnO-NPs could increase malondialdehyde (MDA) level, lessen superoxide dismutase (SOD) level, and elevate the level of neutrophil extracellular traps (NETs). However, deoxyribonuclease I (DNase I) alleviated all biochemical indexes and histopathological changes. Immunofluorescence in vitro confirmed that NETs were composed of citrullinated histone 3, myeloperoxidase, and neutrophil elastase. ZnO-NPs-increased NETs were dependent on reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and were also related to partial processes of glycolysis. Our study confirms that ZnO-NPS has a toxic effect on the liver of crucian carp. DNase I can prevent liver damage caused by ZnO-NPs, which provides a new insight into the immunotoxicity of ZnO-NPs to fish.
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http://dx.doi.org/10.1016/j.fsi.2022.07.025DOI Listing
August 2022

Construction of Circadian Clock Signature for Tumor Microenvironment in Predicting Survival for Cutaneous Melanoma.

Curr Pharm Des 2022 Aug 2. Epub 2022 Aug 2.

Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China.

Objective: We explored circadian clock-related genes (CCRG) to establish a risk model and identify associations with the tumor immune microenvironment in cutaneous melanoma (CM).

Methods: Circadian clock genes were downloaded from Circadian Gene Database. To explore CM-related circadian clock genes, we combined multivariate cox regression associated with least absolute shrinkage and selection operator (LASSO) regression in the Cancer Genome Atlas (TCGA) and validated it in the GSE65904 dataset. Time-dependent receiver operating characteristic curve (ROC) and Kaplan-Meier analysis were calculated to determine a CCRG risk score model. In addition, the overall survival nomograms of clinicopathological factors and circadian clock-associated gene signatures. Additionally, we evaluated the connection between circadian clock-associated genes with immune checkpoint inhibitors and immune cell infiltration.

Results: Two circadian-clock-related signatures were established. The risk model included SEMA4D (p < 0.001, HR: 0.709, 95% CI: 0.581 to 0.867) and SOD-2 (p<=0.009, HR: 0.790, 95% CI: 0.663 to 0.944) in patients with TCGA melanoma. The risk model was based on two CCRGs enriched in base excision repair, glycosylphosphatidyl (GPI ), and one carbon of the folate pathway. The overall survival was lower in the high-risk group. In addition, the circadian-clock signature may be able to evaluate the immunotherapy response.

Conclusions: We developed and validated a circadian signature to characterize the clinical significance and tumor microenvironment of cutaneous melanoma, revealing that circadian rhythms may impact cutaneous melanoma.
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http://dx.doi.org/10.2174/1381612828666220802114517DOI Listing
August 2022

FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.

Cell Mol Gastroenterol Hepatol 2022 Aug 1. Epub 2022 Aug 1.

Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; National Medical Center for Major Public Health Events, Wuhan, China; State Key Laboratory for Zoonotic Diseases. Electronic address:

Background & Aims: Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are two main features of FVH. Here, we aim to investigate the role and mechanism of NETs in the pathogenesis of FVH.

Methods: A mice model of FVH was established by murine hepatitis virus strain-3 (MHV-3) infection. Liver leukocytes of infected or uninfected mice were used for single cell RNA sequencing and whole transcriptome sequencing. NETs depletion was achieved using DNase1. Acetaminophen was used to establish a mice model of non-virus caused acute liver failure. Clinically, NETs-related markers in liver, plasma and peripheral neutrophils were assessed in patients with HBV-related acute liver injury (HBV-ALI).

Results: Increased hepatic NETs formation was observed in MHV-3-infected mice but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. Adoptive transfer experiment showed that neutrophil-specific FGL2 promoted NETs formation. FGL2 was found to directly interact with mucolipin3 (MCOLN3), which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, elevated plasma NETs level was associated with coagulation dysfunction in patients with HBV-ALI. Colocalization of FGL2, NETs and fibrin in liver was observed in these patients.

Conclusion: NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2-MCOLN3-autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH.
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http://dx.doi.org/10.1016/j.jcmgh.2022.07.014DOI Listing
August 2022

Second-line treatment options in advanced thymic carcinoma after failure of platinum-based chemotherapy: A multicenter retrospective study.

Cancer Med 2022 Aug 4. Epub 2022 Aug 4.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

Background: Currently there is no standard therapy recommended for second-line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single-agent chemotherapy, and PD-1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum-based chemotherapy at the clinic.

Methods: The study included patients with thymic carcinoma who failed first-line platinum-based chemotherapy. Kaplan-Meier methods were applied in the study for estimating the progression-free survival (PFS) and overall survival (OS) curves. Pearson chi-square or Fisher's exact chi-square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS.

Results: Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second-line therapy. Thirty-six patients (35.9%) received single-agent chemotherapy, and eight patients (8.7%) underwent PD-1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single-agent chemotherapy and PD-1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second-line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3-4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment-related mortality was not found in any of the groups.

Conclusions: Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single-agent chemotherapy and PD-1 inhibitors. Multidrug chemotherapy is a choice worth considering for second-line therapy in patients with thymic carcinoma if tolerable.
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http://dx.doi.org/10.1002/cam4.5053DOI Listing
August 2022

A novel approach for forensic identification of automotive paints using optical coherence tomography and multivariate statistical methods.

J Forensic Sci 2022 Aug 1. Epub 2022 Aug 1.

Institute of Forensic Science, Ministry of Public Security, Beijing, China.

Automotive paint is one of the most important evidence in solving vehicle-related criminal cases. It contains the critical information about the suspected vehicle, providing essential clues for the investigation. In this study, a novel approach based on optical coherence tomography combined with multivariate statistical methods was proposed to facilitate rapid, accurate and nondestructive identification of different brands of automotive paints. 164 automotive paint samples from 8 different manufacturers were analyzed by a spectral-domain optical coherence tomography system (SD-OCT). Two-dimensional cross-sectional OCT images and three-dimensional OCT reconstruction of vehicle paints of different paints were obtained to show the internal structural differences. Visual discrimination of A-scan data after registration and averaging processing was first used to distinguish different samples. An scanning electron microscope was utilized to obtain the cross-sectional image of the sample to evaluate the effectiveness of OCT technique. Then the original A-scan data, first derivative data and second derivative data of 136 paints with four layers from 7 different manufacturers were collected. Multivariate statistical methods, including principal component analysis (PCA), multi-layer perceptron (MLP), k-nearest neighbor (KNN) algorithm and Bayes discriminant analysis (BDA), were used to analyze different datasets. The results show the hybrid PCA and BDA model based on the first derivative OCT data achieved the best result of 100% accuracy on the testing dataset for identifying automotive paints. It is demonstrated that the OCT technique combined with multivariate statistics could be a promising method for identifying the automotive paints rapidly and accurately.
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http://dx.doi.org/10.1111/1556-4029.15114DOI Listing
August 2022

Identification of early invisible acute ischemic stroke in non-contrast computed tomography using two-stage deep-learning model.

Theranostics 2022 18;12(12):5564-5573. Epub 2022 Jul 18.

Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Although non-contrast computed tomography (NCCT) is the recommended examination for the suspected acute ischemic stroke (AIS), it cannot detect significant changes in the early infarction. We aimed to develop a deep-learning model to identify early invisible AIS in NCCT and evaluate its diagnostic performance and capacity for assisting radiologists in decision making. : In this multi-center, multi-manufacturer retrospective study, 1136 patients with suspected AIS but invisible lesions in NCCT were collected from two geographically distant institutions between May 2012 to May 2021. The AIS lesions were confirmed based on the follow-up diffusion-weighted imaging and clinical diagnosis. The deep-learning model was comprised of two deep convolutional neural networks to locate and classify. The performance of the model and radiologists was evaluated by the area under the receiver operator characteristic curve (AUC), sensitivity, specificity, and accuracy values with 95% confidence intervals. Delong's test was used to compare the AUC values, and a chi-squared test was used to evaluate the rate differences. 986 patients (728 AIS, median age, 55 years, interquartile range [IQR]: 47-65 years; 664 males) were assigned to the training and internal validation cohorts. 150 patients (74 AIS, median age, 63 years, IQR: 53-75 years; 100 males) were included as an external validation cohort. The AUCs of the model were 83.61% (sensitivity, 68.99%; specificity, 98.22%; and accuracy, 89.87%) and 76.32% (sensitivity, 62.99%; specificity, 89.65%; and accuracy, 88.61%) for the internal and external validation cohorts based on the slices. The AUC of the model was much higher than that of two experienced radiologists (65.52% and 59.48% in the internal validation cohort; 64.01% and 64.39% in external validation cohort; all < 0.001). The accuracy of two radiologists increased from 62.00% and 58.67% to 92.00% and 84.67% when assisted by the model for patients in the external validation cohort. : This deep-learning model represents a breakthrough in solving the challenge that early invisible AIS lesions cannot be detected by NCCT. The model we developed in this study can screen early AIS and save more time. The radiologists assisted with the model can provide more effective guidance in making patients' treatment plan in clinic.
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http://dx.doi.org/10.7150/thno.74125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330528PMC
August 2022

Craniocervical Manual Lymphatic Drainage Increases the Efficiency of Atorvastatin-Based Treatment of Chronic Subdural Hematoma.

Transl Stroke Res 2022 Jul 30. Epub 2022 Jul 30.

Department of Neurosurgery, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, China.

The objective of this study is to explore whether craniocervical manual lymphatic drainage (cMLD) can promote hematoma absorption and increase the efficiency of atorvastatin-based conservative treatment in chronic subdural hematoma (CSDH) patients. All CSDH patients treated with atorvastatin-based therapy between October 2020 and February 2022 in our department were retrospectively screened for enrollment. The patients were divided into the control and cMLD groups according to whether cMLD was performed. Head CT or MR images in both groups were obtained before the treatment and 2 weeks and 4 weeks after the treatment. MR images of the deep cervical lymphatic nodes (dCLNs) in 23 patients were obtained in the cMLD group before and approximately 2 weeks after treatment. The volumes of the dCLNs and hematoma were calculated. The primary outcomes are the differences in hematoma volume reduction after 4 weeks of treatment. The secondary outcomes were (1) the differences in hematoma volume reduction between the patients in these two groups in the 2nd week, (2) the dCLN volume change in the cMLD group before and after 2 weeks of treatment, and (3) the percentage of patients who transitioned to surgery because of failure to the conservative treatment. A total of 106 consecutive patients were enrolled in this study for analysis; 54 patients received atorvastatin-based treatment (control group), and 52 were treated with both atorvastatin-based treatment and cMLD (cMLD group). At baseline, the mean hematoma volume was 76.53 ± 42.97 ml in the control group and 88.57 ± 49.01 ml in the cMLD group (p = 0.181). In the 4th week, the absolute number of hematoma reductions (20.79 ± 34.73 ml vs. 37.28 ± 28.24 ml, p = 0.009) and percentage of hematoma reductions (22.58% ± 60.01% vs. 46.43% ± 30.12%, p = 0.012) in the cMLD group were greater than those in the control group. After 2 weeks of treatment, the absolute number of hematoma reductions showed no difference in the two groups, while the percentage of hematoma reduction was higher in the cMLD group (18.18% ± 24.61% vs. 2.08% ± 25.72%, p = 0.001). One patient in cMLD and 8 patients in the control group were transitioned to receive surgical treatment. The dCLN volumes in 23 experimental patients increased significantly after 2 weeks of treatment in the cMLD group (p = 0.032). There were no severe side effects that needed to be reported. Combined with atorvastatin-based therapy, cMLD can promote hematoma absorption and decrease the surgery rate, which provides a new therapeutic strategy for CSDH.
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http://dx.doi.org/10.1007/s12975-022-01062-zDOI Listing
July 2022

Case Report: Malignant Brain Tumors in Siblings With Mutations.

Front Oncol 2022 12;12:920305. Epub 2022 Jul 12.

Institute of Functional Nano and Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, China.

Background: Familial brain tumor incidences are low. Identifying the genetic alterations of familial brain tumors can help better understand the pathogenesis and make therapy regimens for these tumors.

Case Presentation: An elder female and a younger male were diagnosed with brain tumors at the age of 10 and 5, respectively. Whole-genome sequencing analysis of the two patients' blood, primary brain tumor tissues, and their parents' blood samples was performed, which revealed that the two tumor samples harbored extremely high somatic mutation loads. Additionally, we observed pigmentation on the male patient's skin.

Conclusion: Germline, biallelic mutation of -a gene related to DNA mismatch repair whose defect will result in constitutional mismatch repair deficiency (CMMRD)-is causal for the brain tumors of these two siblings.
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http://dx.doi.org/10.3389/fonc.2022.920305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315106PMC
July 2022

Cardiomyocytes induced from hiPSCs by well-defined compounds have therapeutic potential in heart failure by secreting PDGF-BB.

Signal Transduct Target Ther 2022 Jul 29;7(1):253. Epub 2022 Jul 29.

School of Life Science, Beijing University of Chinese Medicine, Beijing, China.

Recent studies have suggested that transplant of hiPS-CMs is a promising approach for treating heart failure. However, the optimally clinical benefits have been hampered by the immature nature of the hiPS-CMs, and the hiPS-CMs-secreted proteins contributing to the repair of cardiomyocytes remain largely unidentified. Here, we established a saponin compound optimally induced system to generate hiPS-CMs with stable functional attributes in vitro and transplanted in heart failure mice. Our study showed enhanced therapeutic effects of optimally induced hiPS-CMs by attenuating cardiac remodeling and dysfunction, these beneficial effects were concomitant with reduced cardiomyocytes death and increased angiogenesis. Moreover, the optimally induced hiPS-CMs could gathering to the injured heart and secret an abundant PDGF-BB. The reparative effect of the optimally induced hiPS-CMs in the hypoxia-injured HCMs was mimicked by PDGF-BB but inhibited by PDGF-BB neutralizing antibody, which was accompanied by the changed expression of p-PI3K and p-Akt proteins. It is highly possible that the PI3K/Akt pathway is regulated by the PDGF-BB secreted from the compound induced hiPS-CMs to achieve a longer lasting myocardial repair effect compared with the standard induced hiPS-CMs. Taken together, our data strongly implicate that the compound induced hiPS-CMs promote the recovery of injured hearts via paracrine action. In this process, the paracrine factor PDGF-BB derived from the compound induced hiPS-CMs reduces isoproterenol-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the PI3K/Akt pathway, suggesting that the optimally induced hiPS-CMs may serve as a new promising cell therapy for clinical applications.
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http://dx.doi.org/10.1038/s41392-022-01045-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334380PMC
July 2022

Effect of elevated progesterone levels the day before ovulation on pregnancy outcomes in natural cycles of frozen thawed embryo transfer.

Gynecol Endocrinol 2022 Jul 28:1-5. Epub 2022 Jul 28.

Centre for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Objective: We aimed to analyze whether elevated progesterone levels on the day before ovulation affected pregnancy outcomes in natural cycles of frozen thawed embryo transfer (NC-FET).

Methods: A retrospective analysis was conducted in a public university hospital. Data on clinical pregnancy, live birth, ectopic pregnancy, and miscarriage rates were collected, along with other patient data. Patients were divided into two groups according to their progesterone levels the day before ovulation: the progesterone elevation (PE) group (progesterone level >1.0 ng/mL) and the normal progesterone (NP) group (progesterone level ≤1.0 ng/mL). We assessed the effect of elevated progesterone levels in NC-FET by performing multivariate logistic regression analysis.

Results: Overall 1159 women with tubal factor infertility who underwent NC-FET were enrolled, including 666 women who received cleavage-stage embryo transfers and 493 women who received blastocyst embryo transfers. When two cleavage-stage embryos were transferred, the clinical pregnancy rate was significantly higher in the PE than in the NP group following NC-FET ( .05). After correcting for various confounders, we found that elevated progesterone levels (adjusted odds ratio [OR]: 1.672; 95% confidence interval [CI]: 1.089-2.566,  = .018) improved the clinical pregnancy rate following transfer of two cleavage-stage embryos but did not affect the pregnancy rate when blastocyst-stage embryos were transferred (adjusted OR: 0.856; 95% CI: 0.536-1.369;  = .517).

Conclusions: The results showed that in patients undergoing cleavage-stage NC-FET, progesterone levels >1.0 ng/mL improved the clinical pregnancy rates. However, the level of progesterone had no effect on the clinical pregnancy rate for patients undergoing blastocyst-stage NC-FET.
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http://dx.doi.org/10.1080/09513590.2022.2103671DOI Listing
July 2022

-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction.

J Agric Food Chem 2022 Aug 28;70(31):9664-9673. Epub 2022 Jul 28.

School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China.

The activation of thrombin-treated endothelial cells resulted in disruption of the vascular tissues. A novel oyster-derived bioactive dodecapeptide (IEELEELEAER, P-2-CG) was reported to protect the human umbilical vein endothelial cells and their barrier function via the decrease of VE-cadherin disruption and the restoration of the F-actin arrangement. The promotion of the extrinsic pathway in this case triggers the release of tissue factors that occurs on the surface of the endothelial cells, thus changing the antithrombotic to prothrombotic. P-2-CG induced accordingly a prolongation of plasma clotting time and thrombin generation time, following the alteration of the antithrombotic phenotype. Furthermore, the antithrombotic activity of P-2-CG was also supported by the reduction of FXa and the inhibition of other factors release, for instance, inflammation factors, ROS, etc. In addition to its antithrombogenic role, P-2-CG displayed anti-inflammatory and antioxidant properties via the mitogen-activated protein kinase cascades and central signaling pathways as shown in an model of endothelial dysfunction.
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http://dx.doi.org/10.1021/acs.jafc.2c02435DOI Listing
August 2022

Anaerobic membrane bioreactors for pharmaceutical-laden wastewater treatment: A critical review.

Bioresour Technol 2022 Jul 22;361:127667. Epub 2022 Jul 22.

Department of Molecular Biosciences and Bioengineering, University of Hawaì'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA. Electronic address:

Pharmaceuticalsare a diverse group of chemical compounds widely used for prevention and treatment of infectious diseases in both humans and animals. Pharmaceuticals, either in their original or metabolite form, find way into the wastewater treatment plants (WWTPs) from different sources. Recently, anaerobic membrane bioreactors (AnMBR) has received significant research attention for the treatment of pharmaceuticals in various wastewater streams. This review critically examines the behaviour and removal of a wide array of pharmaceuticals in AnMBR with primary focus on their removal efficiencies and mechanisms, critical influencing factors, and the microbial community structures. Subsequently, the inhibitory effects of pharmaceuticals on the performance of AnMBR and membrane fouling are critically discussed. Furthermore, the imperative role of membrane biofouling layer and its components in pharmaceuticals removal is highlighted. Finally, recent advancements in AnMBR configurations for membrane fouling control and enhanced pharmaceuticals removal are systemically discussed.
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http://dx.doi.org/10.1016/j.biortech.2022.127667DOI Listing
July 2022

IL-6 secretion of CD4 T cells stimulated by LC3-positive extracellular vesicles in human epithelial ovarian cancer.

Clin Transl Oncol 2022 Jul 23. Epub 2022 Jul 23.

Department of Obstetrics and Gynecology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, Jiangsu, China.

Background: Ovarian cancer (OC) as the most fatal gynecological malignancy worldwide, with epithelial ovarian cancer (EOC) being the predominant and most lethal form, poses a serious threat to human health. LC3-positive extracellular vesicles (LC3 EVs) promote tumorigenesis by educating CD4 T cells in a murine melanoma model. However, regulation of LC3 EVs in human EOC remains largely unknown.  METHODS: Differential analysis of Rab8a, Hsp90α and Il6 expression was performed using GEPIA2. The number of LC3 EVs and the frequency of Heat shock protein 90α LC3 EVs (HSP90α LC3 EVs) in the ascites of EOC patients were tested by flow cytometry. IL-6, IL-10, IFN-γ, IL-4 and TGF-β were measured by ELISA. CD4 T cells were isolated from peripheral blood of healthy human donors using MACS magnetic bead technology.  RESULTS: Higher Rab8a, Hsp90a and Il6 expression of cancer tissues compared with normal adjacent tissues in OC were found. The level of IL-6 was positively correlated with LC3 EVs number, HSP90α LC3 EVs percentage in the ascites, and ROMA index of the patient. In addition, elevated IL-6 production by CD4 T cells induced by LC3 EVs was observed, which was suppressed by anti-HSP90α or anti-TLR2.  CONCLUSIONS: LC3 EVs level and HSP90α LC3 EVs percentage were associated with elevated IL-6 in the ascites of EOC patients. HSP90α on LC3 EVs from human EOC could stimulate CD4 T cell production of IL-6 via TLR2.
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http://dx.doi.org/10.1007/s12094-022-02883-yDOI Listing
July 2022

Enhanced arsenic removal by reusable hexagonal CeO/FeO nanosheets with exposed (0001) facet.

Sci Total Environ 2022 Jul 20;847:157490. Epub 2022 Jul 20.

Key Laboratory of Energy Thermal Conversion and Control of Ministry of Education, School of Energy and Environment, Southeast University, Nanjing, Jiangsu 210096, China. Electronic address:

Arsenite in wastewater has caused increasing concern because of high toxicity and mobility. Iron oxides are widely available and regarded as effective adsorbents for arsenic. However, conventional iron oxides usually are only effective for arsenate (As(V)) adsorption by complexation, but not for As(III) adsorption because of their poor catalytic oxidation activities, which greatly limits arsenic removal efficiency. In this study, a uniform hexagonal FeCe bimetal oxide nanosheets (FeCeO) enclosed by high active (0001) planes was synthesized by a solvothermal method to improve the catalytic activity of FeO. The experimental results showed that adsorption capacity of FeCeO reached 61.1 mg/g for arsenic and 70 % of that at equilibrium was achieved in <10 min. Based on characterization analyses and density functional theory simulation, the new insight in oxidation and complexation mechanism of arsenic was proposed. Firstly, As(III) was adsorbed to adsorbent surface by forming stable structure of Ce-O-As or Fe-O-As, and then converted into As(V) by dissolved oxygen under the catalysis of (0001) planes densely distributed on FeO and CeO surfaces. The formed As(V) species were bound on FeCeO surface by forming bidentate and monodentate surface complexes. Finally, the safety of As-containing solution treated with FeCeO was well proved by the zebrafish embryo developmental toxicity tests.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157490DOI Listing
July 2022

Comparison of alveolar bone width and sagittal tooth angulation of maxillary central incisors in Class I and Class III canine relationships: a retrospective study using CBCT.

BMC Oral Health 2022 07 22;22(1):303. Epub 2022 Jul 22.

Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu Province Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.

Background: Canine relationship is a key reference identifying anterior malocclusion and an important implication for evaluating preimplantation bone morphology at maxillary esthetic zone. This study aimed to compare the differences of maxillary central incisor-related measurements (alveolar bone thickness and tooth sagittal angulation) between Class I and Class III canine relationship and further explore the risk factors for immediate implant placement in the anterior maxilla based on cone beam computed tomography (CBCT) data.

Methods: CBCT digital imaging and communications in medicine (DICOM) files of 107 patients (54 with Class I canine relationship and 53 with Class III canine relationship) were collected and the alveolar bone thickness at mid-root (mid-root buccal thickness/MBT; palatal/MPT), apical regions (apical buccal thickness/ABT; palatal/APT) and sagittal angulation (SA) of the maxillary central incisor at the examined side were measured on the mid-sagittal observation plane. Descriptive statistical analysis and frequency distributions of the measurements based on Class I or Class III canine relationship were established. Statistical analyses were performed using Fisher's exact test, independent samples t test and Pearson correlation test with the significance level set at p < 0.05.

Results: The frequency distributions of maxillary central incisors' MPT, ABT, APT and SA showed significant differences between Class I and Class III canine relationships (p = 0.030, 0.024, 0.000 and 0.000, respectively). MPT (2.48 ± 0.88 mm vs. 3.01 ± 1.04 mm, p = 0.005), APT (6.79 ± 1.65 mm vs. 8.47 ± 1.93 mm, p = 0.000) and SA (12.23 ± 5.62° vs. 16.42 ± 4.49°, p = 0.000) were significantly smaller in patients with Class III canine relationship. Moreover, SA showed a strong positive correlation with APT (R = 0.723, p = 0.000) and a moderate negative correlation with ABT (R = - 0.554, p = 0.000).

Conclusions: In populations with Class III canine relationship, maxillary central incisors were significantly more labially inclined and have a thinner palatal bone plate at the apex compared with Class I relationship. Clinicians should avoid palatal perforation during immediate implantation at sites of originally protrusive maxillary incisors.
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http://dx.doi.org/10.1186/s12903-022-02331-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308311PMC
July 2022

Mechanism on the microbial salt tolerance enhancement by electrical stimulation.

Bioelectrochemistry 2022 Jul 16;147:108206. Epub 2022 Jul 16.

Faculty of Bioengineering, Ghent University, Ghent 9000, Belgium.

The application of biological methods in industrial saline wastewater treatment is limited, since the activities of microorganisms are strongly inhibited by the highly concentrated salts. Acclimatized halotolerant and halophilic microorganisms are of high importance since they can resist the environmental stresses of high salinity. The acclimation to salinity can be passive or active based on whether external simulation is used. However, there is a need for development of economic, efficient and reliable active biological stimulation technologies to accelerate salinity acclimation. Recent studies have shown that electrical stimulation can effectively enhance microbial salt tolerance and pollutant removal ability. However, there have been no comprehensive reviews of the mechanisms involved. Therefore, this mini-review described the mechanisms of electrical stimulation that can significantly improve microbial bioactivity and biodiversity. These mechanisms include regulation of Na and K transporters by changing membranepotential and promoting ATP production, as well as regulation of extracellular polymer substances through enhanced release of low molecular weight EPS and quorum sensing molecules. The information provided herein will facilitate the application of biological high-salinity wastewater treatment.
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http://dx.doi.org/10.1016/j.bioelechem.2022.108206DOI Listing
July 2022

Sulfation of sialic acid is ubiquitous and essential for vertebrate development.

Sci Rep 2022 Jul 21;12(1):12496. Epub 2022 Jul 21.

Bioscience and Biotechnology Center, and Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.

Glycosylation of proteins and lipids occurs in vertebrates, usually terminating with sialylation, which regulates the physicochemical and biological properties of these glycoconjugates. Although less commonly known, sialic acid residues also undergo various modifications, such as acetylation, methylation, and sulfation. However, except for acetylation, the enzymes or functions of the other modification processes are unknown. To the best of our knowledge, this study is the first to demonstrate the ubiquitous occurrence of sulfated sialic acids and two genes encoding the sialate: O-sulfotransferases 1 and 2 in vertebrates. These two enzymes showed about 50% amino acid sequence identity, and appeared to be complementary to each other in acceptor substrate preferences. Gene targeting experiments showed that the deficiency of these genes was lethal for medaka fish during young fry development and accompanied by different phenotypes. Thus, the sulfation of sialic acids is essential for the vertebrate development.
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http://dx.doi.org/10.1038/s41598-022-15143-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304399PMC
July 2022

Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities.

Sci Adv 2022 Jul 13;8(28):eabn4188. Epub 2022 Jul 13.

Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.

Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.
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http://dx.doi.org/10.1126/sciadv.abn4188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278865PMC
July 2022

A hybrid hydrogel encapsulating human umbilical cord mesenchymal stem cells enhances diabetic wound healing.

J Mater Sci Mater Med 2022 Jul 18;33(8):60. Epub 2022 Jul 18.

Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510663, China.

Background: Diabetic wound is a severe complication of diabetes. Stem cell is considered as a promising therapy for diabetic skin wounds. Hydrogel can supply niche for cells adhesion and survival to improve the efficacy of stem cell therapy, but the development of hydrogel with suitable properties remains a great challenge. Thus, our study was conducted to combine an optimized hydrogel with stem cell to improve complex diabetic wound treatment.

Methods: This study constructed a hydrogel with low toxicity and adjustable mechanical properties from gelatin methacrylate (GelMA) and chitosan-catechol (Chi-C), and encapsulated human umbilical cord-mesenchymal stem cells (hUMSCs) to repair full-thickness diabetic wound.

Results: We explored the relationship between mechanical stiffness and cell proliferation and differentiation potency, and found 10% GelMA hydrogel with an optimal stiffness improved hUMSCs adhesion, proliferation, and differentiation potency maintenance in vitro. Assistant with optimized hydrogel encapsulating hUMSCs, diabetic wound healing process was greatly accelerated, including accelerated wound closure, inhibited secretion of inflammatory factors TNF-α and IL-1β, promoted vascular regeneration and collagen deposition after treatment of hUMSCs.

Conclusions: The optimized hydrogel encapsulating hUMSCs improved diabetic wound healing, and has a broad implication for the treatment of diabetic complication. Diabetic wound is a severe complication of diabetes. Stem cell is considered as a promising therapy for diabetic skin wounds. Hydrogel can supply niche for cells adhesion and survival to improve the efficacy of stem cell therapy. This study constructed a hydrogel with low toxicity and adjustable mechanical properties from gelatin methacrylate (GelMA) and chitosan-catechol (Chi-C), and encapsulated human umbilical cord-mesenchymal stem cells (hUMSCs) to repair full-thickness diabetic wound. Hydrogel of 10% GelMA with an optimal stiffness improved hUMSCs adhesion, proliferation, and differentiation potency maintenance in vitro. Assistant with optimized hydrogel encapsulating hUMSCs, diabetic wound healing process was greatly accelerated, including accelerated wound closure, inhibited secretion of inflammatory factors TNF-α and IL-1β, promoted vascular regeneration and collagen deposition after treatment of hUMSCs. The study supplies an alternative treatment for diabetic complication. Hydrogel-hUMSCs combined treatment accelerates wound closure in diabetic mice. A. Representative images of wounds during 21-day in vivo experiments. B. Quantification of wound closure rate (%) over 21-day period. C. HE staining of wounds at days 7, 14 and 21. The bar corresponds to 200 μm.
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http://dx.doi.org/10.1007/s10856-022-06681-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293866PMC
July 2022

Phosphorus Nutrition in Songpu Mirror Carp ( Songpu) During Chronic Carbonate Alkalinity Stress: Effects on Growth, Intestinal Immunity, Physical Barrier Function, and Intestinal Microflora.

Front Immunol 2022 29;13:900793. Epub 2022 Jun 29.

Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China.

Carbonate alkalinity is a major environmental stress factor affecting aquatic feed configuration, which easily causes oxidative stress and hypoimmunity for fish. Hence, the purpose of the study is to assess the potential effect of phosphorus on growth, intestinal oxidation resistance, physical barrier function, and microflora for Songpu mirror carp ( Songpu) (initial average weight of 2.95 ± 0.21 g) reared at the high-concentration carbonate alkalinity environment. A two-factor, three-level (2 × 3) design was applied, in which diets with three different phosphorus levels (3.6, 7.0, and 10.5 g/kg dry matter) were randomly assigned to 0 and 15 mmol/L carbonate alkalinity groups with three replicate aquariums. After the 8-week trial, we found that weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and lipase and amylase activities in the intestine significantly ( < 0.05) declined with increasing carbonate alkalinity. Carbonate alkalinity of 15 mmol/L significantly reduced glutathione peroxidase (GSHPx) activities in the intestine ( < 0.05). The relative expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione peroxidase 1a (GPX1a), Clautin3, Clautin11, and tumor necrosis factor β (TNF-β) in the intestine were markedly downregulated by increasing carbonate alkalinity levels ( < 0.05), whilst the relative expressions of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the intestine were markedly upregulated ( < 0.05). At the 15 mmol/L carbonate alkalinity treatment, Songpu mirror carp suffer from hypoimmunity status with failed digestion, antioxidant, inflammation, and immune response, thereby inducing impaired growth. Additionally, significant increments in the abundance of Proteobacteria and a significant decrease in the abundance of Fusobacteria and the Firmicutes/Bacteroidetes ratio were caused due to excessively high carbonate alkalinity (15 mmol/L) and excessively low dietary phosphorus supply (3.6 g/kg). Collectively, 7.0 g/kg dietary phosphorus supplementation was effective in promoting intestinal antioxidant enzyme activities and the corresponding gene expression the Keap1-Nrf2 signaling pathway and in enhancing intestinal immunity by upregulating anti-inflammatory and downregulating pro-inflammatory genes. Appropriate dietary phosphorus supply could promote the formation of beneficial microflora in freshwater, and it has the potential ability to transfer the adverse effect of carbonate alkalinity stress to the structural composition of intestinal microflora. Hence, consideration should be given to suitable phosphorus supply for fish under the chronic carbonate alkalinity stress.
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http://dx.doi.org/10.3389/fimmu.2022.900793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278090PMC
July 2022

Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia.

J Exp Clin Cancer Res 2022 Jul 16;41(1):225. Epub 2022 Jul 16.

Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.

Background: Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis.

Methods: ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells.

Results: We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells.

Conclusions: In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.
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http://dx.doi.org/10.1186/s13046-022-02428-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288051PMC
July 2022

Physiologically Based Pharmacokinetics Modeling in Biopharmaceutics: Case Studies for Establishing the Bioequivalence Safe Space for Innovator and Generic Drugs.

Pharm Res 2022 Jul 15. Epub 2022 Jul 15.

Pharmaceutical Sciences, MRL, Merck & Co., Inc., Rahway, New Jersey, 07065, USA.

For successful oral drug development, defining a bioequivalence (BE) safe space is critical for the identification of newer bioequivalent formulations or for setting of clinically relevant in vitro specifications to ensure drug product quality. By definition, the safe space delineates the dissolution profile boundaries or other drug product quality attributes, within which the drug product variants are anticipated to be bioequivalent. Defining a BE safe space with physiologically based biopharmaceutics model (PBBM) allows the establishment of mechanistic in vitro and in vivo relationships (IVIVR) to better understand absorption mechanism and critical bioavailability attributes (CBA). Detailed case studies on how to use PBBM to establish a BE safe space for both innovator and generic drugs are described. New case studies and literature examples demonstrate BE safe space applications such as how to set in vitro dissolution/particle size distribution (PSD) specifications, widen dissolution specification to supersede f2 tests, or application toward a scale-up and post-approval changes (SUPAC) biowaiver. A workflow for detailed PBBM set-up and common clinical study data requirements to establish the safe space and knowledge space are discussed. Approaches to model in vitro dissolution profiles i.e. the diffusion layer model (DLM), Takano and Johnson models or the fitted PSD and Weibull function are described with a decision tree. The conduct of parameter sensitivity analyses on kinetic dissolution parameters for safe space and virtual bioequivalence (VBE) modeling for innovator and generic drugs are shared. The necessity for biopredictive dissolution method development and challenges with PBBM development and acceptance criteria are described.
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http://dx.doi.org/10.1007/s11095-022-03319-6DOI Listing
July 2022

Retraction notice to "Znhit1 inhibits breast cancer by up-regulating PTEN to deactivate the PI3K/Akt/mTOR pathway" [Life Sci. 224 (2019) 204-211].

Life Sci 2022 09 13;305:120746. Epub 2022 Jul 13.

Department of Breast Surgery, The First Hospital of Jilin University, Changchun 130021, China.

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http://dx.doi.org/10.1016/j.lfs.2022.120746DOI Listing
September 2022

Topical Neck Cooling Without Systemic Hypothermia Attenuates Myocardial Ischemic Injury and Post-ischemic Reperfusion Injury.

Front Cardiovasc Med 2022 28;9:893837. Epub 2022 Jun 28.

Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States.

Background: Following acute myocardial infarction (MI), irreversible damage to the myocardium can only be reduced by shortening the duration between symptom onset and revascularization. While systemic hypothermia has shown promising results in slowing pre-revascularization myocardial damage, it is resource intensive and not conducive to prehospital initiation. We hypothesized that topical neck cooling (NC), an easily implemented therapy for en route transfer to definitive therapy, could similarly attenuate myocardial ischemia-reperfusion injury (IRI).

Methods: Using an mouse model of myocardial IRI, moderate systemic hypothermia or NC was applied following left coronary artery (LCA) occlusion and subsequent reperfusion, at early, late, and post-reperfusion intervals. Vagotomy was performed after late NC in an additional group. Hearts were harvested to measure infarct size.

Results: Both hypothermia treatments equally attenuated myocardial infarct size by 60% compared to control. The infarct-sparing effect of NC was temperature-dependent and timing-dependent. Vagotomy at the gastroesophageal junction abolished the infarct-sparing effect of late NC. Cardiac perfusate isolated following ischemia had significantly reduced cardiac troponin T, HMGB1, cell-free DNA, and interferon α and β levels after NC.

Conclusions: Topical neck cooling attenuates myocardial IRI in a vagus nerve-dependent manner, with an effect comparable to that of systemic hypothermia. NC attenuated infarct size when applied during ischemia, with earlier initiation resulting in superior infarct sparing. This novel therapy exerts a cardioprotective effect without requiring significant change in core temperature and may be a promising practical strategy to attenuate myocardial damage while patients await definitive revascularization.
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http://dx.doi.org/10.3389/fcvm.2022.893837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274088PMC
June 2022
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