General Synthesis of meso-1,4-Dialdehydes and Their Application in Ir-Catalyzed Asymmetric Tishchenko Reactions.

A practical synthesis of meso-1,4-dialdehydes based on the oxidative cleavage of cyclobutanediol derivatives using polymer-supported periodate was developed. The meso-1,4-dialdehydes were obtained in up to >99% yield and subsequently employed in Ir-catalyzed asymmetric Tishchenko reactions to give the corresponding chiral lactones, which are versatile synthetic intermediates, in good yield with moderate enantiomeric excess. The catalytically active species was identified by means of cold-spray ionization mass spectrometry and 1H NMR spectroscopy.

Population genetic analysis based on the polymorphisms mediated by transposons in the genomes of pig.

Transposable elements (TEs) mobility is capable of generating a large number of structural variants (SVs), which can have considerable potential as molecular markers for genetic analysis and molecular breeding in livestock. Our results showed that the pig genome contains mainly TE-SVs generated by short interspersed nuclear elements (51,873/76.49%), followed by long interspersed nuclear elements (11,131/16.41%), and more than 84% of the common TE-SVs (Minor allele frequency, MAF > 0.10) were validated to be polymorphic. Subsequently, we utilized the identified TE-SVs to gain insights into the population structure, resulting in clear differentiation among the three pig groups and facilitating the identification of relationships within Chinese local pig breeds. In addition, we investigated the frequencies of TEs in the gene coding regions of different pig groups and annotated the respective TE types, related genes, and functional pathways. Through genome-wide comparisons of Large White pigs and Chinese local pigs utilizing the Beijing Black pigs, we identified TE-mediated SVs associated with quantitative trait loci and observed that they were mainly involved in carcass traits and meat quality traits. Lastly, we present the first documented evidence of TE transduction in the pig genome.

Unveiling the Genetic Secrets of Chinese Indigenous Pigs from Guizhou Province: Diversity, Evolution and Candidate Genes Affecting Pig Coat Color.

The local pig breeds in Guizhou possess exceptional meat quality, robust adaptability, and resilience to harsh feeding conditions, making them ideal for producing high-quality pork. With over 10 local pig breeds in the region, we focused on 7 specific breeds: Baixi pigs (BX), Congjiang Xiang pigs (CJX), Guanling pigs (GL), Jianhe White Xiang pigs (JHBX), Jiangkou Luobo pigs (JKLB), Kele pigs (KL), and Qiandong Hua pigs (QDH). Unfortunately, these breeds face threats such as introduced species and inbreeding, resulting in a decline in population size and numbers. To better protect and utilize these breeds, we employed genome-wide single-nucleotide polymorphism (SNP) markers to investigate the population structure, genetic diversity, and selection characteristics of 283 pigs across these seven breeds. Our findings revealed distinct ancestral sources between Chinese and Western pig breeds, as demonstrated by principal component analysis, adjacent tree analysis, and ADMIXTURE analysis. Notably, JHBX exhibited a distant genetic relationship from the other six local pig breeds in Guizhou province, showcasing unique genetic characteristics. While the genetic diversity of the six Chinese native pig populations, excluding JHBX, was generally moderate in Guizhou province, the JHBX population displayed low genetic diversity. Therefore, it is imperative to intensify selection efforts to prevent inbreeding decline in JHBX while further enhancing the protection measures for the other six pig populations. Additionally, we identified candidate genes influencing the size disparity among pigs in Guizhou province through signal selection. Our study outcomes serve as a reference for developing effective conservation and utilization plans for pig breeds in Guizhou province and deepen our understanding of the genetic mechanisms underlying pig body size.

Nurses' perspectives on workplace environment needs associated to resilience: a qualitative descriptive study.

Objective: The purpose of this study was to explore the demands of nurses on the workplace environment related to psychological resilience. Methods: A qualitative descriptive design was employed for this study. Purposeful sampling was chosen from a tertiary hospital in Henan Province, China. Semi-structured in-depth interviews were conducted with 20 nurses. The interview data was analyzed using the Colaizzi's method and results were reported following the COREQ standards. Results: Analysis of the interview data revealed three main themes: (1) Career Support and Development, (2) Practical Support & Development, and (3) Personal Support and Development. Conclusion: The perspectives of nurses for a workplace environment demands needs to be appreciated, and in addition, it is worth noting that the key role of building a good workplace environment in strengthening the resilience of nurses emphasizes the need for careful consideration. Nursing administrators should formulate policies and measures from multiple perspectives based on the real needs of nurses in terms of professional, practical, and personal dimensions.

Nanozymes: a new approach for leukemia therapy.

Leukemia is a type of clonal disorder of hematopoietic stem and progenitor cells characterized by bone marrow failure, differentiation arrest, and lineage skewing. Despite leukemia being a complex disease and it being difficult to identify a single driving force, redox homeostasis, the balance between reactive oxygen species (ROS) producers and cellular antioxidant systems, is normally impaired during leukemogenesis. In this context, the modulation of ROS in leukemia cells can be harnessed for therapeutic purposes. Nanozymes are functional nanomaterials with enzyme-like characteristics, which address the intrinsic limitations of natural enzymes and exhibit great potential in synergistic antitumor therapy. Nanozymes possess catalytic activities (e.g., peroxidase-like activity, catalase-like activity, superoxide dismutase-like activity, and oxidase-like activity) to regulate ROS levels in vitro and in vivo, making them promising for leukemia therapy. On account of the rapid development of nanozymes recently, their application potentials in leukemia therapy are gradually being explored. To highlight the achievements of nanozymes in the leukemia field, this review summarizes the recent studies of nanozymes with anti-leukemia efficacy and the underlying mechanism. In addition, the challenges and prospects of nanozyme research in leukemia therapy are discussed.

Quercitrin attenuates the progression of osteoarthritis via inhibiting NF-κB signaling pathways and enhance glucose transport capacity.

Osteoarthritis (OA) is a common musculoskeletal disorder that impairs function and reduces the quality of life. Extracellular matrix (ECM) degradation and inflammatory mechanisms are crucial to the progression of OA. In this study, we aimed to investigate the anti-inflammatory activity, anti-ECM degradation property, and glucose transport capacity of quercitrin (QCT) on IL-1ß-treated rat primary chondrocytes. Rat primary chondrocytes were treated with IL-1ß to simulate inflammatory environmental conditions and OA in vitro. We examined the effects of QCT at concentrations ranging from 0 to 200 µM on the viability of rat chondrocytes and selected 5 µM for further study. Using qRT-PCR, immunofluorescent, immunocytochemistry, and western blotting techniques, we identified the potential molecular mechanisms and signaling pathways that are responsible for these effects. We established an OA rat model through anterior cruciate ligament transection (ACLT). The animals were then periodically injected with QCT into the knee articular cavity. Our in vivo and in vitro study showed that QCT could inhibit IL-1ß-activated inflammation and ECM degradation in chondrocyte. Furthermore, QCT could inhibit the NF-κB signal pathway and enhance glucose transport capacity in the IL-1ß-stimulated chondrocytes. In vivo study proved that QCT attenuates OA progression in rats. Overall, QCT inhibited the activation of NF-κB and enhanced glucose transport capacity to alleviate the progression of OA.

Associations of genome-wide structural variations with phenotypic differences in cross-bred Eurasian pigs.

BACKGROUND: During approximately 10,000 years of domestication and selection, a large number of structural variations (SVs) have emerged in the genome of pig breeds, profoundly influencing their phenotypes and the ability to adapt to the local environment. SVs (≥ 50 bp) are widely distributed in the genome, mainly in the form of insertion (INS), mobile element insertion (MEI), deletion (DEL), duplication (DUP), inversion (INV), and translocation (TRA). While studies have investigated the SVs in pig genomes, genome-wide association studies (GWAS)-based on SVs have been rarely conducted. RESULTS: Here, we obtained a high-quality SV map containing 123,151 SVs from 15 Large White and 15 Min pigs through integrating the power of several SV tools, with 53.95% of the SVs being reported for the first time. These high-quality SVs were used to recover the population genetic structure, confirming the accuracy of genotyping. Potential functional SV loci were then identified based on positional effects and breed stratification. Finally, GWAS were performed for 36 traits by genotyping the screened potential causal loci in the F2 population according to their corresponding genomic positions. We identified a large number of loci involved in 8 carcass traits and 6 skeletal traits on chromosome 7, with FKBP5 containing the most significant SV locus for almost all traits. In addition, we found several significant loci in intramuscular fat, abdominal circumference, heart weight, and liver weight, etc. CONCLUSIONS: We constructed a high-quality SV map using high-coverage sequencing data and then analyzed them by performing GWAS for 25 carcass traits, 7 skeletal traits, and 4 meat quality traits to determine that SVs may affect body size between European and Chinese pig breeds.

Short-term safety of inactivated SARS-Cov-2 vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases.

Objective: This study aims to evaluate the short-term safety of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases (CNS IDDs). Methods: A web-based survey was conducted among patients with CNS IDDs from April 15 to 19, 2022 in China. In total, 645 patients with CNS IDDs were identified, including 425 patients with multiple sclerosis (MS), 194 with neuromyelitis optica spectrum disorder (NMOSD), and 26 with other CNS IDDs. The questionnaire consisted of demographic data, clinical records, history of SARS-CoV-2 vaccination, and vaccination-related symptoms within one month after vaccination. The demographic data, clinical information, and relapse rates between vaccinated and non-vaccinated patients were compared. Results: Among 645 patients with CNS IDDs, 78 were vaccinated and 567 were non-vaccinated with the vaccination rate of 12.1 %. Compared to non-vaccinated group, a lower percentage of patients on DMDs therapy (41.0 % vs. 71.8 %, P < 0.001) and an increased proportion of patients with other vaccination in past 3 years (17.9 % vs. 4.8 %, P < 0.001) were observed in vaccinated group. Six patients experienced a relapse within 30 days of a vaccination. Additionally, vaccine-associated relapse rates in vaccinated patients did not significantly differ from these in non-vaccinated patients among 2020, 2021, and from January 1 to October 1, 2022. Conclusions: No increased risk of vaccination-associated relapses among Chinese patients with CNS IDDs indicated that inactivated SARS-CoV-2 vaccines appear to be safe for this population.

Tracking groundwater pollution plumes at landfill sites using borehole hydrochemical and hydrodynamic profile (BHHP) method.

Groundwater pollution at landfill sites poses a significant risk to human health and ecological security. However, efficiently tracking pollution plumes in a polluted aquifer with variable pollutants remains challenging. In order to track groundwater pollution plumes at landfill sites, an in-situ borehole hydrochemical and hydrodynamic profile (BHHP) method was developed. Total dissolved solids (TDS), oxidation-reduction potential (ORP), and ammonia nitrogen were selected as the hydrochemical indicators. Meanwhile, the hydrodynamic indicators included flow direction and flow velocity of groundwater. Among the three hydrochemical indicators, TDS and ORP were analyzed to be the prior alternative ones for the BHHP application. The BHHP method was successfully applied to track groundwater pollution plumes at a typical valley-type landfill site and its neighboring downstream zone. Consequently, four groundwater pollution plumes of different types and different scales were identified in both horizontal and vertical directions within the depth of 0-50 m, and the various pollution sources for the detected pollution plumes were revealed. Furthermore, the BHHP method was validated using sampling test results of groundwater chloride and chemical oxygen demand at the surveyed landfill site.

The clinicopathological features of BRG1-deficient non-small cell lung cancer and its response to immunotherapy: A single-center retrospective study.

PURPOSE: BRG1-deficient NSCLCs have been more intriguing recently for its highly aggressive clinical behavior and no effective therapies. This study characterized the clinical and pathological features of BRG1-deficient NSCLCs and investigated their response to immunotherapy. METHODS: Forty-seven cases with BRG1-deficient NSCLC were included. Immunohistochemical markers such as BRG1, CK7, TTF-1, NapsinA, P40, HepPar-1, Ki-67, BRM, ARID1A and ARID1B were stained. Additionally, the PD-L1 expression level, overall survival, progression-free survival and disease control rate of patients received immunotherapy were evaluated. RESULTS: This study revealed that: (1) Patients with BRG1-deficient NSCLC have a male predominance (89.4 %), smoker enrichment (76.6 %) and poor prognosis (median OS: 7.0 months for advanced stage). (2) Histologically, BRG1-deficient NSCLCs presented significant morphological diversity and no lepidic pattern. Inflammatory infiltration and tumor necrosis was a prominent feature. Immunohistochemical analyses showed a distinctive uniform immunophenotype (TTF-1-/NapsinA-/CK7+) in 60.9 % (28/46) of cases and HepPar-1 positive in 46.5 % (20/43) of cases. BRM loss or significant reduction coexisted in 11.8 % (4/34) of cases. No case (0/37) showed loss of ARID1A or ARID1B. (3) Eight patients with advanced tumor stage had received immunotherapy and 4 cases achieved a sustainable clinical response with the disease control rate of 50 %. CONCLUSION: BRG1-deficient NSCLC showed diverse histopathological patterns and a unique immunohistochemical phenotype. ICIs-based immunotherapy is a promising therapy needs to be investigated further for BRG1- deficient NSCLC.

Engineering the viscoelasticity of gelatin methacryloyl (GelMA) hydrogels via small "dynamic bridges" to regulate BMSC behaviors for osteochondral regeneration.

The dynamic extracellular matrix (ECM) constantly affects the behaviors of cells. To mimic the dynamics of ECM with controllable stiffness and energy dissipation, this study proposes a strategy in which a small molecule, 3,4-dihydroxybenzaldehyde (DB), was used as fast "dynamic bridges'' to construct viscoelastic gelatin methacryloyl (GelMA)-based hydrogels. The storage modulus and loss modulus of hydrogels were independently adjusted by the covalent crosslinking density and by the number of dynamic bonds. The hydrogels exhibited self-healing property, injectability, excellent adhesion and mechanical properties. Moreover, the in vitro results revealed that the viscous dissipation of hydrogels favored the spreading, proliferation, osteogenesis and chondrogenesis of bone marrow mesenchymal stem cells (BMSCs), but suppressed their adipogenesis. RNA-sequencing and immunofluorescence suggested that the viscous dissipation of hydrogels activated Yes-associated protein (YAP) by stabilizing integrin ß1, and further promoted nuclear translocation of smad2/3 and ß-catenin to enhance chondrogenesis and osteogenesis. As a result, the viscoelastic GelMA hydrogels with highest loss modulus showed best effect in cartilage and subchondral bone repair. Taken together, findings from this study reveal an effective strategy to fabricate viscoelastic hydrogels for modulating the interactions between cells and dynamic ECM to promote tissue regeneration.

Gardenoside ameliorates inflammation and inhibits ECM degradation in IL-1ß-treated rat chondrocytes via suppressing NF-κB signaling pathways.

Osteoarthritis (OA) places a significant burden on society and finance, and there is presently no effective treatment beside late replacement surgery and symptomatic relief. The therapy of OA requires additional research. Gardenoside is a naturally compound extracted from Gardenia jasminoides Ellis, which has a variety of anti-inflammatory effects. However, few studies have been conducted to determine the role of gardenoside in OA. This study aimed to explore whether gardenoside has effect in OA treatment. Rat primary chondrocytes were treated with IL-1ß to simulate inflammatory environmental conditions and OA in vitro. We examined the effects of gardenoside at concentrations ranging from 0 to 200 µM on the viability of rat chondrocytes and selected 10 µM for further study. Via in vitro experiments, our study found that gardenoside lowers the gene expression of COX-2, iNOS, IL-6, and reduced the ROS production of chondrocytes induced by IL-1ß. Moreover, it effectively alleviates ECM degradation caused by IL-1ß and promotes the ECM synthesis in chondrocytes by upregulating collagen-II and the ACAN expression, downregulating the expression of MMP-3, MMP-13, and ADAMTS-5 expression. Further, our study showed that gardenoside inhibits NF-κB signaling pathway activated by IL-1ß in chondrocytes. We established an OA rat model by anterior cruciate ligament transection (ACLT). The animals were then periodically injected with gardenoside into the knee articular cavity. In vivo study suggested that gardenoside attenuates OA progression in rats. As a whole, in vitro and in vivo results highlight gardenoside is a promising OA treatment agent.

Designer Exosomes for Targeted Delivery of a Novel Therapeutic Cargo to Enhance Sorafenib-Mediated Ferroptosis in Hepatocellular Carcinoma.

Sorafenib is one of the few effective first-line drugs approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common among individuals with HCC. Recent evidence indicated that the anticancer activity of sorafenib mainly relies on the induction of ferroptosis. Furthermore, in our study, genes that suppress ferroptosis, especially GPX4 and DHODH, were enriched in sorafenib-resistant cells and primary tissues and were associated with poor prognosis of HCC patients who received sorafenib treatment. Therefore, a new ferroptosis inducer comprising a multiplex small interfering RNA (multi-siRNA) capable of simultaneously silencing GPX4 and DHODH was created. Then, exosomes with high multi-siRNA loading and HCC-specific targeting were established by fusing the SP94 peptide and the N-terminal RNA recognition motif (RRM) of U1-A with the exosomal membrane protein Lamp2b. The results from the in vitro and in vivo experiments indicate that this tumor-targeting nano-delivery system (ExoSP94-lamp2b-RRM-multi-siRNA) could enhance sorafenib-induced ferroptosis and overcome sorafenib resistance. Taken together, HCC-targeted exosomes (ExoSP94-Lamp2b-RRM) could specifically deliver multi-siRNA to HCC tissues, enhance sorafenib-induced ferroptosis by silencing GPX4 and DHODH expression and consequently increase HCC sensitivity to sorafenib, which opens a new avenue for clinically overcoming sorafenib resistance from the perspective of ferroptosis.

Multifunctional Nanofibrous Scaffolds with Angle-Ply Microstructure and Co-Delivery Capacity Promote Partial Repair and Total Replacement of Intervertebral Disc.

There is an urgent clinical need for the treatment of annulus fibrosus (AF) impairment caused by intervertebral disc (IVD) degeneration or surgical injury. Although repairing injured AF through tissue engineering is promising, the approach is limited by the complicated angle-ply microstructure, inflammatory microenvironment, poor self-repairing ability of AF cells and deficient matrix production. In this study, electrospinning technology is used to construct aligned core-shell nanofibrous scaffolds loaded with transforming growth factor-ß3 (TGFß3) and ibuprofen (IBU), respectively. The results confirm that the rapid IBU release improves the inflammatory microenvironment, while sustained TGFß3 release enhances nascent extracellular matrix (ECM) formation. Biomaterials for clinical applications must repair local AF defects during herniectomy and enable AF regeneration during disc replacement, so a box defect model and total IVD replacement model in rat tail are constructed. The dual-drug delivering electrospun scaffolds are assembled into angle-ply structure to form a highly biomimetic AF that is implanted into the box defect or used to replace the disc. In two animal models, it is found that biomimetic scaffolds with good anti-inflammatory ability enhance ECM formation and maintain the mechanical properties of IVD. Findings from this study demonstrate that the multifunctional nanofibrous scaffolds provide inspirations for IVD repair.

Nucleus pulposus cell senescence is regulated by substrate stiffness and is alleviated by LOX possibly through the integrin ß1-p38 MAPK signaling pathway.

Intervertebral disc degeneration (IVDD) is a main contributor to induce low back pain, and the pathogenic mechanism of IVDD remains unclear. The nucleus pulposus (NP) is a component of the intervertebral disc (IVD) that provides protection from mechanical stimuli. The matrix stiffness of NP tissue increases during the process of disc degeneration. Although several studies have found that pathological mechanical stimuli induce NP cell senescence, which is relevant for NP degeneration, however, the effect of matrix stiffness on NP cell senescence is not clear. Therefore, in the present study, we used polyvinyl alcohol (PVA) hydrogel with controllable stiffness to mimic the matrix stiffness of normal (4 kPa) and severely degenerated (20 kPa) NP tissue. Rat NP cells were isolated and cultured on substrates with different stiffness, and the cell proliferation, SA-ß-gal activity, cell cycle, telomerase activity and the phenotype markers of NP cells were analyzed. Moreover, cytoskeleton staining and NP cellular Young's modulus on different substrates were also measured. To further investigate how substrate stiffness affects NP cell senescence, lysyl oxidase (LOX) was used to restore the extracellular matrix (ECM) synthesis of NP cells. The expression levels of integrin ß1 and p38 MAPK were then measured. Our results showed that the 20 kPa substrate significantly induced NP cell senescence compared to the 4 kPa substrate. NP cells cultured on the 20 kPa substrate failed to maintain the expression of their phenotype markers. Furthermore, the 20 kPa substrate induced an increase of Young's modulus of NP cells, which possibly through up regulating the expressions of integrin ß1 and p38 MAPK. These results indicated that the integrin ß1-p38 MAPK signaling pathway may participated in substrate stiffness induced senescence of NP cells. LOX significantly increased ECM synthesis and inhibited substrate stiffness induced NP cell senescence, which indicated that matrix mechanics may be essential for maintaining the function of NP cell. Our results may provide a new perspective on the mechanism of IVDD by pathological matrix mechanics.

Fucoidan-loaded nanofibrous scaffolds promote annulus fibrosus repair by ameliorating the inflammatory and oxidative microenvironments in degenerative intervertebral discs.

Tissue engineering holds potential in the treatment of intervertebral disc degeneration (IDD). However, implantation of tissue engineered constructs may cause foreign body reaction and aggravate the inflammatory and oxidative microenvironment of the degenerative intervertebral disc (IVD). In order to ameliorate the adverse microenvironment of IDD, in this study, we prepared a biocompatible poly (ether carbonate urethane) urea (PECUU) nanofibrous scaffold loaded with fucoidan, a natural marine bioactive polysaccharide which has great anti-inflammatory and antioxidative functions. Compared with pure PECUU scaffold, the fucoidan-loaded PECUU nanofibrous scaffold (F-PECUU) decreased the gene and protein expression related to inflammation and the oxidative stress in the lipopolysaccharide (LPS) induced annulus fibrosus cells (AFCs) significantly (p<0.05). Especially, gene expression of Il 6 and Ptgs2 was decreased more than 50% in F-PECUU with 3.0 wt% fucoidan (HF-PECUU). Moreover, the gene and protein expression related to the degradation of extracellular matrix (ECM) were reduced in a fucoidan concentration-dependent manner significantly, with increased almost 3 times gene expression of Col1a1 and Acan in HF-PECUU. Further, in a 'box' defect model, HF-PECUU decreased the expression of COX-2 and deposited more ECM between scaffold layers when compared with pure PECUU. The disc height and nucleus pulposus hydration of repaired IVD reached up to 75% and 85% of those in the sham group. In addition, F-PECUU helped to maintain an integrate tissue structure with a similar compression modulus to that in sham group. Taken together, the F-PECUU nanofibrous scaffolds showed promising potential to promote AF repair in IDD treatment by ameliorating the harsh degenerative microenvironment. STATEMENT OF SIGNIFICANCE: Annulus fibrosus (AF) tissue engineering holds potential in the treatment of intervertebral disc degeneration (IDD), but is restricted by the inflammatory and oxidative microenvironment of degenerative disc. This study developed a biocompatible polyurethane scaffold (F-PECUU) loaded with fucoidan, a marine bioactive polysaccharide, for ameliorating IDD microenvironment and promoting disc regeneration. F-PECUU alleviated the inflammation and oxidative stress caused by lipopolysaccharide and prevented extracellular matrix (ECM) degradation in AF cells. In vivo, it promoted ECM deposition to maintain the height, water content and mechanical property of disc. This work has shown the potential of marine polysaccharides-containing functional scaffolds in IDD treatment by ameliorating the harsh microenvironment accompanied with disc degeneration.

A ROS-Responsive Simvastatin Nano-Prodrug and its Fibronectin-Targeted Co-Delivery System for Atherosclerosis Treatment.

Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1ß were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.

The Diagnostic and Grading Accuracy of 68Ga-DOTATATE and 18F-FDG PET/MR for Pancreatic Neuroendocrine Neoplasms.

Accurate diagnosis and grading are critical for pancreatic neuroendocrine neoplasm (pNEN) management. This study compares the diagnostic and grading value of 68Ga-DOTATATE PET/MR and 18F-FDG PET/MR for pNENs separately as well as in combination. A total of 36 patients with histologically confirmed pNENs, who underwent both 68Ga-DOTATATE PET/MR and 18F-FDG PET/MR within 2 weeks from 2020 to 2021, were retrospectively collected and analyzed. The maximum standardized uptake values of 68Ga-DOTATATE (G-SUVmax) and 18F-FDG (F-SUVmax) on PET and the minimum values of apparent diffusion coefficient (ADCmin) on MR were measured on the lesions with known histological grading (25 by surgery, 11 by biopsy). Receiver-operating characteristic analysis was applied to determine the cutoffs of these parameters or their combinations for differentiation between G1 and G2, as well as between low-grade and high-grade pNENs. The Spearman rank correlation coefficient was used to assess the correlation between the imaging parameters and the maximum tumor diameters. The detection rate of 68Ga-DOTATATE PET imaging alone was 95%, 87.5%, and 37.5% for G1, G2, and G3, respectively. Adding 18F-FDG PET or MR sequences of PET/MR increased the detection rate to 100% in all grades. Among the three parameters, G-SUVmax had the highest diagnostic rate in predicting tumor grade. It presented a sensitivity of 87.5% and a specificity of 80.0% with a cutoff value of 42.75 for differentiating G2 from G1 pNETs and a sensitivity and specificity of 100% and 71.4% with a cutoff value of 32.75 in predicting high-grade pNENs. The ratio of G-SUVmax to F-SUVmax (G-SUVmax/F-SUVmax) showed slight improvement in the diagnostic rate, while the product of G-SUVmax and ADCmin (G-SUVmax*ADCmin) did not improve the diagnostic rate. 68Ga-DOTATATE PET/MR alone is sufficient for the diagnosis of pNENs and the prediction of various grades.

Deep Learning-Based Classification of Cancer Cell in Leptomeningeal Metastasis on Cytomorphologic Features of Cerebrospinal Fluid.

Background: It is a critical challenge to diagnose leptomeningeal metastasis (LM), given its technical difficulty and the lack of typical symptoms. The existing gold standard of diagnosing LM is to use positive cerebrospinal fluid (CSF) cytology, which consumes significantly more time to classify cells under a microscope. Objective: This study aims to establish a deep learning model to classify cancer cells in CSF, thus facilitating doctors to achieve an accurate and fast diagnosis of LM in an early stage. Method: The cerebrospinal fluid laboratory of Xijing Hospital provides 53,255 cells from 90 LM patients in the research. We used two deep convolutional neural networks (CNN) models to classify cells in the CSF. A five-way cell classification model (CNN1) consists of lymphocytes, monocytes, neutrophils, erythrocytes, and cancer cells. A four-way cancer cell classification model (CNN2) consists of lung cancer cells, gastric cancer cells, breast cancer cells, and pancreatic cancer cells. Here, the CNN models were constructed by Resnet-inception-V2. We evaluated the performance of the proposed models on two external datasets and compared them with the results from 42 doctors of various levels of experience in the human-machine tests. Furthermore, we develop a computer-aided diagnosis (CAD) software to generate cytology diagnosis reports in the research rapidly. Results: With respect to the validation set, the mean average precision (mAP) of CNN1 is over 95% and that of CNN2 is close to 80%. Hence, the proposed deep learning model effectively classifies cells in CSF to facilitate the screening of cancer cells. In the human-machine tests, the accuracy of CNN1 is similar to the results from experts, with higher accuracy than doctors in other levels. Moreover, the overall accuracy of CNN2 is 10% higher than that of experts, with a time consumption of only one-third of that consumed by an expert. Using the CAD software saves 90% working time of cytologists. Conclusion: A deep learning method has been developed to assist the LM diagnosis with high accuracy and low time consumption effectively. Thanks to labeled data and step-by-step training, our proposed method can successfully classify cancer cells in the CSF to assist LM diagnosis early. In addition, this unique research can predict cancer's primary source of LM, which relies on cytomorphologic features without immunohistochemistry. Our results show that deep learning can be widely used in medical images to classify cerebrospinal fluid cells. For complex cancer classification tasks, the accuracy of the proposed method is significantly higher than that of specialist doctors, and its performance is better than that of junior doctors and interns. The application of CNNs and CAD software may ultimately aid in expediting the diagnosis and overcoming the shortage of experienced cytologists, thereby facilitating earlier treatment and improving the prognosis of LM.

Ocular manifestations of multiple sclerosis in patients from three countries: A Web-based survey.

OBJECTIVE: This study evaluates the epidemiological characteristics, ophthalmological manifestations, and different therapeutic options available for patients with multiple sclerosis (MS) in China, Spain, and Cuba. METHODS: A self-designed questionnaire was used to conduct a comparable descriptive cross-sectional study on patients with MS. The survey included patients' demographic data, ocular manifestations related to MS, and treatment methodology followed in the three countries. The online survey was designed using the Wenjuanxing survey platform, and a survey link was circulated through WhatsApp, WeChat, and emails. Quantitative data were expressed as mean and standard deviation, the Kruskal-Wallis test was used for non-parametric variables. Qualitative data were expressed as numerical and percentage. The chi-square test (χ2) was used to compare the group's response categories. The statistical difference was considered significant when p < 0.05. RESULTS: The female-to-male ratio in all the three countries was 2-3:1, and relapsing-remitting MS (RRMS) was the most frequent in all three countries. Vision loss was slow and progressive in half of the patients from the three countries, with no significant differences (p = 0.524). A higher percentage of steroid treatment was observed in Chinese patients in comparison with the patients from other two countries (p < 0.001), and a similar trend was seen in the use of traditional medicines. Almost one-third of patients who did not receive any treatment recovered spontaneously in all the three countries (p = 0.097). CONCLUSIONS: MS occurs more frequently in the relapsing-remitting clinical form and there is a clear female predominance. The first ocular crisis or clinical debut of MS is characterized by slow and progressive visual impairment, increasing and adding to other ocular manifestations during its evolutionary course. Spontaneous recovery of vision after an attack of optic neuritis in the course of MS is possible.