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Yan Guo,1,* Jing-Jing Pan,2,* Wen Zhu,1 Mu-Zi Wang,3 Tian-Yu Liu,4 Xiao-Xin Wang,5 Qian-Qian Wu,1 Yi-Xin Cheng,1 Yi-Sen Qian,1 Xiao-Guang Zhou,1 Yang Yang1 1Department of Neonatology, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Neonatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, People’s Republic of China; 4Department of Neonatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, People’s Republic of China; 5Department of Pediatrics, Shandong Tumor Hospital, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Guang Zhou; Yang Yang, Department of Neonatology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email gzzhouxg@163.com; yy860507@126.comObjective: This prospective study is to explore the role of specific circRNAs in predicting the development of bronchopulmonary dysplasia (BPD).Methods: From July 1, 2021 to December 1, 2021, peripheral blood samples were collected from 62 premature infants with gestational age (GA) ≤ 32 weeks on the 7th, 14th, and 28th day after birth. Then, on the 28th day, the included infants were divided into the BPD group and the non-BPD group according to the definition of BPD. Serum exosomal circRNAs from peripheral blood were identified, sequenced, and compared between the BPD and non-BPD groups at different time points. Specific differentially expressed circRNAs were further verified from another 42 enrolled premature infants (GA ≤ 32 weeks). The classical lung biological markers in serum were also measured simultaneously.Results: Hsa_circ_0001359 in serum exosomes showed continuous differential expression between the BPD group and the non-BPD group on the 7th, 14th, and 28th day. Compared with that, classical lung biological markers like IL-6, IL-33, KL-6, and ET-1 did not exhibit continuous differences. Moreover, the expression of hsa_circ_0001359 on day 7 had a higher predictive value in predicting BPD (area under curve:0.853, 95% CI:0.738– 0.968; adjusted odds ratio:6.033, 95% CI:2.373– 13.326). The calibration curve further showed the mean absolute error = 0.033, mean squared error = 0.00231, and quantile of absolute error = 0.058.Conclusion: Hsa_circ_0001359 in serum exosomes is a promising marker for predicting BPD in preterm infants with gestational age ≤ 32 weeks.Keywords: bronchopulmonary dysplasia, circular RNAs, high-throughput sequencing, preterm infants

Wei-Wei Tang,1,* Qingquan Wu,3,* Su-Qing Li,1 Yu-Suo Tong,1 Zi-Hao Liu,1 Tong-Xin Yang,1 Yong Xu,1,2 Xiu-Feng Cao1 1Department of Surgical Oncology, Nanjing First Hospital, 2Cancer Center, Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Cardiothoracic Surgery, Huaian No 1 People’s Hospital, Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China *Indicates both are first authors Abstract: Long non-coding RNAs (lncRNAs), transcripts as longer than 200 nt in length with a great number of varieties in human genomics, play important roles in the regulation of genetics and epigenetics including gene transcription and post-transcription. Increasing evidence have demonstrated the upregulation of lncRNAs in tumorigenesis and metastasis of esophageal cancer (EC), a type of malignant tumors particularly in Asia. In this review, we briefly discuss the profiles and functions of lncRNAs involved in the progression of EC, which may provide a new approach to improve EC diagnosis and treatment. Keywords: long non-coding RNAs, esophageal cancer, biomarker, review

Yan Chen, Lei Zhou, Ling Yuan, Zhen-hai Zhang, Xuan Liu, Qingqing WuKey Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, Jiangsu, ChinaBackground: Nanostructured lipid carriers (NLCs) are attractive materials for topical drug delivery, and in a previous study, we demonstrated that NLCs loaded with tripterine enhance its deposition. However, the surface charge of nanoparticles influences percutaneous drug penetration. Therefore, we aimed to evaluate the influence of the surface charge of NLCs on in vitro skin permeation and in vivo pharmacodynamics of tripterine and optimize tripterine-loaded NLCs for the treatment of skin diseases.Methods: Different solid and liquid matrices were selected to prepare cationic, anionic, and neutral NLCs by the solvent evaporation method. The in vitro studies were evaluated by using Franz diffusion cells. The effect of surface-charged NLCs on cellular uptake was appraised across HaCaT and B16BL6 cells. The in vitro and in vivo anticancer activity of surface-charged NLCs was evaluated in B16BL6 cells and melanoma-bearing mice, respectively.Results: The average particle sizes of the cationic, anionic, and neutral NLCs were 90.2 ± 9.7, 87.8 ± 7.4, and 84.5 ± 10.2 nm, respectively; their encapsulation efficiencies were 64.3% ± 5.1%, 67.8% ± 4.4%, and 72.5% ± 4.9%, respectively. In vitro studies showed delayed tripterine release, and the order of skin permeation was cationic NLCs > anionic NLCs > neutral NLCs. Further, in vitro cytotoxicity studies showed that the cationic NLCs had the highest (P < 0.05) inhibition ratio in B16BL6 (melanoma) cells. Moreover, in vivo pharmacodynamic experiments in melanoma-bearing mice indicated that the cationic NLCs had significantly higher (P < 0.05) antimelanoma efficacy than the anionic and neutral NLCs.Conclusion: The surface charge of NLCs has a great influence on the skin permeation and pharmacodynamics of tripterine. Cationic tripterine-loaded NLCs could enhance the percutaneous penetration and antimelanoma efficacy of tripterine and offer several advantages over tripterine alone. Therefore, they are promising carriers of tripterine for topical antimelanoma therapy.Keywords: surface charge, nanostructured lipid carriers, tripterine, percutaneous penetration, cellular uptake, antimelanoma efficacy

Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C max ) and the area under the concentration-time curve (AUC 0-t ) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. Systematic Review Registration: http://www.chinadrugtrials.org.cn, identifier CTR20210064., Competing Interests: Authors Q-BL, Y-JZ, Y-LZh, LD, Y-LZu, and LL were employed by Sunshine Lake Pharma Co, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gui, Wang, Wu, Ding, Qian, Lu, Zhang, Zhuang, Deng, Zuo, Luo and Jia.)

The asymmetrical distribution of auxin supports high intensity blue light (HBL)-mediated phototropism. Flavonoids, secondary metabolites induced by blue light and TRANSPARENT TESTA GLABRA1 (TTG1), alter auxin transport. However, the role of TTG1 in HBL-induced phototropism in Arabidopsis (Arabidopsis thaliana) remains unclear. We found that TTG1 regulates HBL-mediated phototropism. HBL-induced degradation of CRYPTOCHROME 1 (CRY1) was repressed in ttg1-1, and depletion of CRY1 rescued the phototropic defects of the ttg1-1 mutant. Moreover, overexpression of CRY1 in a cry1 mutant background led to phototropic defects in response to HBL. These results indicated that CRY1 is involved in the regulation of TTG1-mediated phototropism in response to HBL. Further investigation showed that TTG1 physically interacts with CRY1 via its N-terminus and that the added TTG1 promotes the dimerization of CRY1. The interaction between TTG1 and CRY1 may promote HBL-mediated degradation of CRY1. TTG1 also physically interacted with blue light inhibitor of cryptochrome 1 (BIC1) and Light-Response Bric-a-Brack/Tramtrack/Broad 2 (LRB2), and these interactions either inhibited or promoted their interaction with CRY1. Exogenous gibberellins (GA) and auxins, two key plant hormones that crosstalk with CRY1, may confer the recovery of phototropic defects in the ttg1-1 mutant and CRY1-overexpressing plants. Our results revealed that TTG1 participates in the regulation of HBL-induced phototropism by modulating CRY1 levels, which are coordinated with GA or IAA signaling., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Langerhans cell histiocytosis (LCH) involving the gastrointestinal tract is a rare condition for which clinical experience is limited. We describe the cases of two patients who initially presented with chronic diarrhoea, hypoproteinaemia, and intermittent fever. These findings suggest that in cases of refractory diarrhoea accompanied by recurrent hypoalbuminaemia, especially with abdominal rash, LCH should be considered. Gastrointestinal endoscopy, biopsy, and imaging studies are essential for obtaining a definitive diagnosis. This approach might be helpful for the early recognition of gastrointestinal tract involvement in LCH., (© 2024. The Author(s).)

Recently, organic photoelectrochemical transistor (OPECT) bioanalysis has become a prominent technique for the high-performance detection of biomolecules. However, as a sensitive index of the OPECT, the dynamic regulation transconductance ( g m ) is still severely deficient. Herein, this work reports a new photosensitive metal-organic framework (MOF-on-MOF) heterostructure for the effective modulation of maximum g m and natural bienzyme interfacing toward choline detection. Specifically, the bidentate ligand MOF (b-MOF) was assembled onto the UiO-66 MOF (u-MOF) by a modular assembly method, which could facilitate the charge separation and generate enhanced photocurrents and offer a biophilic environment for the immobilization of choline oxidase (ChOx) and horseradish peroxidase (HRP) through hydrogen-bonded bridges. The transconductance of the OPECT could be flexibly altered by increased light intensity to maximal value at zero gate bias, and sensitive choline detection was achieved with a detection limit of 0.2 μM. This work reveals the potential of MOF-on-MOF heterostructures for futuristic optobioelectronics.

Purpose: Extensively-drug-resistant Gram-negative bacteria (XDR GNB)-related post-neurosurgical infection is closely related to mortality, which represents a major challenge for neurosurgeons. There is an urgent need to review and evaluate methods to reduce mortality., Methods: Both international and Chinese databases were searched independently from their inception to 15 June 2023. A meta-analysis was conducted using RevMan 5.4 to compare the efficacy and safety of intravenous (IV) treatment in combination with intrathecal or intraventricular (ITH/IVT) treatment with IV treatment alone for post-neurosurgical meningitis or ventriculitis due to GNB. Mortality, microbiological clearance and adverse events were considered as primary outcomes., Results: In total, 18 eligible studies involving 602 patients were included in the meta-analysis. The IV + ITH/IVT group was associated with significantly lower mortality (especially in the XDR GNB subgroup) and acceptable safety. In terms of microbiological clearance, a significant decrease was shown in the XDR GNB subgroup. Significant benefits were shown in laboratory parameters and clinical symptoms after patients were treated with ITH/IVT., Conclusion: Additional ITH/IVT treatment may promote XDR GNB clearance and reduce mortality. In addition, ITH/IVT administration can improve clinical symptoms and cerebrospinal fluid indicators of patients with post-neurosurgical infections. Significantly, ITH/IVT treatment does not increase the incidence of adverse events at the recommended dose., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

The tropone skeleton exists in a number of natural products and bioactive substances, and currently, the applications of substituted tropones are significantly limited by their preparative methods. Herein, we report a very convenient method to access 2-alkyltropones via organic base-catalyzed tandem reaction of tropinone-derived quaternary ammonium salts. Tropinone methiodide reacted with a wide variety of aromatic and aliphatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane to afford structurally diverse 2-alkyltropones in moderate to excellent yields with extremely high site selectivity. The reaction employs readily available feedstocks and reagents, is free of transition metals and compatible with water and air, tolerates a variety of functional groups, and can be easily scaled up. Moreover, the products are amenable to various synthetic transformations. Preliminary mechanistic studies revealed that the reaction proceeded via tandem deamination, aldol condensation, and isomerization.

The canine transmissible venereal tumor (CTVT) is a clonal cell-mediated cancer with a long evolutionary history and extensive karyotype rearrangements in its genome. However, little is known about its genetic similarity to human tumors. Here, using multi-omics data we identified 11 germline gene fusions (GGFs) in CTVT, which showed higher genetic susceptibility than others. Additionally, we illustrate a mechanism of a complex gene fusion of three gene segments ( HSD17B4 - DMXL1 - TNFAIP8 ) that we refer to "greedy fusion". Our findings also provided evidence that expressions of GGFs are downregulated during the tumor regressive phase, which is associated with DNA methylation level. This study presents a comprehensive landscape of gene fusions (GFs) in CTVT, which offers a valuable genetic resource for exploring potential genetic mechanisms underlying the development of cancers in both dogs and humans., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Honeycomb sandwich structures have been widely used in the field of engineering owing to their outstanding mechanical properties. However, for a honeycomb sandwich structure with large spatial periodicity, there is a low-frequency sound insulation valley. Here, the sound transmission across locally resonant honeycomb sandwich meta-structures was investigated to overcome this sound-insulation valley. An analytical model was developed based on the space-harmonic approach and the low-frequency sound insulation valley was determined analytically and numerically. The results indicate that the resonator distributed at the center of the face panel has a significant impact on the sound transmission performance of the honeycomb sandwich structure, whereas the resonator distributed on the wall of the honeycomb core does not contribute to overcoming this sound-insulation valley. Based on the research results, a design strategy for overcoming this sound-insulation valley was determined by tuning the damping parameter and constructing graded resonators. Moreover, sound transmission under the excitation of oblique incidence sound waves was also investigated. Compared with the method of filling porous materials, the proposed design method is more effective, and more importantly, the mass of the resonator is only 1.23% of that of the porous materials., (© 2023 Acoustical Society of America.)

Background: Paraplegia after spinal cord ischemia is a devastating condition in the clinic. Here, we develop an awake rabbit model of spinal cord ischemia with delayed paraplegia and explore the influence of ambient temperature on the outcomes after injury., Methods: A total of 47 male rabbits were involved in the present study. Transient spinal cord ischemia was induced by occluding the infrarenal abdominal aorta of awake rabbits at different ambient temperatures. To find the optimal conditions for developing delayed paraplegia, hindlimb motor function after ischemia was evaluated between experiments., Results: The onset and magnitude of ischemic injury varied with the ambient temperature maintained during the peri-ischemia period. More serious spinal cord injury occurred when ischemia was induced at higher temperatures. At 18°C, 25-minute ischemia resulted in 74% of rabbits developing delayed paraplegia. At a temperature of 28°C or higher, most of the animals developed acute paraplegia immediately. While at 13°C, rabbits usually regained normal motor function without paraplegia., Conclusion: This awake rabbit model is highly reproducible and will be helpful in future studies of delayed paraplegia after spinal cord ischemia. The ambient temperature must be considered while using this model during investigation of therapeutic interventions., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling., (© 2023 Xu et al.)

Objectives: The surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron infections has affected most Chinese residents at the end of 2022, including a number of patients with systemic autoimmune rheumatic diseases (SARDs)., Methods: To investigate the antibody level of the Omicron variant in SARD patients after SARS-CoV-2 Omicron infection, we tested BA.5.2 and BF.7 Omicron variant IgG antibody levels using ELISA on blood samples collected from 102 SARD patients and 19 healthy controls (HCs). The type of SARD, demographics, concurrent treatment, doses of SARS-CoV-2 vaccines and outcomes were also recorded., Results: A total of 102 SARD patients (mean age: 40.3 years; 89.2% female), including 60 SLE, 32 RA and 10 other SARDs, were identified. Of these, 87 (85.3%) were infected with SARS-CoV-2. We found that the BA.5.2 and BF.7 antibody levels of infected SARD patients were lower than those of HCs ( P  <   0.05). Sixty-five (63.7%) patients had at least one dose of a SARS-CoV-2 vaccine. SARD patients with at least two doses of SARS-CoV-2 vaccine had a higher level of BA.5.2 and BF.7 antibodies than the unvaccinated group ( P  <   0.05). There was no evidence for a significant inhibitory effect of glucocorticoids (GCs) on the BA.5.2 and BF.7 Omicron variant antibody levels in SARD patients. SLE patients using biologic DMARDs had a lower BA.5.2 Omicron variant antibody level than patients using GCs and/or HCQ., Conclusion: These data suggest that patients with SARDs had a lower antibody response than HCs after Omicron infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To investigate the incidence of and factors influencing postoperative delirium (POD) in Parkinson disease after deep brain stimulation (DBS) surgery., Methods: A total of 272 patients with Parkinson disease who underwent DBS completed the Visual Impairment in Parkinson Disease Questionnaire (VIPD-Q) and underwent neuro-ophthalmologic examinations including optical coherence tomography and fundus vessel analysis. We retrospect the prevalence of POD in groups with different VIPD-Q scores, retinal nerve fiber layer (RNFL) thicknesses, and vessel percentage areas (VPA). A predictive model based on the VIPD-Q was constructed using multivariate logistic regression and verified using bootstrap validation., Results: POD was experienced by 65 (23.9%) of 272 patients. Patients with PD who had visual impairment (VIPD-Q > 6) had a higher incidence of POD (chi-square, P < 0.001). The thickness of the RNFL and VPA were also correlated with POD risk. Differences in implantation locations (subthalamic nucleus or pars interna of globus pallidus), operation times, and general anesthesia times did not affect the prevalence of DBS-related POD. A nomogram was constructed based on ophthalmic events to predict the risk of POD., Conclusions: The study findings provide convincing evidence of the relationship between visual dysfunction and the risk of POD. In view of the higher risk of POD, visually impaired patients with PD should undergo closer monitoring after DBS surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder affecting 10%-22% of adults. Its development is closely related to the gut microbiota, and the inflammatory and immune responses triggered by the gut microbiota can lead to IBS. Vitamin D (VD) effectively treats IBS with fewer side effects by improving gut microbiota, immune regulation, and anti-inflammatory effects. In the future, it is necessary to carry out epidemiological studies on the relationship between VD and IBS, clinical studies on the efficacy of supplementing VD to improve IBS, and animal studies on the mechanism of VD improving IBS. Therefore, this paper discussed the relationship between VD and IBS., Competing Interests: Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Neoadjuvant therapy favors the prognosis of various cancers, including esophagogastric junction cancer (EGC). However, the impacts of neoadjuvant therapy on the number of dissected lymph nodes (LNs) have not yet been evaluated in EGC., Methods: We selected EGC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2006-2017). The optimal number of resected LNs was determined using X-tile software. Overall survival (OS) curves were plotted with the Kaplan-Meier method. Prognostic factors were evaluated using univariate and multivariate COX regression analyses., Results: Neoadjuvant radiotherapy significantly decreased the mean number of LN examination compared to the mean number of patients without neoadjuvant therapy (12.2 vs. 17.5, P = 0.003). The mean LN number of patients with neoadjuvant chemoradiotherapy was 16.3, which was also statistically lower than 17.5 (P = 0.001). In contrast, neoadjuvant chemotherapy caused a significant increase in the number of dissected LNs (21.0, P < 0.001). For patients with neoadjuvant chemotherapy, the optimal cutoff value was 19. Patients with > 19 LNs had a better prognosis than those with 1-19 LNs (P < 0.05). For patients with neoadjuvant chemoradiotherapy, the optimal cutoff value was 9. Patients with  > 9 LNs had a better prognosis than those with 1-9 LNs (P < 0.05)., Conclusions: Neoadjuvant radiotherapy and chemoradiotherapy decreased the number of dissected LNs, while neoadjuvant chemotherapy increased it in EGC patients. Hence, at least 10 LNs should be dissected for neoadjuvant chemoradiotherapy and 20 for neoadjuvant chemotherapy, which could be applied in clinical practice., (© 2023. The Author(s).)

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. As the molecular mechanism for liver metastasis of CRC has not yet been completely discovered, identification of hub genes and pathways of this disease is of importance for revealing potential molecular mechanism of colorectal cancer progression. This study aimed to identify potential biomarkers and survival analysis of hub genes for CRC treatment., Methods: The differentially expressed genes (DEGs) between colorectal cancer liver metastasis and primary tumor were screened using microarray data from two datasets GSE179979, GSE144259 obtained from the Gene Expression Omnibus (GEO) database. Gene ontology (GO) and KEGG pathway enrichment analyses were performed for DEGs using DAVID database, the protein-protein interaction (PPI) network was constructed using the Cytoscape software, and module analysis was performed using MCODE. Then, overall survival (OS), progression free interval (PFI) and disease specific survival (DSS) analysis of hub genes was performed by using TCGA database. The correlations between hub genes and clinical values were validated through CRN and immunohistochemistry (IHC) stain., Results: A total of 64 DEGs were obtained, KEGG pathway analysis showed that the significant pathways included PPAR signaling pathway, Complement and coagulation cascades. Four hub genes (ITIH2, ALB, CPB2, HGFAC) and two biomarkers (CPB2, HGFAC) with significantly prognostic values were verified by Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) cohort., Conclusions: CPB2 and HGFAC may serve as new biomarkers in diagnosing liver metastasis of CRC or potential drug target., Competing Interests: Declaration of Competing Interest No competing interests for this article, (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Two classes of spiro[4 H -pyran-3,3'-oxindole] derivatives were prepared via the one pot reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile successfully catalyzed by a Tröger's base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1 H -pyrazol [b,f ][4,5]-1,5-diazadicyclo[3.3.1]-2,6-octadiene). The antibacterial activity of products against three wild-type bacteria ( B. subtilis, S. aureus , and E. coli) and two resistant strains (Methicillin-resistant S. aureus (18H 8 ) and E. coli carrying the BlaNDM-1 gene (18H 5 )) was evaluated using the minimum inhibitory concentration (MIC).., Methods: 1-Phenyl-1,3-butanedione 2 or dibenzoylmethane 2' (0.42 mmol), substituted isatin 3 (0.4 mmol), malononitrile 4 (0.8 mmol), Tröger's base derivative 1b (0.08 mmol), and 10 mL of acetonitrile were added to a 50 mL round bottom flask and refluxed. After the completion (TLC monitoring), water (10 mL) was added to the reaction mixture; pH = 7 was adjusted with saturated NaHCO 3 (aq.), and the mixture was extracted with CH 2 Cl 2 (50 mL × 3). Organic layers were combined and dried with anhydrous Na 2 SO 4 ; the solvent was removed under vacuum, and the residue was purified by column chromatography (V DCM : V MeOH = 80: 1) to afford product 5. The antibacterial activity was tested by the MTT method., Results: Seventeen spiro[4 H -pyran-3,3'-oxindole] derivatives were synthesized through the reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins, and malononitrile in one-pot in medium to high yields. Four compounds showed antibacterial activity, and two of them showed the same activity as the positive control Ceftazidime on S. aureus (MIC = 12.5 μg/mL)., Conclusion: Two classes of spiro[4 H -pyran-3,3'-oxindole] derivatives were prepared, and their antibacterial activity was evaluated. Tröger's base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1 H -pyrazol[ b,f ][4,5]- 1,5-diazadicyclo[3,3,1]-2,6-octadiene) was used as an efficient organocatalyst for the reaction of low reactive chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins, and malononitrile in one-pot successfully and effectively by providing multiple active sites and alkaline environment. By the theoretical calculation, we explained the possible reaction sequence and mechanism. Due to the superiority and high efficiency of the TB framework as an organocatalyst, the reaction showed many advantages, including mild reaction conditions, low catalyst loading, and a wide substrate range. It expanded the application of Tröger's base to the multicomponent reaction in organocatalysis. Some products were screened due to their high antibacterial activity in vitro , showing their potential in new antibacterial drug development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The toxicity of triphenyl phosphate (TPhP) to aquatic organisms in surface waters has been demonstrated; However, an understanding of toxicity profiles of TPhP in amphibians is limited. Therefore, the adverse effects and threshold concentrations of TPhP on metamorphosis, growth, locomotion, and hepatic antioxidants of Gosner stage 25 Polypedates megacephalus tadpoles under long-term (35 d) exposure to six TPhP concentrations until complete metamorphosis were assessed. Additionally, the overall effect of using integrated multiple biomarkers were determined to demonstrate the potential ecological risks of waterborne TPhP at environmentally relevant concentrations in amphibian tadpoles. With increasing TPhP concentrations, physical parameters (snout-vent length, body mass, condition factor, and hepatic somatic index), jumping distance, hepatic catalase, and superoxide dismutase activities decreased, whereas metamorphosis time and malondialdehyde content increased. The threshold concentration of TPhP that affected the tadpole biomarker, except for metamorphosis rate and jumping distance, was 50-400 μg/L. Furthermore, the standardized scores of the examined integrated biomarkers in the six TPhP concentrations were visualized using radar plots and calculated as the integrated biomarker responses (IBRs). The varying TPhP concentrations had different scores in the radar plots, and the threshold for affecting the IBR value was 10 μg/L, which was close to the TPhP concentration in surface waters. Additionally, IBR values were strongly positively correlated with the TPhP concentrations. These findings indicate that environmentally relevant exposure to waterborne TPhP can pose an ecological risk to amphibian tadpoles. This study can serve as a reference and assist in the formulation of relevant policies and strategies to control TPhP pollution in water bodies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and C max increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T 1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for C max and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on C max and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19., (© 2022. The Author(s).)

Background and Purpose: This study aims to evaluate whether dosimetric parameters affect the intrahepatic out-field recurrence or distant metastasis-free survival following the stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC)., Materials and Methods: A total of 76 patients with HCC who were treated with SBRT from January 2015 to May 2020 were included in this retrospective study. The main clinical endpoints considered were intrahepatic out-field free survival (OutFFS) and distant metastasis-free survival (DMFS). The target parameters and the liver were documented including tumor diameters, gross tumor volume (GTV), Liver minus GTV volume (LGV), and Liver minus GTV mean dose (LGD). Multivariable Cox regression with forward stepwise selection was performed to identify independent risk factors for OutFFS and DMFS. Maximally selected rank statistics were used to determine the most informative cut-off value for age and LGD., Results: The median follow-up was 28.2 months (range, 7.7-74.5 months). LGD higher than 12.54 Gy [HR, 0.861(0.747-0.993); p = 0.040] and age greater than 67-year-old [HR, 0.966(0.937-0.997); p = 0.030] are two independent predictors of OutFFS, previous TACE treatment [HR, 0.117(0.015-0.891); p = 0.038] was an independent predictor of DMFS., Conclusions: The results of this study suggested that the higher the dose received by the normal liver (greater than 12.54 Gy) the better the intrahepatic out-field recurrence-free survival (RFS) rate. Further study is warranted to confirm and to better understand this phenomenon., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Visual impairment is a common non-motor symptom (NMS) in patients with Parkinson's disease (PD) and its implications for cognitive impairment remain controversial. We wished to survey the prevalence of visual impairment in Chinese Parkinson's patients based on the Visual Impairment in Parkinson's Disease Questionnaire (VIPD-Q), identify the pathogens that lead to visual impairment, and develop a predictive model for cognitive impairment risk in Parkinson's based on ophthalmic parameters., Methods: A total of 205 patients with Parkinson's disease and 200 age-matched controls completed the VIPD-Q and underwent neuro-ophthalmologic examinations, including ocular fundus photography and optical coherence tomography. We conducted nomogram analysis and the predictive model was summarized using the multivariate logistic and LASSO regression and verified via bootstrap validation., Results: One or more ophthalmologic symptoms were present in 57% of patients with Parkinson's disease, compared with 14% of the controls (χ 2 -test; p < 0.001). The visual impairment questionnaire showed good sensitivity and specificity (area under the curve [AUC] = 0.918, p < 0.001) and a strong correlation with MoCA scores (Pearson r = -0.4652, p < 0.001). Comparing visual impairment scores between pre- and post-deep brain stimulation groups showed that DBS improved visual function ( U -test, p < 0.001). The thickness of the retinal nerve fiber layer and vessel percentage area predicted cognitive impairment in PD., Interpretation: The study findings provide novel mechanistic insights into visual impairment and cognitive decline in Parkinson's disease. The results inform an effective tool for predicting cognitive deterioration in Parkinson's based on ophthalmic parameters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Wu, Hou, Wang, Zhang, Zhao, Wang, Wang and Li.)

Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.• Tax1bp1 may become a target of new therapeutic methods for treating heart failure., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Cathepsin B (CTSB), a member of lysosomal cathepsin, is involved in cell autophagy and apoptosis. We previously reported that CTSB increased cardiomyocyte apoptosis in mice heart during pressure overload, while the role of CTSB on diabetic cardiomyopathy has not been fully elucidated. The aim of this study is to explore the role and the underlying mechanism of CTSB on diabetic cardiomyopathy. Mice were subjected to streptozotocin injection to induce a diabetes model. Neonatal rat cardiomyocytes were isolated and cultured with high glucose (33.3 mM) to establish an in vitro model. CTSB protein level was increased in diabetic cardiomyopathy (DCM) mice heart as well as in cardiomyocytes stimulated with high glucose. CTSB knockout mice showed ameliorated cardiac function, cardiac fibrosis, cardiac inflammation, and pyroptosis level. Oppositely, DCM mice with CTSB transgene showed exacerbated cardiac dysfunction, fibrosis, inflammation, and pyroptosis. We found that CTSB could bind to NLR family pyrin domain containing 3 (NLRP3), thus increasing the activation of the NLRP3/caspase-1 inflammasome pathway. When we used a NLRP3 knockout mice, the deteriorating effect of CTSB overexpression via adeno-associated virus (AAV)9 delivery was abolished. Taken together, CTSB aggravates diabetic cardiomyopathy via promoting NLRP3-mediated pyroptosis., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Author(s).)

Introduction: Osteogenesis imperfecta (OI) is a rare mendelian skeletal dysplasia with autosomal dominant or recessive inheritance pattern, and almost the most common primary osteoporosis in prenatal settings. The diversity of clinical presentation and genetic etiology in prenatal OI cases presents a challenge to counseling yet has seldom been discussed in previous studies., Methods: Ten cases with suspected fetal OI were enrolled and submitted to a genetic detection using conventional karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES). Sanger sequencing was used as the validation method for potential diagnostic variants. In silico analysis of specific missense variants was also performed., Results: The karyotyping and CMA results of these cases were normal, while WES identified OI-associated variants in the COL1A1/2 genes in all ten cases. Six of these variants were novel. Additionally, four cases here exhibited distinctive clinical and/or genetic characteristics, including the situations of intrafamilial phenotypic variability, parental mosaicism, and "dual nosogenesis" (mutations in collagen I and another gene)., Conclusion: Our study not only expands the spectrum of COL1A1/2 -related OI, but also highlights the complexity that occurs in prenatal OI and the importance of clarifying its pathogenic mechanisms.

Background: For patients with portal hypertension (PH), portal vein thrombosis (PVT) is a fatal complication after splenectomy. Postoperative platelet elevation is considered the foremost reason for PVT. However, the value of postoperative platelet elevation rate (PPER) in predicting PVT has never been studied., Aim: To investigate the predictive value of PPER for PVT and establish PPER-based prediction models to early identify individuals at high risk of PVT after splenectomy., Methods: We retrospectively reviewed 483 patients with PH related to hepatitis B virus who underwent splenectomy between July 2011 and September 2018, and they were randomized into either a training ( n = 338) or a validation ( n = 145) cohort. The generalized linear (GL) method, least absolute shrinkage and selection operator (LASSO), and random forest (RF) were used to construct models. The receiver operating characteristic curves (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were used to evaluate the robustness and clinical practicability of the GL model (GLM), LASSO model (LSM), and RF model (RFM)., Results: Multivariate analysis exhibited that the first and third days for PPER (PPER1, PPER3) were strongly associated with PVT [odds ratio (OR): 1.78, 95% confidence interval (CI): 1.24-2.62, P = 0.002; OR: 1.43, 95%CI: 1.16-1.77, P < 0.001, respectively]. The areas under the ROC curves of the GLM, LSM, and RFM in the training cohort were 0.83 (95%CI: 0.79-0.88), 0.84 (95%CI: 0.79-0.88), and 0.84 (95%CI: 0.79-0.88), respectively; and were 0.77 (95%CI: 0.69-0.85), 0.83 (95%CI: 0.76-0.90), and 0.78 (95%CI: 0.70-0.85) in the validation cohort, respectively. The calibration curves showed satisfactory agreement between prediction by models and actual observation. DCA and CIC indicated that all models conferred high clinical net benefits., Conclusion: PPER1 and PPER3 are effective indicators for postoperative prediction of PVT. We have successfully developed PPER-based practical models to accurately predict PVT, which would conveniently help clinicians rapidly differentiate individuals at high risk of PVT, and thus guide the adoption of timely interventions., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Purpose: To evaluate the different response patterns after Stereotactic Body Radiation Therapy (SBRT) and their predictive value in local control and progression of hepatocellular carcinoma (HCC)., Materials and Methods: Seventy-two HCC patients who were treated with SBRT during 2015-2020 were included in this retrospective study. The assessment was made using MRI, CT, and PET-CT. Local and systemic responses were determined according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria during follow up. Patients were categorized as early responders (complete response during 6 months after radiotherapy) or non-early responders (the rest of the patients). Prognostic factors were determined using multivariate logistic models., Results: The median follow-up was 24.0 months (range, 7.7-74.5 months). We found that 84.7%（61/72) of patients achieved a complete response. Early responses occurred in 45 patients (45/72, 62.5%), and they had 1-, 2-, and 5- year intrahepatic outfield-free survival (OutFFS) rates of 86.2%, 80.3%, and 76.3% vs. 55.3%, 44.7%, and 33.5% in non-early responses patients, whereas the 1-, 2-, and 5- year distant metastasis-free survival (DMFS) were 95.5%, 84.5% and 79.5% and 74.1%, 56.2% and 56.2%, respectively. The 1-, 2-, and 5-year overall survival (OS) were 97.7%, 92.1%, 79.1%, and 85.2%, 53.8%, and 40.3%, respectively. Multivariate analysis revealed that early tumor response was an independent predictor of OutFFS, DMFS, and OS., Conclusions: Early complete tumor response within 6 months after radiotherapy predicted better intrahepatic outfield-free survival, distant metastasis-free survival, and overall survival outcomes. Confirmation is warranted for early response on SBRT to guide decision making., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Spermatogenesis is a complex biological process that produces haploid spermatozoa and requires precise regulation by many tissue-specific factors. In this study, we explored the role and mechanism of Fork head box J2 (FOXJ2, which is highly expressed in spermatocytes) in the regulation of spermatogenesis using a germline-specific conditional Foxj2 knock-in mouse model (Stra8-Cre; Foxj2 tg/tg mouse). Foxj2 overexpression in mouse testes led to spermatogenesis failure, which started at the initiation of meiosis, and resulted in male infertility. Lysosomes and autophagy-related genes were upregulated in Stra8-cre; Foxj2 tg/tg mouse testes and the number of autolysosomes in the spermatocytes in Stra8-cre; Foxj2 tg/tg mice was increased. Chromatin immunoprecipitation-PCR and Dual-luciferase reporter assays showed that Lamp2 (encoding lysosome-associated membrane protein-2) was a target of FOXJ2. Foxj2 overexpression increased the expression levels of Lamp2a and Hsc70 (70-kDa cytoplasmic heat shock protein) in the Stra8-cre; Foxj2 tg/tg mouse testes. Our results suggested that Foxj2 overexpression in the germ cells of mouse testes affects chaperone-mediated autophagy by upregulating LAMP2A, leading to spermatogenesis failure at the initiation of meiosis, thus resulting in male infertility. Our findings provide a new insight into the function of FOXJ2 in spermatogenesis and the significance of autophagy regulation in spermatogenesis., (© 2022. The Author(s).)

Pancreatic β cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of β cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of β cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues β cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention-induced preservation of β cell function. CTCF expression is markedly decreased in β cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate β cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for β cell glucose metabolism and stress response., (© 2022 Wang et al.)

Epidemiological studies suggest a bidirectional association between depression and obesity; however, the biological mechanisms that link the development of depression to a metabolic disorder remain unclear. Even though nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists show anti-depressive effect, and high-fat diet-(HFD)-induced PPARγ dysfunction is involved in the pathogenesis of metabolic disorders, the neuronal PPARγ has never been studied in HFD-induced depression. Thus, we aimed to investigate the effect of neuronal PPARγ on depressive-like behaviors in HFD-induced obese mice.We fed male C57BL/6 J mice with HFD to generate obese mice and conducted a series of behavioral tests to assess the effects of HFD feeding on depression. We generated neuron-specific PPARγ knockout mice (NKO) to determine whether neuronal PPARγ deficiency was correlated with depressive-like behaviors. To further prove whether PPARγ in the medial prefrontal cortex (mPFC) neurons is involved in depressive-like behaviors, we applied AAV- CaMKIIα-Cre approach to specifically knockout PPARγ in the mPFC neurons of LoxP mice and used AAV-syn-PPARγ vectors to overexpress PPARγ in the mPFC neurons of NKO mice.We observed a low mPFC PPARγ level and an increase in depressive-like behaviors in the HFD-fed mice. Moreover, neuronal-specific PPARγ deficiency in mice induced depressive-like behaviors, which could be abolished by imipramine. Furthermore, overexpressing PPARγ in the mPFC reversed the depressive-like behaviors in HFD-fed mice as well as in neuronal-specific PPARγ knockout mice.These results implicate that dysregulation of neuronal PPARγ in the mPFC may contribute to an increased risk for depression in obese populations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We have previously shown that natural killer (NK) cells expand, and increase their function after interaction with cells that exhibit a number of different knock-down genes. We hypothesized that deletion or knockdown of a variety of key genes such as RAG may cause de-differentiation of the cells which could lead to increased NK expansion and function since we have shown previously that NK cells are activated and expanded by less differentiated cells. When comparing the function of NK cells from bone marrow (BM), spleen, pancreas, adipose tissue, and gingiva from WT mice to those from Rag2 -/- mice, we observed a significant increase in IFN-γ secretion in all tissues of Rag2 -/- mice versus in WT mice, with the exception of the gingivae in which similar levels were observed. After injecting WT mice with zoledronic acid (ZOL) and tooth extraction, immune cells from BM, spleen, and purified NK cells from spleen exhibited very high induction of IFN-γ and NK cell-mediated cytotoxicity with the exception of gingiva in which immune cells exhibited the opposite. In Rag2 -/- mice, ZOL injection and tooth extraction stimulated IFN-γ secretion from BM immune cells but inhibited IFN-γ secretion from both spleen and gingivae. In both WT and Rag2 -/- mice, immune cells from gingivae exhibited decreased IFN-γ secretion when activated, indicating significant regulation of immune cell function in the gingival microenvironment. However, even though significantly lower induction of IFN-γ was observed in both WT and Rag2 -/- gingival cells after ZOL injection, ZOL mediated secretion of IFN-γ was still higher in the gingivae of WT mice when compared to those of Rag2 -/- gingival cells. These results suggest an important role for IFN-γ in the pathogenesis of osteonecrosis lesions observed in post-tooth extraction jawbone., (Copyright © 2022. Published by Elsevier Inc.)

Exosomes, one of three main types of extracellular vesicles, are ~30-100 nm in diameter and have a lipid bilayer membrane. They are widely distributed in almost all body fluids. Exosomes have the potential to regulate unknown cellular and molecular mechanisms in intercellular communication, organ homeostasis, and diseases. They are critical signal carriers that transfer nucleic acids, proteins, lipids, and other substances into recipient cells, participating in cellular signal transduction and material exchange. ncRNAs are non-protein-coding genes that account for over 90% of the genome and include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). ncRNAs are crucial for physiological and pathological activities in the liver by participating in gene transcription, posttranscriptional epigenetic regulation, and cellular processes through interacting with DNA, RNA, or proteins. Recent evidence from both clinical and preclinical studies indicates that exosome-derived noncoding RNAs (ncRNAs) are highly involved in the progression of acute and chronic liver diseases by regulating hepatic lipid metabolism, innate immunity, viral infection, fibrosis, and cancer. Therefore, exosome-derived ncRNAs have promising potential and clinical implications for the early diagnosis, targeted therapy, and prognosis of liver diseases., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

A study addressing the influence of type 2 diabetes on the prognosis of acute-on-chronic liver failure patients was reviewed. Some statistical deficiencies were found in the reviewed article, and the sample size was too small to support the study. In addition, age should have been considered as one of the prognostic factors., Competing Interests: Conflict-of-interest statement: Each author has reviewed the statement by the Baishideng Publishing Group on conflict of interest, and every author stated that there is no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Children with intestinal failure (IF) have frequent catheter-related bloodstream infections (CRBSIs). This study aimed to analyze the clinical presentation and laboratory parameters of CRBSIs in children with IF., Methods: This 6-year retrospective study was conducted among IF children with CRBSIs at an intestinal rehabilitation center in China. Clinical data were collected, including data of temperature and gastrointestinal symptoms. Blood/catheter culture, fecal tests, and calculation of inflammatory index were performed, which were obtained within 1 week since CRBSI onset., Results: Fifty children with 87 CRBSIs were identified, of which there were 17 suspected and 70 confirmed cases. Seventy-two pathogens were cultured from 70 positive blood cultures: 63% were Gram-positive organisms, 23% were Gram-negative organisms, and 11% were fungal organisms. Overall, 48.6% were enteric organisms; 47.2% of bacterial pathogens were consistent between fecal and blood cultures. Moreover, 46.3% fecal routines showed abnormalities including increased white blood cells, occult blood positive and the presence of fat droplets. The consistent symptom at onset of CRBSIs was fever and gastrointestinal symptoms including increased stool output, abdominal distension, or both. C-reactive protein (CRP) and procalcitonin (PCT) were elevated, i.e., 16.5 mg/L [interquartile range (IQR) 8.7-44.7] and 0.48 ng/mL (IQR 0.2-1.76), respectively., Conclusions: IF children had a high rate of CRBSIs, of which larger proportions were due to Gram-positive and enteric organisms. Fever and/or gastrointestinal symptoms, combined with elevated CRP and PCT, is conducive to the early diagnosis of CRBSIs in IF patients., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Background: This study aims to validate the diagnostic accuracy of the International Ovarian Tumor Analysis (IOTA) the Assessment of Different NEoplasias in the adneXa (ADNEX) model in the preoperative diagnosis of adnexal masses in the hands of nonexpert ultrasonographers in a gynaecological oncology centre in China., Methods: This was a single oncology centre, retrospective diagnostic accuracy study of 620 patients. All patients underwent surgery, and the histopathological diagnosis was used as a reference standard. The masses were divided into five types according to the ADNEX model: benign ovarian tumours, borderline ovarian tumours (BOTs), stage I ovarian cancer (OC), stage II-IV OC and ovarian metastasis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of the ADNEX model to classify tumours into different histological types with and without cancer antigen 125 (CA 125) results., Results: Of the 620 women, 402 (64.8%) had a benign ovarian tumour and 218 (35.2%) had a malignant ovarian tumour, including 86 (13.9%) with BOT, 75 (12.1%) with stage I OC, 53 (8.5%) with stage II-IV OC and 4 (0.6%) with ovarian metastasis. The AUC of the model to differentiate benign and malignant adnexal masses was 0.97 (95% CI, 0.96-0.98). Performance was excellent for the discrimination between benign and stage II-IV OC and between benign and ovarian metastasis, with AUCs of 0.99 (95% CI, 0.99-1.00) and 0.99 (95% CI, 0.98-1.00), respectively. The model was less effective at distinguishing between BOT and stage I OC and between BOT and ovarian metastasis, with AUCs of 0.54 (95% CI, 0.45-0.64) and 0.66 (95% CI, 0.56-0.77), respectively. When including CA125 in the model, the performance in discriminating between stage II-IV OC and stage I OC and between stage II-IV OC ovarian metastasis was improved (AUC increased from 0.88 to 0.94, P = 0.01, and from 0.86 to 0.97, p = 0.01)., Conclusions: The IOTA ADNEX model has excellent performance in differentiating benign and malignant adnexal masses in the hands of nonexpert ultrasonographers with limited experience in China. In classifying different subtypes of ovarian cancers, the model has difficulty differentiating BOTs from stage I OC and BOTs from ovarian metastases., (© 2021. The Author(s).)

Tree trunk cankers represent serious fungal diseases that pose significant threats to Chinese hickory trees ( Carya cathayensis ). To characterize the pathogen diversity associated with this disease, tissues were collected between 2016 and 2018 from the primary Chinese hickory plantation regions. A total of 97 cultures were isolated from trees in six towns (Longgang, Qingliangfeng, Changhua, Tuankou, Taiyang Town, and Lin'an urban area) within the Linan district, where 60% of Chinese hickory tree yields originate. The isolated cultures caused cankers on Chinese hickory tree branches, but infections did not occur on fruits or leaves under tested conditions. Combined morphological observations and phylogenetic analysis of multiple genes ( ITS , β- tubulin , and EF ) indicated that five Botryosphaeriaceae species were recovered, including 89 isolates of Botryosphaeria dothidea , 4 isolates of Botryosphaeriaceae fabicerciana , 1 isolate of Botryosphaeriaceae qingyuanensis , 1 isolate of Botryosphaeriaceae corticis , and two isolates of Lasiodiplodia theobromae . B . dothidea was the most prevalent, and this is the first report of B . corticis , B . qingyuanensis , and L . theobromae infections in Chinese hickory trees. We investigated the mycelial growth, spore germination, and pathogenicity of these species at different temperatures. L . theobromae grew the fastest and B . cortices grew the slowest on potato dextrose agar. The optimum temperature of spore germination for all species was 30°C. L . theobromae was the most virulent species, followed by B . dothidea and B . qingyuanensis , then B . fabicerciana , and finally B . cortices . These new insights into fungal pathogen diversity provide critical new information to understand and manage tree trunk cankers of Chinese hickory.

This study aimed to measure the expression of SAA2 in plasma and to assess its diagnostic efficacy as a biomarker for non-small cell lung cancer (NSCLC). The gene expression of SAA2 in NSCLC was analyzed based on a database. Then, SAA2 expression was detected by immunohistochemistry in lung tissue and by enzyme-linked immunosorbent assay in 90 patients with NSCLC and 61 normal controls. Finally, the diagnostic performance was assessed in terms of accuracy, sensitivity, and specificity. At the gene and protein levels, the SAA2 expression was significantly higher in the NSCLC group than in the control group (p<0.01). It was higher in lung squamous carcinoma than in lung adenocarcinoma and in males than in females, and this trend was also observed in the lung squamous carcinoma group. Of note, the expression of SAA2 increased with increasing disease stage. Receiver operating characteristic (ROC) curve analysis revealed that the sensitivity of SAA2 was 83.61%, the specificity was 91.11%, and the area under the curve (AUC) was 0.9252. Its accuracy was 68.89%, which was higher than that of other conventional diagnostic biomarkers, and the combined application can effectively improve the diagnostic efficiency. Based on the results, SAA2 expression was positively correlated with the disease stage of NSCLC. Notably, SAA2 is more concerning in male patients with lung squamous carcinoma, and it can help in the screening and diagnosis of NSCLC. SAA2 may represent a novel diagnostic biomarker in NSCLC.

Purpose: To assess the efficacy and safety of different peri-operative regimens using the network meta-analysis for hepatocellular carcinoma (HCC) with portal/hepatic vein tumor thrombosis. The interested modalities included neoadjuvant three-dimensional radiotherapy (3D-CRT), post-operative intensity modulated radiation therapy (IMRT), post-operative transarterial chemoembolization (TACE), 3DCRT plus TACE and surgery alone., Methods: PubMed and Cochrane Library electronic databases were systematically searched for eligible studies published up to March 2021. Data related to treatment efficacy including overall survival (OS) and disease-free survival (DFS) were extracted and compared using a Bayesian approach. Adverse events (AEs) were assessed and compared., Results: Five studies published between 2009 and 2021 were enrolled in this network meta-analysis. The comparison showed that surgery with IMRT ranks relatively higher in prolonging OS in advanced HCC patients, followed by neoadjuvant 3DCRT and surgery plus TACE. Neoadjuvant 3DCRT and postoperative IMRT appear to be better choices than 3DCRT plus TACE in terms of OS. IMRT, TACE and neoadjuvant 3DCRT group were all superior to surgery alone in terms of DFS. The rate of AEs did not differ significantly., Conclusions: Adjuvant IMRT showed more favorable treatment responses compared to other regimens in HCC patients as a peri-operative regimen.

Protracted alcohol withdrawal symptoms (PAWS), characterized by the presence of substance-specific signs and symptoms (including anxiety, irritability, mood instability, insomnia, and cravings), make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics. The goal of this study was to evaluate the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on PAWS and plasma brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin levels in patients with alcohol dependency. A total of 114 patients with alcohol dependence were randomly divided into two groups: the treatment group and the control group. The patients in the treatment group were treated with taVNS of the bilateral auricular concha using an ear vagus nerve stimulator. The Pennsylvania Alcohol Craving Scale was used to evaluate the extent of craving for alcohol. The Self-Rating Anxiety Scale and Self-Rating Depression Scale (SDS) were used to evaluate the extent of anxiety and depression symptoms, respectively. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Enzyme-linked immunosorbent assay was used to measure plasma BDNF, IL-6, TNF-α, and leptin levels. The results showed that the SDS and PSQI scores were significantly lower in the treatment group than in the control group. Moreover, compared with the control group, the average BDNF levels in the treatment group were significantly increased. These results suggest that taVNS could improve the depression symptoms and sleep quality in alcohol-dependent patients after withdrawal, which might be related to the upregulation of plasma BDNF levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Xu, Zhai, Wu, Huang, Liang, Sun and Xu.)

High-mobility group A1 (HMGA1) acts as a transcription factor in several cardiovascular diseases. However, the implications of HMGA1 in cardiac fibrosis remain unknown. Here, we investigated the impact of HMGA1 on cardiac fibrosis. A mouse cardiac fibrosis model was constructed via subcutaneous injection of isoproterenol (ISO) or angiotensin II (Ang II) infusion. Adult mouse cardiac fibroblasts (CFs) were isolated and cultured. CFs were stimulated with transforming growth factor-β1 (TGF-β1) for 24 h. As a result, HMGA1 was upregulated in fibrotic hearts, as well as TGF-β-stimulated CFs. Overexpression of HMGA1 in CFs aggravated TGF-β1-induced cell activation, proliferation, and collagen synthesis. Overexpression of HMGA1 in fibroblasts, by an adeno-associated virus 9 dilution system with a periostin promoter, accelerated cardiac fibrosis and cardiac dysfunction. Moreover, HMGA1 knockdown in CFs inhibited TGF-β1-induced cell activation, proliferation, and collagen synthesis. Mechanistically, we found that HMGA1 increased the transcription of FOXO1. The FOXO1 inhibitor AS1842856 counteracted the adverse effects of HMGA1 overexpression in vitro . HMGA1 silencing in mouse hearts alleviated Ang II-induced cardiac fibrosis and dysfunction. However, FOXO1 knockdown in mouse hearts abolished the deteriorating effects of HMGA1 overexpression in mice. Collectively, our data demonstrated that HMGA1 plays a critical role in the development of cardiac fibrosis by regulating FOXO1 transcription., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xie, Yao, Hu, Cai, Zhao, Yuan, Wu and Tang.)

Background: Prenatal evaluation of fetal lung maturity (FLM) is a challenge, and an effective non-invasive method for prenatal assessment of FLM is needed. The study aimed to establish a normal fetal lung gestational age (GA) grading model based on deep learning (DL) algorithms, validate the effectiveness of the model, and explore the potential value of DL algorithms in assessing FLM., Methods: A total of 7013 ultrasound images obtained from 1023 normal pregnancies between 20 and 41 + 6 weeks were analyzed in this study. There were no pregnancy-related complications that affected fetal lung development, and all infants were born without neonatal respiratory diseases. The images were divided into three classes based on the gestational week: class I: 20 to 29 + 6 weeks, class II: 30 to 36 + 6 weeks, and class III: 37 to 41 + 6 weeks. There were 3323, 2142, and 1548 images in each class, respectively. First, we performed a pre-processing algorithm to remove irrelevant information from each image. Then, a convolutional neural network was designed to identify different categories of fetal lung ultrasound images. Finally, we used ten-fold cross-validation to validate the performance of our model. This new machine learning algorithm automatically extracted and classified lung ultrasound image information related to GA. This was used to establish a grading model. The performance of the grading model was assessed using accuracy, sensitivity, specificity, and receiver operating characteristic curves., Results: A normal fetal lung GA grading model was established and validated. The sensitivity of each class in the independent test set was 91.7%, 69.8%, and 86.4%, respectively. The specificity of each class in the independent test set was 76.8%, 90.0%, and 83.1%, respectively. The total accuracy was 83.8%. The area under the curve (AUC) of each class was 0.982, 0.907, and 0.960, respectively. The micro-average AUC was 0.957, and the macro-average AUC was 0.949., Conclusions: The normal fetal lung GA grading model could accurately identify ultrasound images of the fetal lung at different GAs, which can be used to identify cases of abnormal lung development due to gestational diseases and evaluate lung maturity after antenatal corticosteroid therapy. The results indicate that DL algorithms can be used as a non-invasive method to predict FLM., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Although bioactive sphingolipids have been shown to regulate cardiometabolic homeostasis and inflammatory signaling pathways in rodents, population-based longitudinal studies of relationships between sphingolipids and onset of metabolic syndrome (MetS) are sparse. We aimed to determine associations of circulating sphingolipids with inflammatory markers, adipokines, and incidence of MetS. Among 1242 Chinese people aged 50-70 years who completed the 6-year resurvey, 76 baseline plasma sphingolipids were quantified by high-throughput liquid chromatography-tandem mass spectrometry. There were 431 incident MetS cases at 6-year revisit. After multivariable adjustment including lifestyle characteristics and BMI, 21 sphingolipids mainly from ceramide and hydroxysphingomyelin subclasses were significantly associated with incident MetS. Meanwhile, the baseline ceramide score was positively associated (RR Q4 versus Q1 = 1.31; 95% CI 1.05, 1.63; p trend = 0.010) and the hydroxysphingomyelin score was inversely associated (RR Q4 versus Q1 = 0.60; 95% CI 0.45, 0.79; p trend < 0.001) with incident MetS. When further controlling for clinical lipids, both associations were attenuated but remained significant. Comparing extreme quartiles, RRs (95% CIs) of MetS risk were 1.34 (95% CI 1.06, 1.70; p trend = 0.010) for ceramide score and 0.71 (95% CI 0.51, 0.97; p trend = 0.018) for hydroxysphingomyelin score, respectively. Furthermore, a stronger association between ceramide score and incidence of MetS was evidenced in those having higher inflammation levels (RR Q4 versus Q1 1.57; 95% CI 1.16, 2.12; p interaction = 0.004). Our data suggested that elevated ceramide concentrations were associated with a higher MetS risk, whereas raised hydroxysphingomyelin levels were associated with a lower MetS risk beyond traditional clinical lipids.

Abstract: Early determination of coronavirus disease 2019 (COVID-19) pneumonia from numerous suspected cases is critical for the early isolation and treatment of patients.The purpose of the study was to develop and validate a rapid screening model to predict early COVID-19 pneumonia from suspected cases using a random forest algorithm in China.A total of 914 initially suspected COVID-19 pneumonia in multiple centers were prospectively included. The computer-assisted embedding method was used to screen the variables. The random forest algorithm was adopted to build a rapid screening model based on the training set. The screening model was evaluated by the confusion matrix and receiver operating characteristic (ROC) analysis in the validation.The rapid screening model was set up based on 4 epidemiological features, 3 clinical manifestations, decreased white blood cell count and lymphocytes, and imaging changes on chest X-ray or computed tomography. The area under the ROC curve was 0.956, and the model had a sensitivity of 83.82% and a specificity of 89.57%. The confusion matrix revealed that the prospective screening model had an accuracy of 87.0% for predicting early COVID-19 pneumonia.Here, we developed and validated a rapid screening model that could predict early COVID-19 pneumonia with high sensitivity and specificity. The use of this model to screen for COVID-19 pneumonia have epidemiological and clinical significance., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)