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1.
IEEE Trans Cybern ; PP2024 May 07.
Article En | MEDLINE | ID: mdl-38713577

State responses for several classes of linear systems are investigated in this article. The involved systems include state-delayed linear systems, and high-order linear systems. At first, the single-fundamental-matrix-based approach is extended to these systems, and their state responses are expressed by their fundamental matrices (FMs). In addition, the multiple-FMs-based approach is presented for these systems. Based on a group of FMs, the state responses for the considered time-invariant systems are derived. For the considered time-variant systems, their state responses are explicitly expressed by their transition matrices. As an application of the fundamental-matrix-based approach, a stabilizing control law is designed for a class of high-order fully actuated continuous-time linear systems with a single input-delay.

2.
Asian J Androl ; 2024 May 03.
Article En | MEDLINE | ID: mdl-38722110

ABSTRACT: Ejaculation is regulated by the central nervous system. However, the central pathophysiology of primary intravaginal anejaculation (PIAJ) is unclear. The present study aimed to examine the changes in regional brain activity and functional connectivity underlying PIAJ. A total of 20 PIAJ patients and 16 healthy controls (HCs) were enrolled from September 2020 to September 2022 in the Department of Andrology, Nanjing Drum Tower Hospital (Nanjing, China). Magnetic resonance imaging data were acquired from all participants and then were preprocessed. The measures of fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) were calculated and compared between the groups. PIAJ patients showed increased fALFF values in the left precuneus compared with HCs. Additionally, PIAJ patients showed increased ReHo values in the left precuneus, left postcentral gyrus, left superior occipital gyrus, left calcarine fissure, right precuneus, and right middle temporal gyrus, and decreased ReHo values in the left inferior parietal gyrus, compared with HCs. Finally, brain regions with altered fALFF and ReHo values in PIAJ patients showed increased FC with widespread cortical regions, which included the frontal, parietal, temporal, and occipital regions, compared with HCs. In conclusion, increased regional brain activity in the parietal, temporal, and occipital regions, and increased FC between these brain regions, may be associated with PIAJ occurrence.

3.
Phytochemistry ; 223: 114120, 2024 May 04.
Article En | MEDLINE | ID: mdl-38705265

Eleven previously undescribed sesquiterpenoids (8-18), one undescribed jasmonic acid derivative (35) and 28 known compounds were isolated from the leaves of Artemisia stolonifera. Undescribed compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction and ECD calculation. Compound 8 was identified as a rare sesquiterpenoid featuring a rearranged 5/8 bicyclic ring system, whereas compound 17 was found to be an unprecedented monocyclic sesquiterpenoid with methyl rearrangement. Evaluation of biological activity showed that compounds 1-5 and 7 displayed cytotoxicity against six tumor cells. In the meantime, compounds 11, 12, 18 and 35 exhibited inhibitory effects against LPS-stimulated NO production in RAW 264.7 macrophage cells and reduced the transcription of IL-6 and IL-1ß in a dose-dependent manner at 25, 50 and 100 µM. Moreover, the anti-inflammatory-based network pharmacology and molecular docking analyses revealed potential target proteins of 11, 12, 18 and 35.

4.
Heliyon ; 10(8): e30123, 2024 Apr 30.
Article En | MEDLINE | ID: mdl-38699735

Background: Tumor genetic anomalies and immune dysregulation are pivotal in the progression of multiple myeloma (MM). Accurate patient stratification is essential for effective MM management, yet current models fail to comprehensively incorporate both molecular and immune profiles. Methods: We examined 776 samples from the MMRF CoMMpass database, employing univariate regression with LASSO and CIBERSORT algorithms to identify 15 p53-related genes and six immune cells with prognostic significance in MM. A p53-TIC (tumor-infiltrating immune cells) classifier was constructed by calculating scores using the bootstrap-multicox method, which was further validated externally (GSE136337) and through ten-fold internal cross-validation for its predictive reliability and robustness. Results: The p53-TIC classifier demonstrated excellent performance in predicting the prognosis in MM. Specifically, patients in the p53low/TIChigh subgroup had the most favorable prognosis and the lowest tumor mutational burden (TMB). Conversely, those in the p53high/TIClow subgroup, with the least favorable prognosis and the highest TMB, were predicted to have the best anti-PD1 and anti-CTLA4 response rate (40 %), which can be explained by their higher expression of PD1 and CTLA4. The three-year area under the curve (AUC) was 0.80 in the total sample. Conclusions: Our study highlights the potential of an integrated analysis of p53-associated genes and TIC in predicting prognosis and aiding clinical decision-making in MM patients. This finding underscores the significance of comprehending the intricate interplay between genetic abnormalities and immune dysfunction in MM. Further research into this area may lead to the development of more effective treatment strategies.

5.
Ecol Evol ; 14(5): e11323, 2024 May.
Article En | MEDLINE | ID: mdl-38694750

Meconopsis biluoensis, a new species of Papaveraceae in an alpine meadow from Yunnan, Southwest China, is described and illustrated. Morphologically, it resembles Meconopsis georgei, while it is distinct in acaulescent and hispid with clearly expanded bases on the leaves. A genus-level molecular phylogenetic analysis supported the closest relationship between M. biluoensis and M. georgei. In a finer population-level molecular phylogenetic analysis using ribosomal DNA (rDNA) and the chloroplast genome, individuals from M. biluoensis and M. georgei were clearly separated, and the extremely short branch length indicated that the two species had a very short differentiation time. The species has currently been assessed as "endangered" (EN) due to its small-sized population and narrow distribution following the IUCN categories and criteria.

6.
Nat Genet ; 2024 Apr 24.
Article En | MEDLINE | ID: mdl-38658794

CRISPR base editing screens enable analysis of disease-associated variants at scale; however, variable efficiency and precision confounds the assessment of variant-induced phenotypes. Here, we provide an integrated experimental and computational pipeline that improves estimation of variant effects in base editing screens. We use a reporter construct to measure guide RNA (gRNA) editing outcomes alongside their phenotypic consequences and introduce base editor screen analysis with activity normalization (BEAN), a Bayesian network that uses per-guide editing outcomes provided by the reporter and target site chromatin accessibility to estimate variant impacts. BEAN outperforms existing tools in variant effect quantification. We use BEAN to pinpoint common regulatory variants that alter low-density lipoprotein (LDL) uptake, implicating previously unreported genes. Additionally, through saturation base editing of LDLR, we accurately quantify missense variant pathogenicity that is consistent with measurements in UK Biobank patients and identify underlying structural mechanisms. This work provides a widely applicable approach to improve the power of base editing screens for disease-associated variant characterization.

7.
World J Gastroenterol ; 30(13): 1887-1898, 2024 Apr 07.
Article En | MEDLINE | ID: mdl-38659480

BACKGROUND: Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy (SG) between patients with familial aggregation of obesity (FAO) and patients with sporadic obesity (SO) have not been elucidated. AIM: To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO. METHODS: A total of 193 patients with obesity who underwent SG were selected. Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity (1SO vs 1FAO, 2SO vs 2FAO). The baseline characteristics, weight loss outcomes, prevalence of obesity-related comorbidities and incidence of major surgery-related complications were compared between groups. RESULTS: We defined FAO as the presence of two or more first-degree relatives with obesity. Patients with FAO did not initially show significant differences in baseline data, short-term postoperative weight loss, or obesity-related comorbidities when compared to patients with SO preoperatively. However, distinctions between the two groups became evident at the two-year mark, with statistically significant differences in both percentage of total weight loss (P = 0.006) and percentage of excess weight loss (P < 0.001). The FAO group exhibited weaker remission of type 2 diabetes mellitus (T2DM) (P = 0.031), hyperlipidemia (P = 0.012), and non-alcoholic fatty liver disease (NAFLD) (P = 0.003) as well as a lower incidence of acid reflux (P = 0.038). CONCLUSION: FAO patients is associated with decreased mid-to-long-term weight loss outcomes; the alleviation of T2DM, hyperlipidemia and NAFLD; and decreased incidence of acid reflux postoperatively.


Gastrectomy , Weight Loss , Humans , Male , Female , Gastrectomy/adverse effects , Gastrectomy/methods , Adult , Treatment Outcome , Middle Aged , Retrospective Studies , Diabetes Mellitus, Type 2/surgery , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Comorbidity , Obesity/surgery , Obesity/diagnosis , Obesity/complications , Obesity/epidemiology , Obesity, Morbid/surgery , Obesity, Morbid/complications , Bariatric Surgery/methods , Propensity Score , Non-alcoholic Fatty Liver Disease/surgery , Non-alcoholic Fatty Liver Disease/diagnosis , Incidence
8.
Talanta ; 275: 126132, 2024 Apr 25.
Article En | MEDLINE | ID: mdl-38669959

Given the levels of pollution in the aquatic environment and the development of antimicrobial resistance, it is essential to develop sensors, with sensitivity, selectivity, stability, and cost-effectiveness, for the determination of antibiotics. The present article highlights the fabrication of an ultra-sensitive graphene and copper sensor, Gr/Cu, supported on glassy carbon (GCE/Gr/Cu) for the electroanalysis of levofloxacin through a cost-effective electrodeposition method. The sequential electrodeposition of graphene and Cu was optimised to give GCE/Gr/Cu, with the Cu particles well dispersed on the graphene sheets. The composite exhibited very good conducting properties as evidenced from electrochemical impedance studies. Using cyclic voltammetry, an impressive sensitivity of 19.7 µA µM-1 cm-2 was achieved with a detection limit of 11.86 nM, providing a promising electrocatalytic material for the determination of this antibiotic. Moreover, good selectivity was observed in the presence of various ions typically found in water and other drug molecules, while very good stability exceeding a 21-day period was achieved, and recovery values between 97.7 and 103.8 % were obtained in tap water.

9.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1196-1205, 2024 Mar.
Article Zh | MEDLINE | ID: mdl-38621966

Processing of Chinese medicinal materials is an important part in the Chinese medicine heritage, and the temperature control in the processing has a direct impact on the quality and efficacy of traditional Chinese medicines. However, the processing of Chinese medicinal materials has the problems of subjective temperature judgement, determination of the end point based on experience, unclear processing mechanism, unstable quality of products, and inconsistent processing standards. The temperature control in the processing is reflected in the appearance and internal quality of Chinese medicinal materials. The theory of quality evaluation through morphological identification is developed based on the comprehensive evaluation of the shape, color, taste, and components, which is associated with the temperature control in the processing. To solve the problems above, this paper puts forward the following solutions. The first is literature mining. By review of the ancient medical works and pharmaceutical experience, the temperature control in processing and the evolution of processing methods can be revealed. Second, according to the ancient method, the processing principle can be explored, on the basis of which the processing technology can be innovated. Third, the standard operating procedure(SOP) should be established to quantify the fire temperature, providing a theoretical basis for the formulation of Chinese medicinal material processing standards. Moreover, it provides a basis for improving the quality of processed products and increasing the safety and effectiveness of traditional Chinese medicines.


Drugs, Chinese Herbal , Humans , Temperature , Medicine, Chinese Traditional , Reference Standards , Technology
10.
World J Hepatol ; 16(3): 477-489, 2024 Mar 27.
Article En | MEDLINE | ID: mdl-38577540

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is commonly utilized as a prognostic indicator in end-stage liver disease (ESLD), encompassing conditions like liver failure and decompensated cirrhosis. Nevertheless, some studies have contested the prognostic value of NLR in ESLD. AIM: To investigate the ability of NLR to predict ESLD. METHODS: Databases, such as Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Weipu, and Wanfang, were comprehensively searched to identify studies published before October 2022 assessing the prognostic ability of NLR to predict mortality in patients with ESLD. Effect sizes were calculated using comprehensive meta-analysis software and SATAT 15.1. RESULTS: A total of thirty studies involving patients with end-stage liver disease (ESLD) were included in the evaluation. Among the pooled results of eight studies, it was observed that the Neutrophil-to-Lymphocyte Ratio (NLR) was significantly higher in non-survivors compared to survivors (random-effects model: standardized mean difference = 1.02, 95% confidence interval = 0.67-1.37). Additionally, twenty-seven studies examined the associations between NLR and mortality in ESLD patients, reporting either hazard ratios (HR) or odds ratios (OR). The combined findings indicated a link between NLR and ESLD mortality (random-effects model; univariate HR = 1.07, 95%CI = 1.05-1.09; multivariate HR = 1.07, 95%CI = 1.07-1.09; univariate OR = 1.29, 95%CI = 1.18-1.39; multivariate OR = 1.29, 95%CI = 1.09-1.49). Furthermore, subgroup and meta-regression analyses revealed regional variations in the impact of NLR on ESLD mortality, with Asian studies demonstrating a more pronounced effect. CONCLUSION: Increased NLR in patients with ESLD is associated with a higher risk of mortality, particularly in Asian patients. NLR is a useful prognostic biomarker in patients with ESLD.

11.
Sci Rep ; 14(1): 7730, 2024 Apr 02.
Article En | MEDLINE | ID: mdl-38565602

Meandering flow can be formed during the advance of natural rivers by the scouring of river banks. However, this phenomenon is not common in artificial cement channels. This study used experimental scouring terrain data for a numerical simulation to study the meandering flow pattern formed between double alternating deflectors in a straight channel. The numerical results showed that the path of the accelerated flow generated by the upstream deflector was changed by installing a downstream deflector while the flow rate remained unchanged. Thus, a meandering flow formed, and a stable, narrow, high-speed zone formed in the downstream area. The accelerated flow between the two deflectors hit the channel bank soon after its direction changed. Then, a strong downward flow formed in this area, which may have produced an elliptical scour hole. A large-scale vortex structure was formed in the elliptical scour hole, which was influenced by the horseshoe vortex system before the downstream deflector.

12.
Science ; 384(6691): 81-86, 2024 Apr 05.
Article En | MEDLINE | ID: mdl-38574137

Thermoelectric materials can realize direct and mutual conversion between electricity and heat. However, developing a strategy to improve high thermoelectric performance is challenging because of strongly entangled electrical and thermal transport properties. We demonstrate a case in which both pseudo-nanostructures of vacancy clusters and dynamic charge-carrier regulation of trapped-hole release have been achieved in p-type lead telluride-based materials, enabling the simultaneous regulations of phonon and charge carrier transports. We realized a peak zT value up to 2.8 at 850 kelvin and an average zT value of 1.65 at 300 to 850 kelvin. We also achieved an energy conversion efficiency of ~15.5% at a temperature difference of 554 kelvin in a segmented module. Our demonstration shows promise for mid-temperature thermoelectrics across a range of different applications.

13.
Front Pharmacol ; 15: 1344113, 2024.
Article En | MEDLINE | ID: mdl-38567351

Introduction: Diabetic kidney disease (DKD) necessitates innovative therapeutic strategies. This study delves into the role of DNA damage-inducing transcription factor 4 (DDIT4) within the VDR-mTOR pathway, aiming to identify a novel target for DKD drug discovery. Methods: Transcriptome data from the Gene Expression Omnibus Database were analyzed to assess the expression of mTOR and VDR expression in human renal tissues. Clinical samples from DKD patients and minimal change disease (MCD) controls were examined, and a DKD animal model using 20-week-old db/db mice was established. DDIT4 plasmid transfection was employed to modulate the VDR-mTOR pathway, with its components evaluated using immunohistochemistry, real-time quantitative PCR (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Results: Changes in the expression of the VDR-mTOR pathway were observed in both DKD patients and the animal model. Overexpression of DDIT4 increased VDR expression and decreased levels of mTOR, p70s6k, and 4E-BP1. Furthermore, DDIT4 treatment regulated autophagy by upregulating LC3I expression and downregulating LC3II expression. Notably, DDIT4 alleviated oxidative stress by reducing the levels of lipid peroxidation product MDA, while simultaneously increasing the levels of superoxide dismutase (SOD) and glutathione (GSH), underscoring the role of DDIT4 in the pathological process of DKD and its potential as a therapeutic target. Conclusion: Unraveling DDIT4's involvement in the VDR-mTOR pathway provides insights for innovative DKD drug discovery, emphasizing its potential as a therapeutic target for future interventions.

14.
Medicine (Baltimore) ; 103(17): e37851, 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38669413

RATIONALE: Eosinophilic pulmonary disease (EPD) is a general term for a large group of diseases with complex etiology. Ulcerative colitis is an inflammatory bowel disease (IBD). Patients with IBD may have pulmonary involvement. We herein present a case of ulcerative colitis complicated with EPD. PATIENT CONCERNS: A 34-year-old woman with ulcerative colitis presented with dry cough. She had peripheral eosinophilia and apical ground glass opacities on CT (computed tomography) of her chest. Antibiotic treatment was ineffective. DIAGNOSES: Lung biopsy revealed eosinophil infiltration in the alveolar space and interstitial space, so EPD was considered. INTERVENTIONS: After oral administration of prednisone, the lung shadow on CT disappeared when the cough symptoms resolved. However, the symptoms recurred after drug withdrawal, and the lung shadow reappeared on imaging. The cough symptoms and lung shadow disappeared after oral prednisone was given again. Prednisone was slowly discontinued after 6 months of treatment. OUTCOMES: The patient stopped prednisone for half a year. No recurrence or abnormal CT findings were detected during the half-year follow-up. LESSONS: The clinical manifestations of EPD are atypical, laboratory and imaging findings are not specific, and it is difficult to make a definite diagnosis before lung biopsy. The diagnosis depends on pathological examination. Glucocorticoid treatment is effective, but some patients may relapse after drug withdrawal. Active follow-up after glucocorticoid treatment is very important for identifying disease recurrence. Patients with IBD are relatively prone to developing EPD. The etiology of EPD is complex. In clinical practice, we need to make a diagnosis and differential diagnosis to clarify its etiology.


Colitis, Ulcerative , Prednisone , Pulmonary Eosinophilia , Humans , Female , Adult , Colitis, Ulcerative/complications , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/drug therapy , Pulmonary Eosinophilia/diagnosis , Pulmonary Eosinophilia/drug therapy , Pulmonary Eosinophilia/etiology , Prednisone/therapeutic use , Prednisone/administration & dosage , Tomography, X-Ray Computed , Glucocorticoids/therapeutic use , Glucocorticoids/administration & dosage , Diagnosis, Differential
15.
Cancer Med ; 13(8): e7215, 2024 Apr.
Article En | MEDLINE | ID: mdl-38659392

OBJECTIVES: The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. MATERIALS AND METHODS: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). RESULTS: Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. CONCLUSION: Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.


Antineoplastic Combined Chemotherapy Protocols , Chemoradiotherapy , Cisplatin , Etoposide , Lung Neoplasms , Propensity Score , Small Cell Lung Carcinoma , Humans , Male , Female , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/mortality , Small Cell Lung Carcinoma/radiotherapy , Small Cell Lung Carcinoma/therapy , Small Cell Lung Carcinoma/pathology , Etoposide/administration & dosage , Etoposide/therapeutic use , Lung Neoplasms/mortality , Lung Neoplasms/therapy , Lung Neoplasms/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Middle Aged , Aged , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Chemoradiotherapy/methods , Retrospective Studies , Prospective Studies , Neoplasm Staging , Adult , Progression-Free Survival , Drug Administration Schedule
16.
Cancer Cell Int ; 24(1): 112, 2024 Mar 25.
Article En | MEDLINE | ID: mdl-38528532

BACKGROUND: Gastric cancer (GC) remains a malignant tumor with high morbidity and mortality, accounting for approximately 1,080,000 diagnosed cases and 770,000 deaths worldwide annually. Disulfidptosis, characterized by the stress-induced abnormal accumulation of disulfide, is a recently identified form of programmed cell death. Substantial studies have demonstrated the significant influence of immune clearance on tumor progression. Therefore, we aimed to explore the intrinsic correlations between disulfidptosis and immune-related genes (IRGs) in GC, as well as the potential value of disulfidptosis-related immune genes (DRIGs) as biomarkers. METHODS: This study incorporated the single-cell RNA sequencing (scRNA-seq) dataset GSE183904 and transcriptome RNA sequencing of GC from the TCGA database. Disulfidptosis-related genes (DRGs) and IRGs were derived from the representative literature on both cell disulfidptosis and immunity. The expression and distribution of DRGs were investigated at the single-cell level in different GC cell types. Pearson correlation analysis was used to identify the IRGs closely related to disulfidptosis. The prognostic signature of DRIGs was established using Cox and LASSO analyses. We then analyzed and evaluated the differences in long-term prognosis, Gene Set Enrichment Analysis (GSEA), immune infiltration, mutation profile, CD274 expression, and response to chemotherapeutic drugs between the two groups. A tissue array containing 63 paired GC specimens was used to verify the expression of 4 DRIGs and disulfidptosis regulator SLC7A11 through immunohistochemistry staining. RESULTS: The scRNA-seq analysis found that SLC7A11, SLC3A2, RPN1 and NCKAP1 were enriched in specific cell types and closely related to immune infiltration. Four DIRGs (GLA, HIF-1α, VPS35 and CDC37) were successfully identified to establish a signature to potently predict the survival time of GC patients. Patients with high risk scores generally experienced worse prognoses and exhibited greater resistant to classical chemotherapy drugs. Furthermore, the expression of GLA, HIF-1α, VPS35, CDC37 and SLC7A11 were elevated in GC tissues. A high expression of GLA, HIF-1α, VPS35 or CDC37 was associated with more advanced clinical stage of GC and increased SLC7A11 expression. CONCLUSION: Current study first highlights the potential value of DRIGs as biomarkers in GC. We successfully constructed a robust model incorporating four DRIGs to accurately predict the survival time and clinicopathological characteristics of GC patients.

17.
J Nat Prod ; 87(4): 966-975, 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38441877

Ten new (1-10) and nine known (11-19) austocystins, along with four known anthraquinones (20-23), were isolated from the culture of Aspergillus ustus NRRL 5856 by bioactivity-guided fractionation. The structures of the new compounds were elucidated by spectroscopic data analysis, X-ray crystallographic study, the modified Mosher's method, [Rh2(OCOCF3)4]-induced ECD spectral analysis, and comparison of the experimental ECD spectra with those of the similar analogues. Compounds 1-8 represent the first examples of austocystins with a C-4' oxygenated substitution. The absolute configuration of 1″-hydroxy austocystin D (11) was determined by single-crystal X-ray diffraction and consideration of its biosynthetic origin. Compounds 5, 9, and 11 exhibited significant inhibitory effects against the proliferation of ConA-induced T cells with IC50 values of 1.1, 1.0, and 0.93 µM, respectively. Furthermore, these compounds suppressed the expression of IL-6 in a dose-dependent manner. Compounds 10-12 and 14 showed pronounced cytotoxicities against MCF-7 with IC50 values of 3.9, 1.3, 0.46, and 2.3 µM, respectively.


Aspergillus , Immunosuppressive Agents , Aspergillus/chemistry , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/isolation & purification , Molecular Structure , Crystallography, X-Ray , Interleukin-6/metabolism , Anthraquinones/pharmacology , Anthraquinones/chemistry , Animals , Drug Screening Assays, Antitumor , T-Lymphocytes/drug effects , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Proliferation/drug effects
18.
Clin Transl Sci ; 17(3): e13769, 2024 03.
Article En | MEDLINE | ID: mdl-38515348

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.


Drug-Related Side Effects and Adverse Reactions , Hematologic Neoplasms , Neoplasms , Humans , Antibodies, Monoclonal, Humanized/pharmacokinetics , Neoplasms/pathology
19.
Environ Geochem Health ; 46(4): 136, 2024 Mar 14.
Article En | MEDLINE | ID: mdl-38483758

Many organic contaminated sites require on-site remediation; excavation remediation processes can release many volatile organic compounds (VOCs) which are key atmospheric pollutants. It is therefore important to rapidly identify VOCs during excavation and map their risk areas for human health protection. In this study, we developed a rapid analysis and assessment method, aiming to and reveal the real-time distribution of VOCs, evaluate their human health risks by quantitative models, and design appropriate control measures. Through on-site diagonal distribution sampling and analysis, VOCs concentration showed a decreasing trend within 5 m from the excavation point and then increased after 5 m with the increase in distance from the excavation point (p < 0.05). The concentrations of VOCs near the dominant wind direction were higher than the concentrations of surrounding pollutants. In contrast with conventional solid-phase adsorption (SPA) and thermal desorption gas chromatography-mass spectrometry (TD-GC/MS) methods for determining the composition and concentration of VOCs, the rapid measurement of VOCs by photo-ionization detector (PID) fitted well with the chemical analysis and modeling assessment of cancer/non-cancer risk. The targeting area was assessed as mild-risk (PID < 10 ppm), moderate-risk (PID from 10 to 40 ppm), and heavy-risk (PID > 40 ppm) areas. Similarly, the human health risks also decreased gradually with the distance from the excavation point, with the main risk area located in the dominant wind direction. The results of rapid PID assessment were comparable to conventional risk evaluation, demonstrating its feasibility in rapidly identifying VOCs releases and assessing the human health risks. This study also suggested appropriate control measures that are important guidance for personal protection during the remediation excavation process.


Air Pollutants , Environmental Pollutants , Volatile Organic Compounds , Humans , Air Pollutants/analysis , Environmental Monitoring/methods , Volatile Organic Compounds/analysis , Gas Chromatography-Mass Spectrometry , Environmental Pollutants/analysis
20.
Molecules ; 29(5)2024 Feb 26.
Article En | MEDLINE | ID: mdl-38474526

Organic afterglow is a fascinating phenomenon with exceptional applications. However, it encounters challenges such as low intensity and efficiency, and typically requires UV-light excitation and facile intersystem crossing (ISC) due to its spin-forbidden nature. Here, we develop a novel strategy that bypasses the conventional ISC pathway by promoting singlet-triplet transition through the synergistic effects of the intra/intermolecular heavy-atom effect in aromatic crystals, enabling the direct population of triplet excited states from the ground state. The resulting materials exhibit a bright organic afterglow with a remarkably enhanced quantum efficiency of up to 5.81%, and a significantly increased organic afterglow lifetime of up to 157 microseconds under visible light. Moreover, given the high-efficiency visible-light excitable organic afterglow emission, the potential application is demonstrated in lifetime-resolved, color-encoded, and excitation wavelength-dependent pattern encryption. This work demonstrates the importance of the direct population method in enhancing the organic afterglow performance and red-shifting the excitation wavelength, and provides crucial insights for advancing organic optoelectronic technologies that involve triplet states.

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