Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy.

Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed and synthesized a series of small molecules as potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR (IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 µM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat cell coculture model. Furthermore, EP26 possessed favorable pharmacokinetic properties (F = 22%) and inhibited tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased CD4+ cells and CD8+ cells in tumor microenvironment. Collectively, these results suggest that EP26 represents the first small-molecule-based PD-L1/EGFR dual inhibitor deserving further investigation as an immunomodulating agent for cancer treatment.

Antidiabetic Close Loop Based on Wearable DNA-Hydrogel Glucometer and Implantable Optogenetic Cells.

Diabetes mellitus and its associated secondary complications have become a pressing global healthcare issue. The current integrated theranostic plan involves a glucometer-tandem pump. However, external condition-responsive insulin delivery systems utilizing rigid glucose sensors pose challenges in on-demand, long-term insulin administration. To overcome these challenges, we present a novel model of antidiabetic management based on printable metallo-nucleotide hydrogels and optogenetic engineering. The conductive hydrogels were self-assembled by bioorthogonal chemistry using oligonucleotides, carbon nanotubes, and glucose oxidase, enabling continuous glucose monitoring in a broad range (0.5-40 mM). The optogenetically engineered cells were enabled glucose regulation in type I diabetic mice via a far-red light-induced transgenic expression of insulin with a month-long avidity. Combining with a microchip-integrated microneedle patch, a prototyped close-loop system was constructed. The glucose levels detected by the sensor were received and converted by a wireless controller to modulate far-infrared light, thereby achieving on-demand insulin expression for several weeks. This study sheds new light on developing next-generation diagnostic and therapy systems for personalized and digitalized precision medicine.

Time delays between physiological signals in interpreting the body's responses to intermittent hypoxia in obstructive sleep apnea.

OBJECTIVE: Intermittent hypoxia, the primary pathology of obstructive sleep apnea (OSA), causes cardiovascular responses resulting in changes in hemodynamic parameters such as stroke volume (SV), blood pressure (BP), and heart rate (HR). However, previous studies have produced very different conclusions, such as suggesting that SV increases or decreases during apnea. A key reason for drawing contrary conclusions from similar measurements may be due to ignoring the time delay in acquiring response signals. By analyzing the signals collected during hypoxia, we aim to establish criteria for determining the delay time between the onset of apnea and the onset of physiological parameter response. Approach. We monitored oxygen saturation (SpO2), transcutaneous oxygen pressure (TcPO2), and hemodynamic parameters SV, HR, and BP, during sleep in 66 patients with different OSA severity to observe body's response to hypoxia and determine the delay time of above parameters. Data were analyzed using the Kruskal-Wallis test, Quade test. and Spearman test. Main Results. We found that simultaneous acquisition of various parameters inevitably involved varying degrees of response delay (7.12 - 25.60 seconds). The delay time of hemodynamic parameters was significantly shorter than that of SpO2 and TcPO2 (p < 0.01). OSA severity affected the response delay of SpO2, TcPO2, SV, MBP, and HR (p < 0.05). SV delay time was negatively correlated with the apnea-hypopnea index (r = -0.4831, p < 0.0001). Significance. The real body response should be determined after removing the effect of delay time, which is the key to solve the problem of drawing contradictory conclusions from similar studies. The methods and important findings presented in this study provide key information for revealing the true response of the cardiovascular system during hypoxia, indicating the importance of proper signal analysis for correctly interpreting the cardiovascular hemodynamic response phenomena and exploring their physiological and pathophysiological mechanisms.

Sub-Second Electrochemiluminescence Imaging Assay of SARS-CoV-2 Nucleocapsid Protein Based on Reticulation of Endo-Coreactants.

The nonphotodriven electrochemiluminescence (ECL) imageology necessitates concentrated coreacting additives plus longtime exposures. Seeking biosafe and streamlined ensembles can help lower the bar for quality ECL bioimaging to which call the crystallized endo-coreaction in nanoreticula might provide a potent solution. Herein, an exo-coreactant-free ECL visualizer was fabricated out in one-pot, which densified the dyad triethylamine analogue: 1,4-diazabicyclo-[2.2.2]octane (DABCO) in the lamellar hive of 9,10-di(p-carboxyphenyl)anthracene (DPA)-Zn2+. This biligated non-noble metal-organic framework (m-MOF) facilitated a self-contained anodic ECL with a yield as much as 70% of Ru(bPy)32+ in blank phosphate buffered saline. Its featured two-stage emissions rendered an efficient and endurant CCD imaging at 1.0 V under mere 0.5 s swift snapshots and 0.1 s step-pulsed stimulation. Upon structural and spectral cause analyses as well as parametric set optimization, simplistic ECL-graphic immunoassay was mounted in the in situ imager to enact an ultrasensitive measurement of coronaviral N-protein in both signal-on and off modes by the privilege of straight surface amidation on m-MOFs, resulting in a wide dynamic range (10-4-10 ng/mL), a competent detection limit down to 56 fg/mL, along with nice precision and parallelism in human saliva tests. The overall work manifests a rudimentary endeavor in self-sufficient ECL visuality for brisk, biocompatible, and brilliant production of point-of-care diagnostic "Big Data".

Single-cell transcriptomics reveals cell atlas and identifies cycling tumor cells responsible for recurrence in ameloblastoma.

Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.

Understanding community-dwelling older adults' preferences for home- and community-based services: A conjoint analysis.

BACKGROUND: Older adults' preference for home- and community-based service programs has been highlighted as an essential but usually ignored ingredient in current care models. Disentangling how preferences contribute to older adults' decision-making could facilitate finding optimal ways to deliver home- and community-based services in times of increasing scarcity. OBJECTIVE: To identify Chinese community-dwelling older adults' preference structure for home- and community-based services and thus to optimize service provision. METHODS: Conjoint analysis, a preference-based technique, was employed to study older adults' preferences. A stepwise qualitative approach was first adopted to identify the attributes and attribute levels of home- and community-based services. Scenarios were defined through an orthogonal fractional factorial design, and a cross-sectional survey was conducted through a face-to-face, anonymous questionnaire. Conjoint analysis was performed to determine preference weights representing the relative importance of the identified attributes, and cluster analysis was performed to identify clusters of participants with similar preference structures. All data analyses were performed using SAS v9.4 and SPSS 22.0. RESULTS: A total of 321 of 350 invited participants completed the questionnaire. Four attributes were identified and used to create the conjoint scenarios: care-giving attitude, price, technical care-giving skills, and the type of service provider. Care-giving attitude was the most valued attribute for older adults when making decisions (relative importance score = 48.28), followed by price (relative importance score = 21.618), technical care-giving skills (relative importance score = 19.518), and finally, the type of service provider (relative importance score = 10.585). Three preference phenotypes were identified by applying cluster analysis: "price-oriented", "comprehensively balanced", and "attitude-oriented". CONCLUSION: The present study underscored the importance of considering attributes valued by Chinese older adults in the design and delivery of home- and community-based services. The preference structure, including the utility score of the attribute levels, differs among older adults. The findings could inform future research and practice and suggest incorporating flexibility during the service delivery stage.

Color Night Light Remote Sensing Images Generation Using Dual-Transformation.

Traditional night light images are black and white with a low resolution, which has largely limited their applications in areas such as high-accuracy urban electricity consumption estimation. For this reason, this study proposes a fusion algorithm based on a dual-transformation (wavelet transform and IHS (Intensity Hue Saturation) color space transform), is proposed to generate color night light remote sensing images (color-NLRSIs). In the dual-transformation, the red and green bands of Landsat multi-spectral images and "NPP-VIIRS-like" night light remote sensing images are merged. The three bands of the multi-band image are converted into independent components by the IHS modulated wavelet transformed algorithm, which represents the main effective information of the original image. With the color space transformation of the original image to the IHS color space, the components I, H, and S of Landsat multi-spectral images are obtained, and the histogram is optimally matched, and then it is combined with a two-dimensional discrete wavelet transform. Finally, it is inverted into RGB (red, green, and blue) color images. The experimental results demonstrate the following: (1) Compared with the traditional single-fusion algorithm, the dual-transformation has the best comprehensive performance effect on the spatial resolution, detail contrast, and color information before and after fusion, so the fusion image quality is the best; (2) The fused color-NLRSIs can visualize the information of the features covered by lights at night, and the resolution of the image has been improved from 500 m to 40 m, which can more accurately analyze the light of small-scale area and the ground features covered; (3) The fused color-NLRSIs are improved in terms of their MEAN (mean value), STD (standard deviation), EN (entropy), and AG (average gradient) so that the images have better advantages in terms of detail texture, spectral characteristics, and clarity of the images. In summary, the dual-transformation algorithm has the best overall performance and the highest quality of fused color-NLRSIs.

Virtual reality-based simulation intervention for enhancing the empathy of informal caregivers of people with dementia: A mixed-methods systematic review.

Dementia is a long-term and progressive syndrome that not only influences the person with dementia (PWD) but also the caregiver. However, informal caregivers are not always empathic and understand the symptoms of dementia, leading to destructive caregiving relationships and poor quality of caregiving. VR-based simulation interventions can provide a more realistic and memorable learning experience for caregivers to walk in PWDs' shoes. This review aimed to provide practitioners and researchers with insights on developing and/or adopting an effective VR-based simulation intervention for enhancing the empathy of informal caregivers of PWD. A mixed-methods systematic review was conducted. Quantitative, qualitative, and mixed-methods studies were searched from MEDLINE, PsycINFO, CINAHL, Scopus, Embase, and Cochrane Library updating. Standard JBI critical appraisal instruments were used for the quality appraisal. A convergent segregated approach was used to synthesize and integrate the data. A total of seven studies were included. Inconsistent quantitative results were reported on the effects of VR-based simulation on empathy enhancement. Significant effects were reported on knowledge of dementia and emotion-focused coping strategies. Two themes were generated from the qualitative studies, including "Informal caregivers gained better insight into problems encountered by older people with dementia" and "Thinking from the perspective of older people with dementia, leading to changes in attitudes and behaviours towards dementia". The qualitative synthesized evidence showed that informal caregivers gained better insight into problems encountered by PWD, but the quantitative synthesized results are inconsistent. Yet, informal caregivers experienced a change in attitude by thinking from the perspective of PWD.

Predicting ICU readmission risks in intracerebral hemorrhage patients: Insights from machine learning models using MIMIC databases.

BACKGROUND: Intracerebral hemorrhage (ICH) is a stroke subtype characterized by high mortality and complex post-event complications. Research has extensively covered the acute phase of ICH; however, ICU readmission determinants remain less explored. Utilizing the MIMIC-III and MIMIC-IV databases, this investigation develops machine learning (ML) models to anticipate ICU readmissions in ICH patients. METHODS: Retrospective data from 2242 ICH patients were evaluated using ICD-9 codes. Recursive feature elimination with cross-validation (RFECV) discerned significant predictors of ICU readmissions. Four ML models-AdaBoost, RandomForest, LightGBM, and XGBoost-underwent development and rigorous validation. SHapley Additive exPlanations (SHAP) elucidated the effect of distinct features on model outcomes. RESULTS: ICU readmission rates were 9.6% for MIMIC-III and 10.6% for MIMIC-IV. The LightGBM model, with an AUC of 0.736 (95% CI: 0.668-0.801), surpassed other models in validation datasets. SHAP analysis revealed hydrocephalus, sex, neutrophils, Glasgow Coma Scale (GCS), specific oxygen saturation (SpO2) levels, and creatinine as significant predictors of readmission. CONCLUSION: The LightGBM model demonstrates considerable potential in predicting ICU readmissions for ICH patients, highlighting the importance of certain clinical predictors. This research contributes to optimizing patient care and ICU resource management. Further prospective studies are warranted to corroborate and enhance these predictive insights for clinical utilization.

Intestinal flora study reveals the mechanism of Danggui Shaoyao San and its decomposed recipes to improve cognitive dysfunction in the rat model of Alzheimer's disease.

Background: Alzheimer's disease (AD), characterized by a severe decline in cognitive function, significantly impacts patients' quality of life. Traditional Chinese Medicine (TCM) presents notable advantages in AD treatment, closely linked to its regulation of intestinal flora. Nevertheless, a comprehensive exploration of the precise role of intestinal flora in AD remains lacking. Methods: We induced an AD model through bilateral intracerebroventricular injection of streptozotocin in rats. We divided 36 rats randomly into 6 groups: sham-operated, model, Danggui Shaoyao San (DSS), and 3 DSS decomposed recipes groups. Cognitive abilities were assessed using water maze and open field experiments. Nissl staining examined hippocampal neuron integrity. Western blot analysis determined synaptoprotein expression. Additionally, 16S rDNA high-throughput sequencing analyzed intestinal flora composition. Results: DSS and its decomposed recipe groups demonstrated improved learning and memory in rats (P<0.01). The open field test indicated increased central zone residence time and locomotor activity distance in these groups (P<0.05). Furthermore, the DSS and decomposed recipe groups exhibited reduced hippocampal neuronal damage and increased expression levels of synapsin I (P<0.05) and PSD95 (P<0.01) proteins. Alpha and Beta diversity analyses showed that the intestinal flora species richness and diversity in the DSS and decomposed recipe groups were similar to those in the sham-operated group, signifying a significant restorative effect (P<0.05). Conclusion: The combination of DSS and its decomposed recipes can reduce the abundance of harmful gut microbiota, leading to improvements in cognitive and learning abilities.

Efficacy and safety of remimazolam compared with propofol in hypertensive patients undergoing breast cancer surgery: a single-center, randomized, controlled study.

BACKGROUND: Remimazolam, as a novel anesthetic, has recently been shown to improve hemodynamic stability during anesthesia induction and maintenance; however, it has not been reported in the hypertensive population. This study aimed to compare the effects of remimazolam and propofol on hemodynamic stability in hypertensive patients undergoing breast cancer surgery. METHODS: We enrolled 120 hypertensive patients undergoing breast cancer surgery in this prospective study and randomly allocated them to remimazolam (n = 60) or propofol (n = 60) groups. Anesthesia regimens were consistent between groups, except for the administration of remimazolam and propofol. Our primary outcome was the incidence of post-induction hypotension, which was either an absolute mean arterial pressure (MAP) < 60 mmHg or a > 30% relative drop in MAP compared to baseline within 20 min of induction or from induction to the start of surgery. Secondary outcomes included minimum MAP and MAP at different time points during anesthesia, the application of vasoactive drugs, adverse events, and the patient's self-reported Quality of Recovery-40 scale for the day after surgery. RESULTS: The incidence of post-induction hypotension was lower and the minimum MAP during induction was higher in the remimazolam group than those in the propofol group. There were no significant differences between the two groups in the remaining outcomes. CONCLUSION: Remimazolam is safe and effective in hypertensive patients undergoing breast cancer surgery. Induction with remimazolam in hypertensive patients may result in more stable hemodynamics than propofol. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trials Registry ( http://www.chictr.org.cn ) on 03/12/2020, with registration number ChiCTR2000040579.

Factors influencing the psychosocial well-being of people with dementia and their informal caregivers: A systematic review of dyadic studies.

Individuals with dementia and their informal caregivers face significant challenges to their psychosocial well-being, necessitating immediate attention. In spite of the prevalence of this problem, there is limited data regarding the factors that influence the dyadic psychosocial well-being and potential actor-partner influencing mechanisms. Therefore, this review was conducted to synthesise the factors associated with the psychosocial well-being of people with dementia and their informal caregivers. MEDLINE via EBSCOhost, CINAHL, PsycINFO, Embase and Scopus were systematically searched to identify relevant studies. Quantitative, qualitative or mixed-method studies examining the factors influencing dyadic psychosocial well-being outcomes were included. The quality of included studies was assessed using Joanna Briggs Institute Critical Appraisal checklists. A narrative synthesis approach was employed for data analysis. A total of 3217 records were yield, out of which 26 studies were included in the analysis. Quality of life emerged as the most extensively investigated dyadic psychosocial well-being outcome, followed by depression. The interrelation between the quality of life for people with dementia and caregivers was observed, where individual members' quality of life was influenced by their own, partner and dyadic factors. However, there is a dearth of research exploring the mechanisms through which one member's factors exert influence on both their own and partner's quality of life within the dyad. This gap also exists for other psychosocial well-being outcomes, such as depression and anxiety. Further research is warranted to elucidate the underlying mechanisms through which dyadic members influence their own and their partner's psychosocial well-being.

Characteristics and Mechanism of Upper Airway Collapse Revealed by Dynamic MRI During Natural Sleep in Patients with Severe Obstructive Sleep Apnea.

Purpose: Upper airway collapse during sleep in patients with obstructive sleep apnea (OSA) is a complex and dynamic phenomenon. By observing and analyzing the dynamic changes in the upper airway and its surrounding tissues during airway obstruction, we aim to reveal dynamic characteristics in different obstruction patterns, and the relationship between anatomical features during normal breathing and dynamic characteristics of airway obstruction. Patients and Methods: Dynamic MRI was performed in 23 male patients (age range 26-63) with severe OSA diagnosed by overnight polysomnography, and obstruction events were identified from their images. Dynamic changes in parameters of the upper airway and surrounding tissues were measured to assess the key characteristics in different obstruction patterns. Results: We categorized airway obstruction into four types based on the obstruction location and motion characteristics of tissues during collapse, and detailed the alterations in the airway and surrounding tissues under each obstruction pattern. In all 112 obstruction events extracted from the dynamic images of 23 patients, type A (retropalatal obstruction caused by the soft palate separated from the tongue), BI, BII (both retropalatal obstructions caused by the soft palate attached to the tongue, and C (retropalatal and retroglossal obstruction caused by the soft palate and the tongue), accounted for 28.6%, 44.6%, 12.5%, and 14.3% respectively. In severe OSA patients with tongue and palatal obstruction related to type B or C, the more posterior hyoid position, shorter distance between tongue and uvula, and wider retropalatal space, the larger the tongue displacement and deformation during collapse, and the greater the reduction in airway space. Conclusion: There are multiple airway obstruction patterns, each with its own anatomical characteristics and behaviors during collapse. Hyoid position, tongue and uvula distance, and retropalatal space play an important role in airway collapse and should be paid more attention in the treatment of OSA.

Comprehensive assessment of base excision repair (BER)-related lncRNAs as prognostic and functional biomarkers in lung adenocarcinoma: implications for personalized therapeutics and immunomodulation.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, and comprehending its molecular mechanisms is pivotal for advancing treatment efficacy. This study aims to explore the prognostic and functional significance of base excision repair (BER)-related long non-coding RNAs (BERLncs) in LUAD. METHODS: A risk score model for BERLncs was developed using the least absolute shrinkage and selection operator regression and Cox regression analysis. Model validation and prognostic evaluation were performed using Kaplan-Meier and receiver-operating characteristic curve analyses. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to elucidate the potential biological functions of BERLncs. Comparative analyses were carried out to investigate disparities in tumor mutation burden (TMB), immune infiltration, tumor immune dysfunction and exclusion (TIDE) score, chemosensitivity, and immune checkpoint gene expression between the two risk groups. RESULTS: A predictive risk score model comprising 19 BERLncs was successfully developed. Patients were divided into high-risk and low-risk groups according to the median risk score. The high-risk subgroup exhibited significantly inferior overall survival. Functional enrichment analysis revealed pathways associated with lung cancer development, notably the neuroactive ligand-receptor interaction pathway. High-risk patients demonstrated elevated TMB, diminished TIDE scores, and an immunosuppressive tumor microenvironment, while low-risk patients displayed potential benefits from immunotherapy. Additionally, the risk model identified potential anticancer agents. CONCLUSION: The risk score model based on BERLncs shows promise as a prognostic biomarker for LUAD patients, providing valuable insights for clinical decision-making, therapeutic strategies, and understanding of underlying biological mechanisms.

Mitochondrial dysfunction: A fatal blow in depression.

Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining the metabolic balance through intracellular Ca2+ homeostasis, oxidative stress, and axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to the hippocampal neurons is a key component of the plasticity regulation of synapses and plays a critical role in the mechanism of depression. There is evidence suggesting that mitochondrial dysfunction is associated with synaptic impairment. The maintenance of mitochondrial homeostasis includes quantitative maintenance and quality control of mitochondria. Mitochondrial biogenesis produces new and healthy mitochondria, and mitochondrial dynamics cooperates with mitophagy to remove damaged mitochondria. These processes maintain mitochondrial population stability and exert neuroprotective effects against early depression. In contrast, mitochondrial dysfunction is observed in various brain regions of patients with major depressive disorders. The accumulation of defective mitochondria accelerates cellular nerve dysfunction. In addition, impaired mitochondria aggravate alterations in the brain microenvironment, promoting neuroinflammation and energy depletion, thereby exacerbating the development of depression. This review summarizes the influence of mitochondrial dysfunction and the underlying molecular pathways on the pathogenesis of depression. Additionally, we discuss the maintenance of mitochondrial homeostasis as a potential therapeutic strategy for depression.

Point-of-Care Diagnosis on Selenium Nutrition Based on Time-Resolved Fluorometric Glycoaffinity Chromatography.

Given the lack of timely evaluation of the well-received selenium fortification, a neat lateral-flow chromatographic solution was constructed here by using the recently identified urinary selenosugar (Sel) as a strongly indicative marker. As there are no ready-made receptors for this synthetic standard, phenylboronic acid (PBA) esterification and Dolichos biflorus agglutinin (DBA) affinity joined up to pinch and pin down the analyte into a sandwich-type glycol complex. Pilot lectin screening on homemade glycan microarrays verified such a new pairing between dual recognizers as PBA-Sel-DBA with a firm monosaccharide-binding constant. To quell the sample autofluorescence, europium nanoparticles with efficient long-life afterglow were employed as conjugating probes under 1 µs excitation. After systematic process optimizations, the prepared Sel-dipstick achieved swift and sensitive fluorometry over the physiological level of the target from 0.1 to 10 µM with a detection limit down to 0.06 µM. Further efforts were made to eliminate matrix effects from both temperature and pH via an approximate formula. Upon completion, the test strips managed to quantify the presence of Sel in not just imitated but real human urine, with comparable results to those in the references. As far as we know, this would be the first in-house prototype for user-friendly and facile diagnosis of Se nutrition with fair accuracy as well as selectivity. Future endeavors will be invested to model a more traceable Se-supplementary plan based on the rhythmic feedback of Sel excretion.

Association between preoperative anemia and postoperative short-term outcomes in patients undergoing colorectal cancer surgery - a propensity score matched retrospective cohort study.

BACKGROUND: Based on previous studies which failed to analyze important confounding variables, the association between preoperative anemia and outcomes of patients who underwent colorectal cancer (CRC) surgery has not been clearly demonstrated. This study aimed to investigate the relationship between preoperative anemia and short-term outcomes in patients with CRC. METHODS: Data from a retrospective collective database of patients who underwent CRC surgery at our hospital between September 1, 2019 and September 30, 2021 were retrieved and analyzed, and the short-term postoperative outcomes of anemic (hemoglobin < 120 g dL- 1 for female, hemoglobin < 130 g dL- 1 for male) and non-anemic patients were analyzed, using a 1:1 propensity score matching (PSM) analysis. RESULTS: After excluding some cases, the remaining 1894 patients had complete data available for analysis. The incidence of preoperative anemia was 39.8% (754/1894). Before PSM, preoperative anemia patients had a higher risk of major morbidity than non-anemia patients (27.2% vs. 23.1%, odds ratio [OR] 1.245, 95% confidence interval [CI] 1.008-1.538, P = 0.042). After PSM was performed in the cohort, 609 patients remained in the anemic and non-anemic groups. The incidence of major morbidity (25.8% vs. 24.0%, OR 1.102, 95% CI 0.849-1.429, P = 0.446) between anemic and non-anemic patients was comparable. No significant difference was found between the anemic and non-anemic groups in postoperative length of stay (8.0 [6.0-12.0] vs. 8.0 [7.0-11.0], P = 0.311). The sensitivity analysis results were in accordance with the primary outcome. Furthermore, we did not ascertain any discernible correlation between the extent of anemia and significant major morbidity. CONCLUSIONS: Compared with preoperative non-anemia, anemia status does not seem to be associated with major morbidity in patients with CRC surgery. It is noteworthy that, anemia is insufficient as a solitary risk factor and may be a better marker of poor health resulting from multiple factors. TRIAL REGISTRATION: Registration Authority: Chinese Clinical Trial Registry; Registration number and date: ChiCTR2100049696, 08/08/2021; Principal investigator: Ting Yan; Link to trial registry: http://www.chictr.org.cn/showproj.aspx?proj=131698 ; .

Enzymatic synthesis of branched chain fatty acid-enriched structured triacylglycerols via esterification with glycerol.

While branched-chain fatty acids (BCFA)-enriched triacylglycerols (TAG) has various health benefits, its preparation has not been reported. This study aimed to synthesize high-purity BCFA-enriched structured TAG. First, BCFA was enriched from lanolin through saponification, calcification, and urea complexation. Next, BCFA-enriched TAG was synthesized by enzymatic esterification of BCFA and glycerol. Then, lipases were screened by molecular docking and practical experiments, which suggested that Lipozyme 435 was the best lipase for esterification since it had the lowest binding energy. Structured TAG containing 92.23% BCFA was synthesized under conditions optimized by single-factor experiments. Furthermore, molecular distillation was adapted to remove excess fatty acids and small molecule impurities. Finally, high-purity BCFA-enriched structured lipid containing 70.26% TAG was obtained. Overall, this study successfully developed a method for synthesizing BCFA-enriched structured TAG, which holds great promise for applications in value-added foods.

Discovery of novel 2-aminopyridine derivatives as ROS1 and ALK dual inhibitors to combat drug-resistant mutants including ROS1G2032R and ALKG1202R.

Clinical treatment by FDA-approved ROS1/ALK inhibitor Crizotinib significantly improved the therapeutic outcomes. However, the emergence of drug resistance, especially driven by acquired mutations, have become an inevitable problem and worsened the clinical effects of Crizotinib. To combat drug resistance, some novel 2-aminopyridine derivatives were designed rationally based on molecular simulation, then synthesised and subjected to biological test. The preferred spiro derivative C01 exhibited remarkable activity against CD74-ROS1G2032R cell with an IC50 value of 42.3 nM, which was about 30-fold more potent than Crizotinib. Moreover, C01 also potently inhibited enzymatic activity against clinically Crizotinib-resistant ALKG1202R, harbouring a 10-fold potency superior to Crizotinib. Furthermore, molecular dynamic disclosed that introducing the spiro group could reduce the steric hindrance with bulky side chain (Arginine) in solvent region of ROS1G2032R, which explained the sensitivity of C01 to drug-resistant mutant. These results indicated a path forward for the generation of anti Crizotinib-resistant ROS1/ALK dual inhibitors.

A Novel and Highly Selective Epidermal Growth Factor Receptor Inhibitor, SMUZ106, for the Treatment of Glioblastoma.

Targeting the epidermal growth factor receptor (EGFR) is one of the potential ways to treat glioblastoma (GBM). In this study, we investigate the anti-GBM tumor effects of the EGFR inhibitor SMUZ106 in both in vitro and in vivo conditions. The effects of SMUZ106 on the growth and proliferation of GBM cells were explored through MTT and clone formation experiments. Additionally, flow cytometry experiments were conducted to study the effects of SMUZ106 on the cell cycle and apoptosis of GBM cells. The inhibitory activity and selectivity of SMUZ106 to the EGFR protein were proved by Western blotting, molecular docking, and kinase spectrum screening methods. We also conducted a pharmacokinetic analysis of SMUZ106 hydrochloride following i.v. or p.o. administration to mice and assessed the acute toxicity level of SMUZ106 hydrochloride following p.o. administration to mice. Subcutaneous and orthotopic xenograft models of U87MG-EGFRvIII cells were established to assess the antitumor activity of SMUZ106 hydrochloride in vivo. SMUZ106 could inhibit the growth and proliferation of GBM cells, especially for the U87MG-EGFRvIII cells with a mean IC50 value of 4.36 µM. Western blotting analyses showed that compound SMUZ106 inhibits the level of EGFR phosphorylation in GBM cells. It was also shown that SMUZ106 targets EGFR and presents high selectivity. In vivo, the absolute bioavailability of SMUZ106 hydrochloride was 51.97%, and its LD50 exceeded 5000 mg/kg. SMUZ106 hydrochloride significantly inhibited GBM growth in vivo. Furthermore, SMUZ106 inhibited the activity of U87MG-resistant cells induced by temozolomide (TMZ) (IC50: 7.86 µM). These results suggest that SMUZ106 hydrochloride has the potential to be used as a treatment method for GBM as an EGFR inhibitor.