Anion-Coordination Foldamer-Based Polymer Network: from Molecular Spring to Elastomer.

Foldamer is a scaled-down version of coil spring, which can absorb and release energy by conformational change. Here, polymer networks with high-density of molecular springs were developed by employing anion-coordination-based foldamers as the monomer. The coiling of the foldamer is controlled by oligourea ligands coordinating to chloride ions; subsequently, the folding and unfolding of foldamer conformations endow the polymer network with excellent energy dissipation and toughness. The mechanical performance of the corresponding polymer network shows a dramatic increase from P-L2UCl (non-folding), P-L4UCl (a full turn) to P-L6UCl (1.5 turns), in terms of strength (2.62 MPa; 14.26 Mpa; 22.93 Mpa), elongation at break (70%; 325%; 352%), Young's modulus (2.69 MPa; 63.61 Mpa; 141.50 Mpa), and toughness (1.12 MJ/m3; 21.39 MJ/m3; 49.62 MJ/m3), respectively, which are also better than those without anion centers and the non-foldamer based counterparts. Moreover, P-L6UCl shows enhanced strength and toughness than most of the molecular-spring based polymer networks.Moreover, P-L6UCl shows enhanced strength and toughness than most of the molecular-spring based polymer networks. Thus, an effective strategy for designing high-performance anion-coordination-based materials is presented in this study.

A comprehensive review of the botany, phytochemistry, pharmacology, and toxicology of Murrayae Folium et Cacumen.

Ethnopharmacological relevance: Murrayae Folium et Cacumen (MFC) is a plant considered to be a traditional Chinese medicine with culinary value as well. The dry leaves and twigs of Murraya paniculata and M. exotica are used to treat stomach aches, rheumatism, toothaches, swelling, and insect and snake bites. They are also used to prepare spicy chicken dishes. Aim of the review: This review comprehensively summarizes the available information on the botanical characterization, phytochemistry, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC. Methods: Relevant scientific literature up to August 2023 was included in the study. Chinese and English studies on MFC were collected from databases, including PubMed, Elsevier, Web of Science, Springer, Science Direct, Wiley, ACS, and CNKI (Chinese). Doctoral and Master's dissertations were also included. Results: In total, 720 compounds have been identified and reported in the literature, including flavonoids, coumarins, alkaloids, sterols, phenylpropenols, organic acids, spirocyclopentenones, and volatile oils. Flavonoids and coumarins are the two most important bioactive compounds responsible for these pharmacological activities. MFC has anti-inflammatory, anti-bacterial, anti-microbial, anti-diabetic, anti-tumor, anti-oxidant, anti-depressant, potential anti-Alzheimer's disease, chondroprotective, and analgesic properties. The pharmacological effects include interrupting the STAT3/NF-κB/COX-2 and EGFR signaling pathways, downregulating EpCAM expression, inhibiting NF-κB and ERK signals, inhibiting the EP/cAMP/PKA signaling pathway and miR-29a/Wnt/ß-catenin signaling activity, and upregulating Foxo3a expression. Conclusion: This review demonstrates that the chemical constituents, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC support its use in traditional Chinese botanical medicines. MFC contains a wide range of chemical compounds. Flavonoids and coumarins promote strong pharmacological activity and, are low-toxicity natural phytomedicines that are widely used in medicine, food, ornamentation, and cosmetics, making MFC a promising compound for development and use in the treatment of several medical conditions.

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009-17.7 µM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.

Beyond the ß-amino alcohols framework: identification of novel ß-hydroxy pyridinium salt-decorated pterostilbene derivatives as bacterial virulence factor inhibitors.

BACKGROUND: Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. RESULTS: A series of novel ß-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an half maximal effective concentration (EC50) value of 0.28 µg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analysis of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity: 71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. CONCLUSION: Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. © 2024 Society of Chemical Industry.

Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma.

INTRODUCTION: Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options. METHODS: A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy. RESULTS: In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy. CONCLUSION: PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.

Preparation of surface molecularly imprinted polymers with Fe3O4/ZIF-8 as carrier for detection of Dimethoate in cabbage.

In this study, molecularly imprinted polymers (MIPs) were prepared for the specific recognition of organophosphorus pesticides and a rapid, efficient and simple method was established for the detection of dimethoate (DIT) in food samples. Fe3O4 magnetic nanoparticles were synthesized by co-precipitation, and Fe3O4/ZIF-8 complexes were prepared by a modified in-situ polymerization method, and then magnetic molecularly imprinted polymers (MMIPs) were prepared and synthetic route was optimized by applying density functional theory (DFT). The morphological characterization showed that the MMIPs were coarse porous spheres with an average particle size of 50 nm. The synthesized materials are highly selective for the organophosphorus pesticide dimethoate with an adsorption capacity of 461.50 mg·g-1 and are effective resistance to matrix effects. A novel method for the determination of DIT in cabbage was developed using the prepared MMIPs in combination with HPLC. The practical results showed that the method can meet the requirements for the determination of DIT in cabbage with recoveries of 85.6-121.1 % and detection limits of 0.033 µg·kg-1.

Molecularly imprinted ratiometric fluorescence sensor for visual detection of 17ß-estradiol in milk: A generalized strategy toward imprinted ratiometric fluorescence construction.

17ß-Estradiol (E2) is the typical endocrine disruptor of steroidal estrogens and is widely used in animal husbandry and dairy processing. In the environment, even lower concentrations of E2 can cause endocrine dysfunction in organisms. Herein, we have developed a novel molecularly imprinted ratiometric fluorescent sensor based on SiO2-coated CdTe quantum dots (CdTe@SiO2) and 7-hydroxycoumarin with a post-imprint mixing strategy. The sensor selectively detected E2 in aqueous environments due to its two fluorescent signals with a self-correction function. The sensor has been successfully used for spiking a wide range of real water and milk samples. The results showed that the sensor exhibited good linearity over the concentration range 0.011-50 µg/L, obtaining satisfactory recoveries of 92.4-110.6% with precisions (RSD) < 2.5%. Moreover, this sensor obtained an ultra-low detection limit of 3.3 ng/L and a higher imprinting factor of 13.66. By using estriol (E3), as a supporting model, it was confirmed that a simple and economical ratiometric fluorescent construction strategy was provided for other hydrophobic substances.

Clinical performance of metagenomic next-generation sequencing for diagnosis of invasive fungal disease after hematopoietic cell transplant.

Background: Timely diagnosis and appropriate antifungal therapy are critical for improving the prognosis of patients with invasive fungal disease (IFD) after hematopoietic stem cell transplantation (HSCT). We evaluated the performance of metagenomic next-generation sequencing (mNGS) and conventional microbiological testing (CMT), as well as the diagnosis, therapeutic management, and outcomes of IFD after HSCT. Methods: We retrospectively studied 189 patients who underwent HSCT and were considered at risk for IFD. In total, 46 patients with IFD were enrolled in this study. The IFD consensus was followed for classifying IFD incidents. Results: Forty-six patients were diagnosed with proven/probable (n = 12), possible (n = 27), and undefined (n = 7) IFD. Aspergillus was the most commonly detected fungal genus. Mucormycosis was found in 15 patients; two had Aspergillus, and one had Candida infections. Compared to CMT, mNGS significantly reduced the time required to identify pathogens (P = 0.0016). mNGS had a much higher sensitivity than CMT (84.78% vs. 36.96%; P < 0.0001). A total of 76.09% of patients received antifungal prophylaxis during fungal infections. All Pneumocystis infections occurred later than 100 days after transplantation. Among patients with Pneumocystis infection, 71.43% occurred following sulfonamide withdrawal, and subsequent treatment with sulfonamide alone or in combination with other drugs was effective. Based on the empirical antifungal treatment, the dosages, modes of administration, frequency of administration, or antifungal of 55.26% of the patients were changed according to the mNGS results. The 4-year overall survival rate of patients diagnosed with IFD after transplantation was 71.55% (95% CI, 55.18%-85.82%). Hypoproteinemia and corticosteroid use are independent risk factors for IFD. Conclusion: mNGS, which has a high sensitivity and a short detection time, aids in the diagnosis and prognosis of pathogenic fungi. As a powerful technology, mNGS can influence treatment decisions in patients with IFD following HSCT.

Accuracy of Genomic prediction for fleece traits in Inner Mongolia Cashmere goats.

The fleece traits are important economic traits of goats. With the reduction of sequencing and genotyping cost and the improvement of related technologies, genomic selection for goats has become possible. The research collect pedigree, phenotype and genotype information of 2299 Inner Mongolia Cashmere goats (IMCGs) individuals. We estimate fixed effects, and compare the estimates of variance components, heritability and genomic predictive ability of fleece traits in IMCGs when using the pedigree based Best Linear Unbiased Prediction (ABLUP), Genomic BLUP (GBLUP) or single-step GBLUP (ssGBLUP). The fleece traits considered are cashmere production (CP), cashmere diameter (CD), cashmere length (CL) and fiber length (FL). It was found that year of production, sex, herd and individual ages had highly significant effects on the four fleece traits (P < 0.01). All of these factors should be considered when the genetic parameters of fleece traits in IMCGs are evaluated. The heritabilities of FL, CL, CP and CD with ABLUP, GBLUP and ssGBLUP methods were 0.26 ~ 0.31, 0.05 ~ 0.08, 0.15 ~ 0.20 and 0.22 ~ 0.28, respectively. Therefore, it can be inferred that the genetic progress of CL is relatively slow. The predictive ability of fleece traits in IMCGs with GBLUP (56.18% to 69.06%) and ssGBLUP methods (66.82% to 73.70%) was significantly higher than that of ABLUP (36.73% to 41.25%). For the ssGBLUP method is significantly (29% ~ 33%) higher than that with ABLUP, and which is slightly (4% ~ 14%) higher than that of GBLUP. The ssGBLUP will be as an superiors method for using genomic selection of fleece traits in Inner Mongolia Cashmere goats.

Gas-Liquid Interface Route to Hybrid Copper Bromine Perovskite Single-Crystal Membrane with Dielectric Transitions and Ferromagnetic Exchanges.

Single-crystal membranes (SCMs) show great promise in the fields of sensors, light-emitting diodes, and photodetection. However, the growth of a large-area single-crystal membranes is challenging. We report a new organic-inorganic SCMs [HCMA]2CuBr4 (HCMA = cyclohexanemethylamine) crystallized at the gas-liquid interface. It also has low-temperature ferromagnetic order, high-temperature dielectric anomalies, and narrow band gap indirect semiconductor properties. Specifically, the reversible phase transition of the compound occurs at 350/341 K on cooling/heating and exhibits dielectric anomalies and stable switching performance near the phase transition temperature. The ferromagnetic exchange interaction in the inorganic octahedra and the organic layer enables ferromagnetic ordering at low-temperature 10 K. Finally, the single crystal exhibits an indirect semiconducting property with a narrow band gap of 0.99 eV. Such rich multichannel physical properties make it a potential application in photodetection, information storage and sensors.

Shanghai Community-Based Schizophrenia Cohort (SCS): a protocol for establishing a longitudinal cohort and research database of patients with schizophrenia receiving community-based mental health treatment.

INTRODUCTION: Drivers for remission, relapse and violence-related behaviour among patients with schizophrenia are the most complicated issue. METHODS AND ANALYSIS: This study aims to recruit a longitudinal cohort of patients with schizophrenia. Two suburban districts and two urban districts were randomly selected according to health service facilities, population, geographical region and socioeconomic status. Individuals (>18 years old) who received a diagnosis of schizophrenia following the International Classification of Diseases (10th edition) criteria within the past 3 years will be invited as participants. Assessments will be carried out in local community health centres. Data will be used to (1) establish a community-based schizophrenia cohort and biobank, (2) prospectively determine the course of multidimensional functional outcomes of patients with schizophrenia who are receiving community-based mental health treatment, and (3) map the trajectories of patients with schizophrenia and prospectively determine the course of multidimensional outcomes based on the differential impact of potentially modifiable moderators. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Human Research Ethics Committee of Shanghai Mental Health Center (2021-67). Results of the study will be disseminated through peer-reviewed journals. If effective, related educational materials will be released to the public.

Niobium sulfide nanocomposites as cathode materials for all-solid-state lithium batteries with enhanced electrochemical performance.

All-solid-state lithium batteries coupled with transition metal sulfide cathodes have gained significant attention due to their high energy density and exceptional safety. However, there are still critical challenges impeding their practical application, such as limited capacity delivery, weak ionic reaction kinetics and volume expansion. Herein, an a-NbS4/20%VGCF@15%Li7P3S11 nanocomposite cathode material is employed in all-solid-state batteries. A certain proportion of VGCF is introduced into crystalline NbS4 in order to mitigate the volume expansion and improve electronic conductivity. At the same time, a-NbS4/20%VGCF is in situ coated with a Li7P3S11 solid electrolyte layer to achieve an intimate interfacial contact. The obtained a-NbS4/20%VGCF@15%Li7P3S11 nanocomposite exhibits a remarkable electronic conductivity (1.0 × 10-1 S cm-1) and ionic conductivity (5.5 × 10-4 S cm-1), which are improved by five and two orders of magnitude compared to those of NbS4, respectively. The Li/Li6PS5Cl/a-NbS4/20%VGCF@15%Li7P3S11 battery exhibits a high initial discharge capacity of 1043.25 mA h g-1 at 0.1 A g-1. Even at 0.5 A g-1, it could provide a reversible capacity of 403.2 mA h g-1 after 500 cycles. This work provides a promising cathode material for all-solid-state lithium batteries with improved ionic/electronic conductivity, high reversible capacity and superior cycling stability.

Extrasynaptic GABAA receptors in central medial thalamus mediate anesthesia in rats.

Neuronal depression in the thalamus underlies anesthetic-induced loss of consciousness, while the precise sub-thalamus nuclei and molecular targets involved remain to be elucidated. The present study investigated the role of extrasynaptic GABAA receptors in the central medial thalamic nucleus (CM) in anesthesia induced by gaboxadol (THIP) and diazepam (DZP) in rats. Local lesion of the CM led to a decrease in the duration of loss of righting reflex induced by THIP and DZP. CM microinjection of THIP but not DZP induced anesthesia. The absence of righting reflex in THIP-treated rats was consistent with the increase of low frequency oscillations in the delta band in the medial prefrontal cortex. CM microinjection of GABAA receptor antagonist SR95531 significantly attenuated the anesthesia induced by systemically-administered THIP, but not DZP. Moreover, the rats with declined expression of GABAA receptor δ-subunit in the CM were less responsive to THIP or DZP. These findings explained a novel mechanism of THIP-induced loss of consciousness and highlighted the role of CM extrasynaptic GABAA receptors in mediating anesthesia.

Highly specific vaginal microbiome signature for gynecological cancers.

To investigate the vaginal microbiota signature of patients with gynecologic cancer and evaluate its diagnostic biomarker potential. We incorporated vaginal 16S rRNA-seq data from 529 women and utilized VSEARCH to analyze the raw data. α-Diversity was evaluated utilizing the Chao1, Shannon, and Simpson indices, and ß-diversity was evaluated through principal component analysis using Bray-Curtis distances. Linear discriminant analysis effect size (LEfSe) was utilized to determine species differences between groups. A bacterial co-abundance network was constructed utilizing Spearman correlation analysis. A random forest model of gynecologic tumor risk based on genus was constructed and validated to test its diagnostic efficacy. In gynecologic cancer patients, vaginal α-diversity was significantly greater than in controls, and vaginal ß-diversity was significantly separated from that of controls; there was no correlation between these characteristics and menopause status among the subject women. Women diagnosed with gynecological cancer exhibited a reduction in the abundance of vaginal Firmicutes and Lactobacillus, while an increase was observed in the proportions of Bacteroidetes, Proteobacteria, Prevotella, Streptococcus, and Anaerococcus. A random forest model constructed based on 56 genus achieved high accuracy (area under the curve = 84.96%) in gynecological cancer risk prediction. Furthermore, there were discrepancies observed in the community complexity of co-abundance networks between gynecologic cancer patients and the control group. Our study provides evidence that women with gynecologic cancer have a unique vaginal flora structure and microorganisms may be involved in the gynecologic carcinogenesis process. A gynecological cancer risk prediction model based on characteristic genera has good diagnostic value.

USP7 promotes cervical cancer progression by stabilizing MTDH expression through deubiquitination.

BACKGROUND: Metadherin (MTDH) and ubiquitin specific protease 7 (USP7) have been identified to involve in the tumorigenesis of cervical cancer (CC). USP7 is one of the deubiquitinating enzymes. Here, this study aimed to explore whether USP7 affected CC progression via interacting with MTDH and regulating its stability via deubiquitination. METHODS: qRT-PCR and western blotting assays detected the levels of genes and proteins. Functional analysis was conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays, respectively. Proteins between USP7 and MTDH were identified by co-immunoprecipitation assay. A mouse xenograft model was established for in vivo analysis. RESULTS: MTDH was highly expressed in CC tissues and cells, silencing of MTDH suppressed CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization. Mechanistically, USP7 directly bound to MTDH, and maintained its stability by removing ubiquitination on MTDH. CC tissues and cells showed high USP7 expression, and USP7 knockdown also inhibited CC cell proliferation, migration, invasion, angiogenesis and macrophage M2 polarization, and these effects mediated by USP7 knockdown were reversed by MTDH overexpression. Moreover, USP7 knockdown impeded CC growth in vivo by regulating MTDH. CONCLUSION: Collectively, USP7 promoted CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization in vitro, as well as tumor growth in vivo by regulating MTDH.

Metagenome reveals the possible mechanism that microbial strains promote methanogenesis during anaerobic digestion of food waste.

For better understanding the mechanism of microbial strains promoting methane production, four strains Hungatella xylanolytica A5, Bacillus licheniformis B1, Paraclostridium benzoelyticum C2 and Advenella faeciporci E1 were inoculated into anaerobic digestion systems. After bioaugmentation, the cumulative methane production of A5, B1, C2 and E1 groups elevated by 11.68%, 8.20%, 18.21% and 15.67% compared to CK group, respectively. The metagenomic analysis revealed that the species diversity and uniformity of the experimental groups was improved, and hydrolytic acidifying bacteria, represented by Clostridiaceae, Anaerolineaceae and Oscillospiraceae, and methanogens, such as Methanotrichaceae and Methanobacteriaceae, were enriched. Meanwhile, the abundance of key genes in carbohydrate, pyruvate and methane metabolism was increased in the inoculated groups, providing reasonable reasons for more methane production. The strengthening mechanism of microbial strains in this study offered a theoretical foundation for selecting a suitable bioaugmentation strategy to solve the problems of slow start-up and low methane production in anaerobic digestion.

MET overexpression correlated with prognosis of EGFR-mutant treatment­naïve advanced lung adenocarcinoma: a real­world retrospective study.

BACKGROUND: About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). METHODS: A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. RESULTS: Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. CONCLUSIONS: MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

Exploration of the molecular biological mechanisms and review of postoperative radiotherapy cases in tenosynovial giant cell tumors.

Tendon Sheath Giant Cell Tumor (TGCT) is a benign tumor that primarily grows within joints and bursae. However, it has a high postoperative recurrence rate, ranging from 15% to 45%. Although radiotherapy may reduce this recurrence rate, its applicability as a standard treatment is still controversial. Furthermore, the pathogenic mechanisms of TGCT are not clear, which limits the development of effective treatment methods. The unpredictable growth and high recurrence rate of TGCT adds to the challenges of disease management. Currently, our understanding of TGCT mainly depends on pathological slice analysis due to a lack of stable cell models. In this study, we first reviewed the medical records of two female TGCT patients who had undergone radiotherapy. Then, by combining bioinformatics and machine learning, we interpreted the pathogenesis of TGCT and its associations with other diseases from multiple perspectives. Based on a deep analysis of the case data, we provided empirical support for postoperative radiotherapy in TGCT patients. Additionally, our further analysis revealed the signaling pathways of differentially expressed genes in TGCT, as well as its potential associations with osteoarthritis and synovial sarcomas.

Is There an Optimal Time Window of Placement of Intracranial Pressure (ICP) Monitor for Elderly Patients With Severe Traumatic Brain Injury? An 11-Year Institutional Cohort Study With Restricted Cubic Spline Analysis.

Severe traumatic brain injury (sTBI) is a prominent contributor to both morbidity and mortality in the elderly population. The monitoring of intracranial pressure (ICP) is crucial in the management of sTBI patients. Nevertheless, the appropriate timing for the placement of ICP monitor in elderly sTBI patients remains uncertain. To determine the optimal timing for the placement of ICP monitor in elderly sTBI patients, in this retrospective cohort study, we collected data from elderly patients (> 65 years) who suffered sTBI and received ICP monitors at Tangdu Hospital, The Fourth Military Medical University, between January 2011 and December 2021. To examine the relationship between the time of ICP monitor placement and in-hospital mortality, we conducted a multi-variate-adjusted restricted cubic spline (RCS) analysis. Additionally, logistic regression analysis was applied to further analyze the influencing factors contributing to early or late ICP monitor placements. A total of 283 eligible elderly TBI patients were included in the current analysis. The in-hospital mortality rate was 73 out of 283 (26%). The RCS analysis demonstrated an inverted U-shaped curve in the relationship between the timing of ICP monitor placement and in-hospital mortality. For the elderly sTBI patient cohort, 6 h was identified as the crucial moment for the treatment strategy. In addition, the protective time window for ICP placement was less than 4.92 h for the GCS 3-5 group, and less than 8.26 h for the GCS 6-8 group. However, the clinical benefit of ICP placement decreased gradually over time. The relationship between ICP placement and in-hospital mortality was non-linear, exhibiting an inverted U-shaped curve in elderly patients with sTBI. For elderly patients with sTBI, early (≤ 6 h) ICP placement was associated with reduced in-hospital mortality. The clinical benefit of ICP placement decreased beyond the optimal time window.

Colon-targeted hydroxyethyl starch-curcumin microspheres with high loading capacity ameliorate ulcerative colitis via alleviating oxidative stress, regulating inflammation, and modulating gut microbiota.

Curcumin (CUR) is a natural polyphenol that holds promise for treating ulcerative colitis (UC), yet oral administration of CUR exhibits limited bioavailability and existing formulations for oral delivery of CUR often suffer from unsatisfactory loading capacity. This study presents hydroxyethyl starch-curcumin microspheres (HC-MSs) with excellent CUR loading capacity (54.52 %), and the HC-MSs can further encapsulate anti-inflammatory drugs dexamethasone (DEX) to obtain a combination formulation (DHC-MSs) with high DEX loading capacity (19.91 %), for combination therapy of UC. The microspheres were successfully engineered, retaining the anti-oxidative and anti-inflammatory activities of parental CUR and demonstrating excellent biocompatibility and controlled release properties, notably triggered by α-amylase, facilitating targeted drug delivery to inflamed sites. In a mouse UC model induced by dextran sulfate sodium, the microspheres effectively accumulated in inflamed colons and both HC-MSs and DHC-MSs exhibited superior therapeutic efficacy in alleviating UC symptoms compared to free DEX. Moreover, mechanistic exploration uncovered the multifaceted therapeutic mechanisms of these formulations, encompassing anti-inflammatory actions, mitigation of spleen enlargement, and modulation of gut microbiota composition. These findings underscore the potential of HC-MSs and DHC-MSs as promising formulations for UC, with implications for advancing treatment modalities for various inflammatory bowel disorders.