Can serum NSE predict and evaluate sepsis-associated encephalopathy: A protocol for a systematic review and meta-analysis.

INTRODUCTION: Brain dysfunction in sepsis is known as sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our systematic review and meta-analysis will aim to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic review and meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of serum NSE for the diagnostic and prognostic value of SAE patients. The primary objective is to evaluate the diagnostic accuracy of serum NSE as an independent biomarker for SAE. The secondary objective is to determine the prognostic strength of serum NSE as an independent biomarker of mortality in septic patients determine. We will perform a systematic search and descriptive review using the MEDLINE database and the PubMed interface. We will assign two independent reviewers to review all collected titles and associated abstracts, review full articles, and extract study data. We will use the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) assessment tool according to the recommendation by the Cochrane Collaboration to evaluate quality and risk of bias of the selected studies. Subgroup and sensitivity analyses will also be used to assess heterogeneity. Review Manager version 5.4 and Stata16.0. will be used for statistical analysis. ETHICS AND DISSEMINATION: The meta-analysis will provide ICU physicians with the most current information to predict which patients are at risk of SAE and take corresponding intervention measures to reduce morbidity and ameliorate neurological outcomes. There is no need for ethics approval for this review. The findings will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42023398736.

Construction and validation of a joint diagnosis model based on random forest and artificial intelligence network for hepatitis B-related hepatocellular carcinoma.

Background: Hepatitis B virus (HBV) is the dominant pathogenic factor of hepatocellular carcinoma (HCC) in Asia and Africa. Early identification and clinical diagnosis are crucial for HBV-related HCC. Random forest (RF) and artificial neural network (ANN) were an innovative and highly effective supervised machine learning (ML) algorithm for the early diagnosis and screening of HBV-related HCC. This study aims to identify significant biomarkers and develop a novel genetic model for the efficient diagnosis of HBV-related HCC. Methods: Gene Expression Omnibus (GEO) Series (GSE)19665, GSE55092, and GSE121248 were used to identify significant differentially expressed genes (DEGs). The enrichment analysis was performed on Metascape online tool. The RF algorithm and ANN were used to select the potential predictive gene panels and construct an HBV-related HCC diagnostic model. Subsequently, GSE17548, GSE104310, GSE44074, and GSE136247 were used to test the accuracy of the ANN model. Finally, the CIBERSORT algorithm was used to assess the abundance of immune infiltrates in all samples. Results: First, 116 genes were identified as DEGs, and the DEGs were particularly enriched in cellular hormone metabolic process, monocarboxylic acid metabolic process, NABA extracellular matrix (ECM) AFFILIATED steroid metabolic process and metabolism of bile acid and bile salt. DNA topoisomerase II alpha (TOP2A), C-type lectin domain family 1 member B (CLEC1B), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), ficolin 2 (FCN2), C-X-C motif chemokine ligand 14 (CXCL14), cyclase associated actin cytoskeleton regulatory protein 2 (CAP2), ficolin 3 (FCN3), kynurenine 3-monooxygenase (KMO) and cadherin related family member 2 (CDHR2) were available to develop an HBV-related HCC diagnostic model. After validation, the diagnostic model showed high sensitivity (88.5%, 90%, 88.5%, 76.5%) and specificity (100%, 81.8%, 89.5%, 72.2%), and the areas under the receiver operating characteristic (ROC) curves showed excellent efficiency (1, 0.927, 0.921, 0.833). Finally, the percentage of infiltrating immune cell types [B cells naïve, B cells memory, plasma cells, T cells CD8, T cells CD4 memory resting, T cells regulatory (Tregs), T cells gamma delta, natural killer (NK) cells resting, NK cells activated, Macrophages M0, Dendritic cells activated, Mast cells activated] for hepatitis B-related HCC were significantly different from that of non-cancerous liver tissue with HBV. Conclusions: A novel early diagnostic model of HBV-related HCC was established, and the model showed better efficiency in distinguishing HBV-related HCC from other non-cancerous with HBV individuals.

Meta-analysis of evaluating neuron specific enolase as a serum biomarker for sepsis-associated encephalopathy.

INTRODUCTION: Brain dysfunction in sepsis is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our Meta-analysis aimed to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic Review and Meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS: The study protocol was registered in the PROSPERO database (CRD42023398736) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a systematic review and Meta-analysis to evaluate the serum NSE's diagnostic accuracy for SAE and prognostic strength for probability of death of septic patients. We systematic searched electronic bibliographic databases from PubMed, MEDLINE, Web of Science, Embase, Cochrane databases, CNKI, CQVIP, and WFSD. QUADAS-2 assessment tool was used to evaluate quality and risk of bias of the selected studies. Subgroup analyses, funnel plots, sensitivity analyses were also carried out. Review Manager version 5.4 and Stata16.0. was used for statistical analysis. RESULTS: This Meta-analysis included 22 studies with 1361 serum samples from SAE patients and 1580 serum samples from no-encephalopathy septic (NE) patients. The Meta-analysis showed that individuals with SAE had higher serum NSE level than NE controls (SMD 1.93 (95 % CI 1.51-2.35), P < 0.00001). In addition, there are 948 serum samples from survival septic patients and 446 serum samples from non-survival septic patients, septic patients with survival outcomes had lower serum NSE levels than those with death outcomes (SMD -1.87 (95 % CI -2.43 to -1.32), P < 0.00001). CONCLUSION: Our Meta-analysis reveals a significant association between elevated NSE concentrations and the increased likelihood of concomitant SAE and mortality during septic patients. This comprehensive analysis will equip ICU physicians with up-to-date insights to accurately identify patients at risk of SAE and implement appropriate intervention strategies to mitigate morbidity and improve neurological outcomes. However, it is important to note that the presence of substantial heterogeneity among studies poses challenges in determining the most effective discrimination cutoff values and optimal sampling collection time.

Microglial Activation: Key Players in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common brain dysfunction, which results in severe cognitive and neurological sequelae and an increased mortality rate in patients with sepsis. Depending on the stimulus, microglia (resident macrophages in the brain that are involved in SAE pathology and physiology) can adopt two polarization states (M1/M2), corresponding to altered microglial morphology, gene expression, and function. We systematically described the pathogenesis, morphology, function, and phenotype of microglial activation in SAE and demonstrated that microglia are closely related to SAE occurrence and development, and concomitant cognitive impairment. Finally, some potential therapeutic approaches that can prime microglia and neuroinflammation toward the beneficial restorative microglial phenotype in SAE were outlined.

Beyond Solvothermal: Alternative Synthetic Methods for Covalent Organic Frameworks.

Covalent organic frameworks (COFs) are crystalline porous organic materials that hold a wealth of potential applications across various fields. The development of COFs, however, is significantly impeded by the dearth of efficient synthetic methods. The traditional solvothermal approach, while prevalent, is fraught with challenges such as complicated processes, excessive energy consumption, long reaction times, and limited scalability, rendering it unsuitable for practical applications. The quest for simpler, quicker, more energy-efficient, and environmentally benign synthetic strategies is thus paramount for bridging the gap between academic COF chemistry and industrial application. This Review provides an overview of the recent advances in alternative COF synthetic methods, with a particular emphasis on energy input. We discuss representative examples of COF synthesis facilitated by microwave, ultrasound, mechanic force, light, plasma, electric field, and electron beam. Perspectives on the advantages and limitations of these methods against the traditional solvothermal approach are highlighted.

Side-effects of hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal cancers.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) produces unwanted side-effects that are mainly caused by chemotherapeutic drugs in the treatment of gastrointestinal (GI) cancers, and these effects have not been systematically summarized. The aim of this article was to provide a comprehensive overview of the side-effects of HIPEC for GI cancers and propose practical strategies for adverse event management. Methodology: PubMed, Web of Science, and the Cochrane Library were systematically searched for side-effects of HIPEC in GI cancers prior to October 20, 2022. A total of 79 articles were included in this review. Results: Adverse events, such as enterocutaneous digestive fistulas, GI tract perforation, neutropenia, postoperative bleeding, ventricular tachycardia, hyperglycemia, hypocalcemia, renal impairment, encapsulating peritoneal sclerosis, scrotal ulceration, and sarcopenia were described, and their clinical management was discussed. These side-effects involve the digestive, hematopoietic, circulatory, metabolic, and urinary systems. Effective methods for adverse event management included an expert multidisciplinary team, replacing chemotherapy drugs, using Chinese medicine, and careful preoperative assessments. Conclusion: The side-effects of HIPEC are frequent and can be minimized by several effective methods. This study proposes practical strategies for adverse event management of HIPEC to assist physicians in choosing the optimal treatment method.

Diagnostic and prognostic value of serum S100B in sepsis-associated encephalopathy: A systematic review and meta-analysis.

Background: In sepsis, brain dysfunction is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Our systematic review and meta-analysis aimed to explore the diagnostic and prognostic value of serum S100 calcium-binding protein B (S100B) in SAE patients. Methods: We conducted a systematic search of the databases PubMed, Web of Science, Embase, Cochrane databases, CNKI, VIP, and WFSD from their inception dates until August 20, 2022. A Meta-analysis of the included studies was also performed using Review Manager version 5.4 and Stata16.0. Results: This meta-analysis included 28 studies with 1401 serum samples from SAE patients and 1591 serum samples from no-encephalopathy septic (NE) patients. The Meta-Analysis showed that individuals with SAE had higher serum S100B level than NE controls (MD, 0.49 [95% CI (0.37)-(0.60), Z =8.29, P < 0.00001]), and the baseline level of serum S100B in septic patients with burn was significantly higher than average (1.96 [95% CI (0.92)-(2.99), Z =3.71, P < 0.0002]) In addition, septic patients with favorable outcomes had lower serum S100B levels than those with unfavorable outcomes (MD, -0.35 [95% CI (-0.50)-(-0.20), Z =4.60, P < 0.00001]). Conclusion: Our Meta-Analysis indicates that higher serum S100B level in septic patients are moderately associated with SAE and unfavorable outcomes (The outcomes here mainly refer to the mortality). The serum S100B level may be a useful diagnostic and prognostic biomarker of SAE.

Fluorinated Cycloplatinated(II) Complexes Bearing Bisphosphine Ligands as Potent Anticancer Agents.

A family of cationic cycloplatinated(II) complexes [Pt(dfppy)(P^P)]Cl, dfppy = 2-(2,4-difluorophenyl)pyridine, incorporating bisphosphine ligands, P^P = bis(diphenylphosphino)methane (1, dppm), 1,2-bis(diphenylphosphino)ethane (2, dppe) and 1,2-bis(diphenylphosphino)benzene (3, dppbz), was prepared. The complexes were characterized by means of several analytical and spectroscopic methods. These complexes displayed acceptable stability in the biological environments which was confirmed by NMR, HR ESI-MS and UV-vis techniques. The antiproliferative properties of these complexes were evaluated by National Cancer Institute (NCI) at National Institutes of Health (NIH) against 60 different human tumor cell lines such as leukemia, melanoma, lung, colon, brain, ovary, breast, prostate and kidney. These complexes showed higher cytotoxicity than cisplatin against a wide variety of cancer cell lines such as K-562 (leukemia), HOP-92 (lung), HCT-116 (colon), OVCAR-8 (ovarian), PC-3 (prostate), MDA-MB-468 (breast), and melanoma cancer cell lines. Complex 3 as the most potent compound in this study furnished an excellent anti-proliferative activity compared to the cisplatin against Hela, SKOV3, and MCF-7 cancer cell lines. The main mode of the interaction of 1-3 with DNA was also determined using molecular docking studies.

Probe metal binding mode of imine covalent organic frameworks: cycloiridation for (photo)catalytic hydrogen evolution from formate.

Metalation of covalent organic frameworks (COFs) is a critical strategy to functionalize COFs for advanced applications yet largely relies on the pre-installed specific metal docking sites in the network, such as porphyrin, salen, 2,2'-bipyridine, etc. We show in this study that the imine linkage of simple imine-based COFs, one of the most popular COFs, readily chelate transition metal (Ir in this work) via cyclometalation, which has not been explored before. The iridacycle decorated COF exhibited more than 10-fold efficiency enhancement in (photo)catalytic hydrogen evolution from aqueous formate solution than its molecular counterpart under mild conditions. This work will inspire more functional cyclometallated COFs to be explored beyond catalysis considering the large imine COF library and the rich metallacycle chemistry.

Catalyst-Enabled In Situ Linkage Reduction in Imine Covalent Organic Frameworks.

New linkages for covalent organic frameworks (COFs) have been continuously pursued by chemists as they serve as the structure and property foundation for the materials. Developing new reaction types or modifying known linkages have been the only two methods to create new COF linkages. Herein, we report a novel strategy that uses H3PO3 as a bifunctional catalyst to achieve amine-linked COFs from readily available amine and aldehyde linkers. The acidic proton of H3PO3 catalyzes the imine framework formation, which is then in situ reduced to the amine COF by the reductive P-H moiety. The amine-linked COF outperforms its imine analogue in promoting Knoevenagel condensation because of the more basic sites and higher stability.

Pt(II)-Decorated Covalent Organic Framework for Photocatalytic Difluoroalkylation and Oxidative Cyclization Reactions.

A new covalent organic framework (COF) based on imine bonds was assembled from 2-(4-formylphenyl)-5-formylpyridine and 1,3,6,8-tetrakis(4-aminophenyl)pyrene, which showed an interesting dual-pore structure with high crystallinity. Postmetallation of the COF with Pt occurred selectively at the N donor (imine and pyridyl) in the larger pores. The metallated COF served as an excellent recyclable heterogeneous photocatalyst for decarboxylative difluoroalkylation and oxidative cyclization reactions.

A C

This work reports the synthesis and characterization of a new C^N-based cycloplatinated(II) fluoride complex, [Pt(ppy)(PPh3)F] (2; ppy = 2-phenylpyridinate), involving a Pt-F bond. The new complex is highly luminescent in the green area with a high quantum yield of 94.6% at 77 K. A comparison study of the heavier halogen derivatives reveals a descending emission quantum yield order of F > Cl > Br > I. Time-dependent density functional theory calculations ascribe the decreased emission efficiency to the decreasing trend of an intraligand (IL) transition from F to I, which accounts for the major radiative pathway. In addition, 2 is capable of the fluorinating alkyl halides, leading to Csp3-F bond formation at room temperature.

(Thio)urea-Based Covalent Organic Framework as a Hydrogen-Bond-Donating Catalyst.

Two-dimensional urea- and thiourea-containing covalent organic frameworks (COFs) were synthesized at ambient conditions at large scale within 1 h in the absence of an acid catalyst. The site-isolated urea and thiourea in the COF showed enhanced catalytic efficiency as a hydrogen-bond-donating organocatalyst compared to the molecular counterparts in epoxide ring-opening reaction, aldehyde acetalization, and Friedel-Crafts reaction. The COF catalysts also had excellent recyclability.

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine.

INTRODUCTION: Glucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine. MATERIALS AND METHODS: Both tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model. RESULTS: The radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18% (n = 10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25% (n = 5) ([18F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors. CONCLUSION: We investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. Advances in Knowledge and Implications for patient care: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

Translation of HDAC6 PET Imaging Using [18F]EKZ-001-cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates.

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [18F]EKZ-001 ([18F]Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [18F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [18F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [18F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/µmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [18F]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [18F]EKZ-001 PET for first-in-human studies.

Applications of Dynamic Covalent Chemistry Concept towards Tailored Covalent Organic Framework Nanomaterials: A Review.

Covalent organic frameworks (COFs) are a rapidly developing class of materials that has been of immense research interest during the last ten years. Numerous reviews have been devoted to summarizing the synthesis and applications of COFs. However, the underlying dynamic covalent chemistry (DCC), which is the foundation of COFs synthesis, has never been systematically reviewed in this context. Dynamic covalent chemistry is the practice of using thermodynamic equilibriums to molecular assemblies. This Critical Review will cover the state-of-the-art use of DCC to both synthesize COFs and expand the applications of COFs. Five synthetic strategies for COF synthesis are rationalized, namely: modulation, mixed linker/linkage, sub-stoichiometric reaction, framework isomerism, and linker exchange, which highlight the dynamic covalent chemistry to regulate the growth and to modify the properties of COFs. Furthermore, the challenges in these approaches and potential future perspectives in the field of COF chemistry are also provided.

Multicomponent Synthesis of Diversified Chromeno[3,2-d]oxazoles.

A practical and efficient synthetic procedure to novel chromeno[3,2-d]oxazoles through a one-pot sequential multistep process is presented. This procedure proceeds efficiently in propylene carbonate (PC) as a green solvent and affords a wide range of the chromenooxazole scaffolds.

Design principle of half-sandwich type erbium single-ion magnets through crystal field engineering: a combined magnetic and electronic structure study.

To conclude the design principle for high-performance erbium-based single-ion magnets (SIMs), two half-sandwich type erbium complexes 1Er [(LOMe)Er(COT)] (LOMe = [(η5-C5H5)Co{P([double bond, length as m-dash]O)(OMe)2}3], COT = cyclooctatetraenyl) and 2Er [(THF)2(OAr)Er(COT)] (Ar = 2,6-Dipp2C6H3, Dipp = 2,6-diisopropylphenyl) were synthesized, and structurally and magnetically characterized. Both of them exhibited SIM behavior. Their magnetic relaxation behaviours were further elucidated by ab initio calculations and near-IR emission spectroscopy. The results demonstrated that an axial ligand with a weaker electron-donating effect was preferential to construct high blocking barrier erbium-based SIMs.

α-Alkylation of Chiral Sulfinimines for Constructing Quaternary Chiral Carbons by Introducing Removable Directing Groups.

This study developed a facile and efficient synthetic strategy to construct quaternary chiral centers at the α-position of imines and ketones. High regioselectivity and diastereoselectivity were achieved through the synergetic effect of electron-withdrawing directing groups and N-tert-butyl sulfinamide as chiral auxiliaries. Either of them could be removed under the optimized conditions without any epimerization.

Micro-flow nanocatalysis: synergic effect of TfOH@SPIONs and micro-flow technology as an efficient and robust catalytic system for the synthesis of plasticizers.

The combination of continuous flow technology with immobilizing of only 0.13 mol% of triflic acid (TfOH) on silica-encapsulated superparamagnetic iron oxide nanoparticles (SPIONs) under solvent-free conditions successfully provided a powerful, efficient, and eco-friendly route for the synthesis of plasticizers. The turnover frequency value in micro-flow conditions varied in the range of 948.7 to 7384.6 h-1 compared to 403.8 to 3099 h-1 for in-flask. This technique works efficiently, encouraging future applications of micro-flow nano-catalysis in green chemistry.