Exploring near-infrared autofluorescence properties in parathyroid tissue: an analysis of fresh and paraffin-embedded thyroidectomy specimens.

Significance: Near-infrared autofluorescence (NIRAF) utilizes the natural autofluorescence of parathyroid glands (PGs) to improve their identification during thyroid surgeries, reducing the risk of inadvertent removal and subsequent complications such as hypoparathyroidism. This study evaluates NIRAF's effectiveness in real-world surgical settings, highlighting its potential to enhance surgical outcomes and patient safety. Aim: We evaluate the effectiveness of NIRAF in detecting PGs during thyroidectomy and central neck dissection and investigate autofluorescence characteristics in both fresh and paraffin-embedded tissues. Approach: We included 101 patients diagnosed with papillary thyroid cancer who underwent surgeries in 2022 and 2023. We assessed NIRAF's ability to locate PGs, confirmed via parathyroid hormone assays, and involved both junior and senior surgeons. We measured the accuracy, speed, and agreement levels of each method and analyzed autofluorescence persistence and variation over 10 years, alongside the expression of calcium-sensing receptor (CaSR) and vitamin D. Results: NIRAF demonstrated a sensitivity of 89.5% and a negative predictive value of 89.1%. However, its specificity and positive predictive value (PPV) were 61.2% and 62.3%, respectively, which are considered lower. The kappa statistic indicated moderate to substantial agreement (kappa = 0.478; P < 0.001 ). Senior surgeons achieved high specificity (86.2%) and PPV (85.3%), with substantial agreement (kappa = 0.847; P < 0.001 ). In contrast, junior surgeons displayed the lowest kappa statistic among the groups, indicating minimal agreement (kappa = 0.381; P < 0.001 ). Common errors in NIRAF included interference from brown fat and eschar. In addition, paraffin-embedded samples retained stable autofluorescence over 10 years, showing no significant correlation with CaSR and vitamin D levels. Conclusions: NIRAF is useful for PG identification in thyroid and neck surgeries, enhancing efficiency and reducing inadvertent PG removals. The stability of autofluorescence in paraffin samples suggests its long-term viability, with false positives providing insights for further improvements in NIRAF technology.

Adsorption of typical NDMA precursors by superfine powdered activated carbon: Critical role of particle size reduction.

Control of N-nitrosodimethylamine (NDMA) in drinking water could be achieved by removing its precursors as one practical way. Herein, superfine powdered activated carbons with a diameter of about 1 µm (SPACs) were successfully prepared by grinding powdered activated carbon (PAC, D50=24.3 µm) and applied to remove model NDMA precursors, i.e. ranitidine (RAN) and nizatidine (NIZ). Results from grain diameter experiments demonstrated that the absorption velocity increased dramatically with decreasing particle size, and the maximum increase in k2 was 26.8-folds for RAN and 33.4-folds for NIZ. Moreover, kinetic experiments explained that rapid absorption could be attributed to the acceleration of intraparticle diffusion due to the shortening of the diffusion path. Furthermore, performance comparison experiments suggested that the removal of RAN and NIZ (C0=0.5 mg/L) could reach 61.3% and 60%, respectively, within 5 min, when the dosage of SAPC-1.1 (D50=1.1 µm) was merely 5 mg/L, while PAC-24.3 could only eliminate 17.5% and 18.6%. The adsorption isotherm was well defined by Langmuir isotherm model, indicating that the adsorption of RAN/NIZ was a monolayer coverage process. The adsorption of RAN or NIZ by SAPC-1.1 and PAC-24.3 was strongly pH dependent, and high adsorption capacity could be observed under the condition of pH > pka+1. The coexistence of humic acid (HA) had no significant effect on the adsorption performance because RAN/NIZ may be coupled with HA and removed simultaneously. The coexistence of anions had little effect on the adsorption also. This study is expected to provide an alternative strategy for drinking water safety triggered by NDMA.

Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis.

Psoriasis is a chronic autoimmune disease that badly affects the life quality of patients and their families. Inadequate efficacy, safety risks, high cost and low compliance of current psoriasis drugs urge development of novel small molecular drugs. In this study, two series of 37 novel compounds were designed and synthesized as inhibitors of phosphodiesterase 4 (PDE4) that specifically hydrolyzes second messenger cAMP and is an effective target for treatment of inflammatory diseases. Comprehensive structural-activity optimization led to finding of inhibitor 2e with IC50 = 2.4 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 2e inhibited the release of TNF-α (IC50 = 21.36 µM) and IL-6 (IC50 = 29.22 µM) in the LPS-stimulated Raw264.7 cells. Topical application of 2e exhibited remarkable therapeutic efficacy in imiquimod-induced psoriasis mice model, suggesting that 2e is a strong drug candidate for treatment of psoriasis.

Pressure-induced piezoelectric response for mitigating membrane fouling in surface water treatment: Insights from continuous operation and biofouling characterization.

Organic fouling and biofouling represents a critical challenge encountered by the membrane-based water treatment process. Herein, a piezoelectric PVDF membrane (PEM), capable of generating electrical responses to hydraulic pressure stimuli, was synthesized and employed for mitigating the fouling in surface water treatment. The surface-hydrophobilized PEM demonstrated sensitive and enhanced underwater output performance in response to increasing transmembrane pressure (TMP) during constant-flux filtration, with signals reaching up to ∼800 mV at a TMP of ∼80 kPa. This in-situ piezoelectric response significantly reduced TMP growth in both short-term (1 h) and long-term (15 days) filtration trials, demonstrating a strong capability to mitigate membrane fouling. Moreover, continuous piezoelectric stimulation effectively inhibited microbial activity and the accumulation of extracellular polymeric substances (EPS) on PEM surface, surpassing the dominant electrokinetic repulsion mechanisms observed in short-term trials. Microbial community analysis suggests that this evolution is primarily due to the targeted impact of piezoelectric stimulation on microbial metabolic behavior. The piezoelectric-induced electrical microenvironment inhibited the growth of microbes associated with high EPS production while promoting the proliferation of electrically active microbes involved in biopolymer digestion. In addition, the PEM demonstrated enhanced permeate quality throughout the filtration process, with DOC and UV254 removal rates increasing from 11.7 % and 15.6 % initially to 28.6 % and 19.5 % by the 15th day, respectively. Given the performance and self-powered capability of PEM compared to current electrified antifouling methods that require an external power supply, these attributes are anticipated to hold practical significance in developing innovative and energy-efficient strategies for mitigating both organic fouling and biofouling.

Source to risk receptor transport and spatial hotspots of heavy metals pollution in peri-urban agricultural soils of the largest megacity in China.

The traditional concentration-based health risk assessment of heavy metal (HMs) pollution in soil has often overlooked the initial loading and toxicity differences of HMs from various sources. This oversight hinders effective identification of the risky source, complicating precise risk management of soil HMs pollution. This study applied a source-oriented health risk assessment framework that integrates source profiling, exposure risk assessment, and spatial cluster analysis. Taking the Shanghai City, the largest megacity in China as a case, the findings revealed that overall environmental quality of peri-urban agricultural soil in Shanghai remains good, though 3.03 % of Cd concentrations exceeded the national reference standards. Industrial & traffic activities, primarily contributing Hg, Cd, and Pb, accounted for the highest proportion (44.3 %) of total metal concentrations and posed the greatest non-cancer risk (54.6 % for children and 53.1 % for adults). Notably, natural activities, mainly contributing Cr, ranked only third in concentration contribution (26.55 %) but induced the highest cancer risk (58.55 % for children and 57.08 % for adults). These findings suggest that sources with lower concentration contributions may still pose significant health risk. Integrating source apportionment with health risk assessment can more precisely identify the risky source and target areas for mitigating the human health hazards.

Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer.

Background: Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined. Methods: Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells. Results: A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells. Conclusion: Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.

Traumatic Brain Injury Exacerbates Alcohol Consumption and Neuroinflammation with Decline in Cognition and Cholinergic Activity.

Traumatic brain injury (TBI) is a global health challenge, responsible for 30% of injury-related deaths and significantly contributing to disability. Annually, over 50 million TBIs occur worldwide, with most adult patients at emergency departments showing alcohol in their system. TBI is also a known risk factor for alcohol abuse, yet its interaction with alcohol consumption remains poorly understood. In this study, we demonstrate that the fluid percussion injury (FPI) model of TBI in mice significantly increases alcohol consumption and impairs cognitive function. At cellular levels, FPI markedly reduced the number and activity of striatal cholinergic interneurons (CINs) while increasing microglial cells. Notably, depleting microglial cells provided neuroprotection, mitigating cholinergic loss and enhancing cholinergic activity. These findings suggest that TBI may promote alcohol consumption and impair cognitive abilities through microglia activation and consequently reduced cholinergic function. Our research provides critical insights into the mechanisms linking TBI with increased alcohol use and cognitive deficits, potentially guiding future therapeutic strategies.

A two-stage recommendation optimization algorithm based on item popularity and user features.

Financial product recommendation algorithms are mainly product-centered. This article proposes a two-stage recommendation optimization algorithm based on item popularity and user features, named CPCF-TSP, that can make full use of the demographic characteristics of users and mitigate the problem of users being more inclined to choose "hot" financial products. A popularity weight factor is introduced to normalize popularity and modify Pearson's similarity function. The modified Pearson's similarity function is combined with popularity normalization and user features to improve modeling performance. The two-stage recommendation optimization procedure was combined with a collaborative filtering algorithm to improve recommendation precision. CPCF-TSP fully considers user features in building a hybrid recommendation model and solves the problem of user cold-start. It can also mitigate popularity deviations and improve recommendation precision. MovieLens data and Santander Bank client trading data were used in a case study. The results show that the algorithm reduces inaccuracy in the calculation of the weights for recommendation popularity and similarity and is especially suitable for recommending financial products in which user information can be easily collected and the number of users is far greater than the number of products considered.

Impact of ultrasonic and heat treatments on the physicochemical properties and rennet-induced coagulation characteristics of milk from various species.

This study investigates the effects of heat and ultrasonic treatments on the physicochemical parameters and rennet-induced coagulation properties of milk from a variety of species, including cow, goat, buffalo, and donkey. Milk samples were subjected to heat treatments at different temperatures (65 °C, 80 °C, 90 °C, 100 °C) and ultrasonic treatment at varying power levels (200 W, 400 W, 600 W, 800 W, 1000 W). The results revealed that changes in turbidity, particle size, zeta potential, secondary structure, and surface hydrophobicity were altered by both ultrasonic and heat treatments, as well as the kind of milk. Ultrasonic treatment of cow milk decreased α-helix content while increasing ß-turn content. Under similar ultrasonic treatment, goat milk showed a considerable increase in ß-sheet content, whereas ß-turn and random coil contents decreased compared to control samples. Notably, the water-holding capacity of gels formed from all four types of milk increased significantly with the intensity of ultrasonic and heat treatments. The hardness of buffalo milk gels increased significantly after ultrasonic and thermal treatments, ranging from 63 °C for 30 min to 90 °C for 15 min, but the hardness of cow and goat milk gels increased in varying degrees compared to their control samples. Furthermore, gels from cow and goat milk had higher storage modulus (G') and loss modulus (G'') than those from buffalo and donkey milk, and changes in G' and G'' from the examined milk were altered by ultrasonic and heat treatments. These findings offer important insights into refining milk processing procedures to improve dairy product quality and usefulness.

Pyrene-Based Metal-Organic Frameworks with Coordination-Enhanced Electrochemiluminescence for Fabricating a Biosensing Platform.

Enhancing the electrochemiluminescence (ECL) properties of polycyclic aromatic hydrocarbons (PAHs) is a significant topic in the ECL field. Herein, we elaborately chose PAH derivative luminophore 1,3,6,8-tetrakis(p-benzoic acid)pyrene (H4TBAPy) as the organic ligand to synthesize a new Ru-complex-free ECL-active metal-organic framework Dy-TBAPy. Interestingly, Dy-TBAPy exhibited a more brilliant ECL emission and higher ECL efficiency than H4TBAPy aggregates. On the one hand, TBAPy luminophores were assembled into rigid MOF skeleton via coordination bonds, which not only enlarged the distance between pyrene cores to eliminate the aggregation-caused quenching (ACQ) effect but also obstructed the intramolecular motions of TBAPy to diminish the nonradiative relaxation, thus realizing a remarkable coordination-enhanced ECL. On the other hand, the ultrahigh porosity of Dy-TBAPy was beneficial to the diffusion of electrons, ions, and coreactant (S2O82-) in the skeleton, which efficiently boosted the excitation of interior TBAPy luminophores and led to a high utilization ratio of TBAPy, further improving ECL properties. More intriguingly, the ECL intensity of the Dy-TBAPy/S2O82- system was about 4.1, 87.0-fold higher than those of classic Ru(bpy)32+/TPrA and Ru(bpy)32+/S2O82- systems. Considering the aforementioned fabulous ECL performance, Dy-TBAPy was used as an ECL probe to construct a supersensitive ECL biosensor for microRNA-21 detection, which showed an ultralow detection limit of 7.55 aM. Overall, our study manifests that coordinatively assembling PAHs into MOFs is a simple and practicable way to improve ECL properties, which solves the ACQ issue of PAHs and proposes new ideas for developing highly efficient Ru-complex-free ECL materials, therefore providing promising opportunities to fabricate high-sensitivity ECL biosensors.

lncRNA VELRP Modulates Pulmonary Arterial Smooth Muscle Cell Proliferation and Promotes Vascular Remodeling in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension is a devastating vascular disorder characterized by extensive pulmonary vascular remodeling, ultimately leading to right ventricular failure and death. Activation of PDGF (platelet-derived growth factor) signaling promotes the hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs), thus contributing to the pulmonary vascular remodeling. However, the molecular mechanisms that govern hyperproliferation of PASMCs induced by PDGF remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). In this study, we aimed to identify a novel lncRNA regulated by PDGF implicated in PASMC proliferation in pulmonary vascular remodeling. METHODS: RNA-sequencing analysis was conducted to identify a novel lncRNA named vessel-enriched lncRNA regulated by PDGF-BB (VELRP). Functional investigations of VELRP were performed using knockdown and overexpression strategies along with RNA sequencing. Validation of the function and potential mechanisms of VELRP were performed through Western blot, RNA immunoprecipitation, and chromatin immunoprecipitation assays. RESULTS: We identified a novel vessel-enriched lncRNA with an increased response to PDGF-BB stimulus. VELRP was identified as an evolutionarily conserved RNA molecules. Modulation of VELRP in PASMCs significantly altered cell proliferation. Mechanistically, VELRP enhances trimethylation of H3K4 by interacting with WDR5 (WD repeat-containing protein 5), leading to increased expression of CDK (cyclin-dependent kinase) 1, CDK2, and CDK4 and consequent hyperproliferation of PASMCs. The pathological relevance of VELRP upregulation in pulmonary artery was confirmed using rat pulmonary hypertension models in vivo, as well as in PASMCs from patients with idiopathic pulmonary arterial hypertension patients. Specific knockdown of VELRP in smooth muscle cells using adeno-associated virus type 9 SM22α (smooth muscle protein 22α) promoter-shRNA-mediated silencing of VELRP resulted in a significant decrease in right ventricular systolic pressure and vascular remodeling in rat pulmonary hypertension model. CONCLUSIONS: VELRP, as an lncRNA upregulated by PDGF-BB, mediates PASMC proliferation via WDR5/CDK signaling. In vivo studies demonstrate that targeted intervention of VELRP in smooth muscle cells can prevent the development of pulmonary hypertension.

Mechanical Properties, Microstructure, Degradation Behavior, and Biocompatibility of Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg Guided Bone Regeneration Barrier Membranes Prepared Using a Powder Metallurgy Method.

Pure zinc exhibits low mechanical properties, making it unsuitable for use in guided bone regeneration (GBR) membranes. The present study focused on the preparation of Zn alloy GBR films using powder metallurgy, resulting in Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg alloy GBR films. The tensile strength of the pure Zn GBR film measured 85.9 MPa, while an elongation at break was 13.5%. In contrast, Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg alloy GBR films demonstrated significantly higher tensile strengths of 145.3 and 164.4 MPa, respectively, whereas elongations at break were 30.2% and 19.3%. The addition of Ti, Fe, and Mg substantially enhanced the mechanical properties of the zinc alloys. Corrosion analysis revealed that Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg alloy GBR membranes exhibited corrosion potentials of -1.298 and -1.316 V, respectively, with corresponding corrosion current densities of 12.11 and 13.32 µA/cm2. These values were translated to corrosion rates of 0.181 and 0.199 mm/year, indicating faster corrosion rates compared to pure Zn GBR membranes, which displayed a corrosion rate of 0.108 mm/year. Notably, both Zn-based alloy GBR membranes demonstrated excellent cytocompatibility, with a cytotoxicity rating of 0-1 in 25% leachate. Additionally, these membranes exhibited favorable osteogenic ability, as evidenced by the quantitative bone volume/tissue volume ratios (BV/TV) of new bone formation, which reached 30.3 ± 1.4% and 65.5 ± 1.8% for the Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg alloy GBR membranes, respectively, after 12 weeks of implantation. These results highlighted the significant potential for facilitating new bone growth. The proposed Zn-0.5Ti-0.5Fe and Zn-0.5Ti-0.5Mg alloy GBR membranes showed promise as viable biodegradable materials for future clinical studies.

Interactive effects of aridity and local environmental factors on the functional trait composition and diversity of macroinvertebrate assemblages in dryland rivers.

Drought and local habitat alteration are major environmental stressors shaping the aquatic biota in dryland rivers. However, the combined effects of these factors on aquatic biodiversity remain poorly understood. We collected macroinvertebrate data from Central Asian dryland rivers in Xinjiang, China, from 2012 to 2022, to investigate the individual and interactive effects of drought (as indicated by increasing values of Aridity, AI) and local habitat conditions (fine sediments, velocity and pH) on aquatic macroinvertebrate functional trait composition and diversity. We found that interactions of the selected environmental stressors exhibited more frequent additive than synergistic or antagonistic effects, leading to shifts in macroinvertebrate functional trait composition and diversity accordingly. Interaction of AI and fine sediments showed more pronounced synergistic effects (positive or negative) compared to others and had positive influences on traits like small body size, ovoviviparity, etc. Functional diversity metrics responded differently to stressor interactions, with FRic and FDis being negatively affected, whereas FEve was positively correlated to stressor interaction, suggesting the complementary roles of functional diversity metrics to diagnose impacts of stressor interactions. Overall, our study provides new insights into macroinvertebrate assemblage-stressor relationships in dryland rivers and can help better assess, predict and manage aquatic biodiversity in these rivers under ongoing environmental change.

Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4.

Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream cancer treatment strategy, with ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor glutathione peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

Systematic optimization of UCNPs-LFA for Helicobacter pylori nucleic acid detection at point-of-care.

Helicobacter pylori (Hp) prevail globally as the primary cause of gastritis, gastric ulcer, and potential gastric cancer, highlighting the need for rapid and precise point-of-care (POC) detection of Hp nucleic acid. Upconversion nanoparticle-based lateral flow assay (UCNPs-LFA) exhibit great potential in POC detection, due to their high optical stability and absence of background fluorescence. However, insufficient sensitivity for nucleic acid detection remains a key challenge. This study systematically optimizes UCNPs-LFA by focusing on target capture, signal transduction, signal separation, and signal analysis, to enhance its detection capabilities for Hp nucleic acid. The optimized UCNPs-LFA platform features a significantly decreased detection limit, a broadened detection range, and high reliability. Results demonstrate that the limit of detection (LOD) is 25 fM, a 105-fold improvement over the initial platform. This systematic optimization strategy is versatile and can be applied to optimize other nanoparticle-based LFAs.

Efficacy and safety of anlotinib plus penpulimab as second-line treatment for small cell lung cancer: A multicenter, open-label, single-arm phase II trial.

Background: Currently, the need for new therapeutic strategies involving programmed cell death protein-1 (PD-1) monoclonal antibodies in the second-line setting of small cell lung cancer (SCLC) is urgent. This study aimed to evaluate the efficacy and safety of anlotinib plus penpulimab as a second-line treatment for patients with SCLC who progressed after first-line platinum-based chemotherapy. Methods: This study included the patients from Cohort 4 of a single-arm, open-label, multicenter, phase II clinical trial. A safety run-in phase was performed under anlotinib (10/12 mg quaque die [QD], days 1-14) plus penpulimab (200 mg intravenously [IV], day 1) in a 21-day cycle, followed by the formal trial in which the patients received anlotinib (12 mg QD, days 1-14) plus penpulimab (200 mg IV, day 1) in a 21-day cycle. The primary endpoint of the safety run-in phase was safety. The primary endpoint of the formal trial phase was the objective response rate (ORR). Results: From April 28, 2020, to November 24, 2020, 21 patients were enrolled from 11 hospitals, including 2 in the safety run-in phase and 19 in the formal trial phase. In the formal trial phase, the ORR was 42.1% (8/19; 95% confidence interval [CI]: 17.7-66.6%). The median progression-free survival was 4.8 months (95% CI: 2.9-11.3 months), and the median overall survival was 13.0 months (95% CI: 4.6-not applicable [NA] months). The incidence of ≥grade 3 treatment-related adverse events (TRAEs) was 52.4% (11/21), and the incidence of treatment-related serious adverse events (AEs) was 28.6% (6/21). Two AE-related deaths occurred. The most common AEs were hypertension (57.1%, 12/21), hypothyroidism (42.9%, 9/21), and hypertriglyceridemia (38.1%, 8/21). Conclusions: In patients with SCLC who progressed after first-line platinum-based chemotherapy, the second-line anlotinib plus penpulimab treatment demonstrates promising anti-cancer activity and a manageable safety profile, which warrants further investigation. Trial registration: No. NCT04203719, https://clinicaltrials.gov/.

Elevated muramyl dipeptide by sialic acid-facilitated postantibiotic pathobiont expansion contributes to gut dysbiosis-induced mastitis in mice.

INTRODUCTION: In responses to antibiotics exposure, gut dysbiosis is a risk factor not only for pathogen infection but also for facilitating pathobiont expansion, resulting in increased inflammatory responses in the gut and distant organs. However, how this process is regulated has not been fully elucidated. OBJECTIVES: In this study, we investigated the role of sialic acid, a host-derived carbohydrate, in the pathogenesis of gut dysbiosis-derived inflammation in distant organs. METHODS: Ampicillin (Amp)-induced gut dysbiotic mice were treated with N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac) for three weeks to assess the role of sialic acids in mastitis. The underlying mechanism by which sialic acids regulate mastitis was explored using 16S rRNA sequencing, transcriptomics and employed multiple molecular approaches. RESULTS: Administration of Neu5Ac and Neu5Gc exacerbated gut dysbiosis-induced mastitis and systemic inflammation. The gut dysbiosis caused by Amp was also aggravated by sialic acid. Notably, increased Enterococcus expansion, which was positively correlated with inflammatory markers, was observed in both Neu5Ac- and Neu5Gc-treated gut dysbiotic mice. Treatment of mice with Enterococcus cecorum (E. cecorum) aggravated gut dysbiosis-induced mastitis. Mechanically, sialic acid-facilitated E. cecorum expansion promoted muramyl dipeptide (MDP) release, which induced inflammatory responses by activating the NOD2-RIP2-NF-κB axis. CONCLUSIONS: Collectively, our data reveal a role of sialic acid-facilitated postantibiotic pathobiont expansion in gut dysbiosis-associated inflammation, highlighting a potential strategy for disease prevention by regulating the MDP-NOD2-RIP2 axis.

Engineered microparticles modulate arginine metabolism to repolarize tumor-associated macrophages for refractory colorectal cancer treatment.

BACKGROUND: Arginase is abundantly expressed in colorectal cancer and disrupts arginine metabolism, promoting the formation of an immunosuppressive tumor microenvironment. This significant factor contributes to the insensitivity of colorectal cancer to immunotherapy. Tumor-associated macrophages (TAMs) are major immune cells in this environment, and aberrant arginine metabolism in tumor tissues induces TAM polarization toward M2-like macrophages. The natural compound piceatannol 3'-O-glucoside inhibits arginase activity and activates nitric oxide synthase, thereby reducing M2-like macrophages while promoting M1-like macrophage polarization. METHODS: The natural compounds piceatannol 3'-O-glucoside and indocyanine green were encapsulated within microparticles derived from tumor cells, termed PG/ICG@MPs. The enhanced cancer therapeutic effect of PG/ICG@MP was assessed both in vitro and in vivo. RESULTS: PG/ICG@MP precisely targets the tumor site, with piceatannol 3'-O-glucoside concurrently inhibiting arginase activity and activating nitric oxide synthase. This process promotes increased endogenous nitric oxide production through arginine metabolism. The combined actions of nitric oxide and piceatannol 3'-O-glucoside facilitate the repolarization of tumor-associated macrophages toward the M1 phenotype. Furthermore, the increase in endogenous nitric oxide levels, in conjunction with the photodynamic effect induced by indocyanine green, increases the quantity of reactive oxygen species. This dual effect not only enhances tumor immunity but also exerts remarkable inhibitory effects on tumors. CONCLUSION: Our research results demonstrate the excellent tumor-targeting effect of PG/ICG@MPs. By modulating arginine metabolism to improve the tumor immune microenvironment, we provide an effective approach with clinical translational significance for combined cancer therapy.

A Trustworthy Curriculum Learning Guided Multi-Target Domain Adaptation Network for Autism Spectrum Disorder Classification.

Domain adaptation has demonstrated success in classification of multi-center autism spectrum disorder (ASD). However, current domain adaptation methods primarily focus on classifying data in a single target domain with the assistance of one or multiple source domains, lacking the capability to address the clinical scenario of identifying ASD in multiple target domains. In response to this limitation, we propose a Trustworthy Curriculum Learning Guided Multi-Target Domain Adaptation (TCL-MTDA) network for identifying ASD in multiple target domains. To effectively handle varying degrees of data shift in multiple target domains, we propose a trustworthy curriculum learning procedure based on the Dempster-Shafer (D-S) Theory of Evidence. Additionally, a domain-contrastive adaptation method is integrated into the TCL-MTDA process to align data distributions between source and target domains, facilitating the learning of domain-invariant features. The proposed TCL-MTDA method is evaluated on 437 subjects (including 220 ASD patients and 217 NCs) from the Autism Brain Imaging Data Exchange (ABIDE). Experimental results validate the effectiveness of our proposed method in multi-target ASD classification, achieving an average accuracy of 71.46% (95% CI: 68.85% - 74.06%) across four target domains, significantly outperforming most baseline methods (p<0.05).

Effect of biosurfactants on the transport of polyethylene microplastics in saturated porous media.

Microplastic (MP) pollution has become a significant global environmental issue, and the potential application of biosurfactants in soil remediation has attracted considerable attention. However, the effects of biosurfactants on the transport and environmental risks of MPs are not fully understood. This study investigated the transport of polyethylene (PE) in the presence of two types of biosurfactants: typical anionic biosurfactant (rhamnolipids) and non-ionic biosurfactant (sophorolipids) using column experiments. We explored the potential mechanisms involving PE surface roughness and the influence of dissolved organic matter (DOM) on PE transport in the column under the action of biosurfactants, utilizing the Wenzel equation and fluorescence analysis. The results revealed that both the concentration of biosurfactants and the surface roughness of PE were advantageous for the adhesion of biosurfactants to the PE surface, thereby enhancing the mobility of PE in the column. The proportion of hydrophobic substances in various DOM sources is a critical factor that enhances PE transport in the column. However, the biosurfactant-mediated enhancement of PE transport was inhibited by the biosurfactant-DOM mixture. This was mainly due to DOM occupying the adhesion sites of biosurfactants on PE surfaces. Moreover, the mobility of PE in the presence of sophorolipids is higher than that in the presence of rhamnolipids because the combined hydrophobic and electrostatic forces between PE and sophorolipids create synergistic effects that improve PE stability. Additionally, the mobility of PE increased with rising pH and decreasing ionic strength. These findings provide a more comprehensive understanding of MP transport when using biosurfactants for soil remediation.