Efficacy and safety of vunakizumab in moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Vunakizumab, a novel anti-IL-17A antibody, has showed promising efficacy for moderate-to-severe plaque psoriasis in a phase 2 trial. OBJECTIVE: We conducted a double-blind, randomized phase 3 trial (NCT04839016) to further evaluate vunakizumab in this population. METHODS: 690 subjects were randomized (2:1) to receive vunakizumab 240 mg or placebo at weeks 0, 2, 4 and 8. At week 12, subjects on placebo were switched to vunakizumab 240 mg (weeks 12, 14, 16 and q4w thereafter). The co-primary endpoints were ≥90% improvement from baseline in the psoriasis area-and-severity index score (PASI 90) and a static Physicians Global Assessment score of 0/1 (sPGA 0/1) at week 12. RESULTS: At week 12, the vunakizumab group showed higher PASI 90 (76.8% vs 0.9%) and sPGA 0/1 (71.8% vs 0.4%) response rates, as well as higher PASI 75 (93.6% vs 4.0%), PASI 100 (36.6% vs 0.0%) and sPGA 0 (38.2% vs 0.0%) response rates (all two-sided P<0.0001 vs placebo). Efficacy was maintained through week 52 with continuous vunakizumab. Possible treatment-related serious adverse events occurred in 0.9% of vunakizumab-treated subjects. LIMITATIONS: Chinese subjects only; no active comparator. CONCLUSION: Vunakizumab demonstrated robust clinical response at week 12 and through week 52, with good tolerability in moderate-to-severe plaque psoriasis.

Polystyrene nanoplastics accelerate atherosclerosis: Unraveling the impact on smooth muscle cells through KIF15-mediated migration.

Microplastics and nanoplastics (MNPs) originating from plastic pollution pose potential threats to cardiovascular health, with prior studies linking MNPs to atherosclerosis. Our earlier research elucidated how nanoplastics enhance macrophages' phagocytic activity, leading to the formation of foam cells and an elevated risk of atherosclerosis. However, the specific influence of MNPs on smooth muscle cells (SMCs) in the context of MNP-induced atherosclerosis remains poorly understood. In this study, ApoE knockout (ApoE-/-) male mice with a high-fat diet were orally exposed to environmentally realistic concentrations of 2.5-250 mg/kg polystyrene nanoplastics (PS-NPs, 50 nm) for consecutive 19 weeks. Cardiovascular toxicity was comprehensively assessed through histopathological, transcriptomic, and proteomic analyses, while mechanisms underlying this toxicity were explored through in vitro studies. Herein, hematoxylin and eosin staining revealed accelerated atherosclerotic plaque development in ApoE-/- mice exposed to PS-NPs. Multi-omics analysis identified kinesin family member 15 (KIF15) as a pivotal target molecule. Both in vitro and in vivo experiments affirmed the specific upregulation of KIF15 in mouse aortic SMCs exposed to PS-NPs. Furthermore, in vitro experiments demonstrated that PS-NPs can promote the migration ability of MOVAS cells. Knockdown of Kif15 revealed its role in reducing MOVAS cell migration, with subsequent exposure to PS-NPs reversing the increased migration ability. This suggests that PS-NPs promote SMC migration by upregulating KIF15, and the migration of SMCs is closely associated with atherosclerosis outcomes. This study significantly advances our understanding of MNP-induced cardiovascular toxicity, providing valuable insights for risk assessment of human MNP exposure.

Time to lymphoma treatment within 24 months in 'watch and wait' follicular lymphoma is associated with inferior outcomes: A multicentre analysis.

Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

A Phase Ib Study of Linperlisib in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-cell Lymphoma.

PURPOSE: Relapsed and/or refractory peripheral T-cell lymphoma (r/r PTCL) is an aggressive and heterogeneous hematologic malignancy with high unmet need. Previously, PI3K inhibitors were shown to be efficacious in B- and T-cell lymphomas, but as a drug class, these agents have frequently been observed to have tolerability limitations. Next-generation agents that improve the tolerability while maintaining efficacy are desirable. PATIENTS AND METHODS: A phase Ib clinical study was conducted with the oral PI3K-delta isoform-selective small-molecule inhibitor, linperlisib, in patients with r/r PTCL, and the clinical benefit was explored by the evaluation of safety and efficacy. RESULTS: In this clinical study, 43 patients with r/r PTCL in China were treated with continuous dosing of 80-mg linperlisib once a day. Treatment-related adverse events (AE) were manageable. The most frequently reported grade 3 AE were neutropenia (21%), pneumonia (11.6%), and hypertriglyceridemia (7%). All other AE were either absent or reported in <5% of the patients. Linperlisib treatment for these patients with r/r PTCL, consisting of the major PTCL subtypes, was observed to have a 60.5% overall response rate with 35% complete responses and led to a median duration of response of 11.1 months, median progression-free survival of 11.8 months, and a median overall survival of >38 months (not reached). CONCLUSIONS: With the very promising clinical activity against r/r PTCL, the results of this study support the further investigation of linperlisib for the treatment of r/r PTCL.

Benign glomus tumor of prostate: a case report.

Glomus tumor (GT) is a neoplastic lesion of mesenchymal origin arising from the neuromyoarterial canal or glomus body. Although most GT occur in the peripheral soft tissue and extremities, these tumors can grow anywhere in the body. Here, we describe an uncommon case of GT involving the prostate.

Diagnostic Performance of Multiparametric MRI for the Detection of suspected Prostate Cancer in Biopsy-Naive Patients: A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: This meta-analysis aimed to assess the diagnostic accuracy of multiparametric MRI (mpMRI) in detecting suspected prostate cancer (PCa) in biopsy-naive men. MATERIALS AND METHODS: PubMed, Scopus, and the Cochrane Library databases were systematically searched for studies published from January 2013 to April 2024. Sixteen studies comprising 4973 patients met the inclusion criteria. Data were extracted to construct 2×2 contingency tables for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A random-effects model was used for pooled estimation, and subgroup analyses were conducted. Summary receiver operating characteristic (SROC) curves were generated to summarize overall diagnostic performance. RESULTS: The overall detection rate of PCa across studies was 57.3%. For detecting any PCa, mpMRI showed pooled sensitivity of 82% (95% CI, 80-83%) and specificity of 62% (95% CI, 60-64%), with positive likelihood ratio (LR) of 1.97 (95% CI, 1.71-2.26), negative LR of 0.28 (95% CI, 0.24-0.34), and diagnostic odds ratio (DOR) of 7.34 (95% CI, 5.60-9.63), and an area under the SROC curve of 0.81. For clinically significant PCa (csPCa), mpMRI had pooled sensitivity of 88% (95% CI, 87-90%) and specificity of 64% (95% CI, 63-66%), with positive LR of 2.49 (95% CI, 2.03-3.05), negative LR of 0.20 (95% CI, 0.16-0.25), DOR of 13.83 (95% CI, 9.14-20.9), and area under the curve of 0.90. CONCLUSION: This meta-analysis suggests that mpMRI is effective in detecting PCa in biopsy-naive patients, particularly for csPCa. It can help reduce unnecessary biopsies and lower the risk of missing clinically significant cases, thereby guiding informed biopsy decisions.

Association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and the risk of post-stroke depression: A cross-sectional study.

BACKGROUND: Limited observational research has explored the relationship between the non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) and the risk of post-stroke depression (PSD). This study aims to investigate the potential associations between NHHR and PSD. METHODS: A cross-sectional study was conducted using data from stroke participants aged 20 and older, sourced from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2018. Depression was assessed using the PHQ-9 questionnaire. The association between NHHR and PSD risk was evaluated through weighted multivariate logistic regression and restricted cubic spline (RCS) models. Subgroup and sensitivity analyses were performed to validate the findings. RESULTS: In the continuous model, the NHHR value for the PSD group (3.23±1.84) was significantly higher than that of the non-PSD group (2.79±1.40, p=0.015). Logistic regression analysis in the fully adjusted model revealed a positive association between NHHR and PSD (OR 1.16, 95 % CI 1.03-1.30, p=0.016). Interaction tests showed no significant differences across strata (p > 0.05 for interaction). Restricted cubic spline results indicated a linear dose-response relationship between NHHR and PSD risk (P for non-linearity = 0.6). This association persisted in various subgroup analyses. CONCLUSION: NHHR was significantly correlated with an increased risk of PSD among U.S. adults. Further re-search on NHHR could contribute to the prevention and treatment of PSD.

Half-life determination of 72Ga.

Gallium-72 is an important Comprehensive Nuclear-Test-Ban Treaty relevant radionuclide that arouses significant interest. However, the reported half-lives of 72Ga are discrepant. In the current work, three solution samples of different concentrations were prepared and sequentially measured by a high-purity Germanium (HPGe) spectrometer. The count rates as a function of time of the 834.1 keV and 630.0 keV γ-lines were followed for the half-life determination. Through mass normalization, the datasets of three samples are combined and the statistical uncertainties are reduced. Half-life values were derived from datasets of each sample and mass normalization and corresponding complete uncertainty budgets are presented. The final half-life determined for 72Ga is 13.94 (2) h, showing a deviation of 1.12% from the last nuclear data sheets (NDS) recommended value. Comparing with the values of previous publications, the result from this work is smaller than most results and consistent with the latest value which has one large uncertainty. A recommended value of 14.07 (3) h is estimated using the power-moderated mean (PMM) method.

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

INTRODUCTION: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature. OBJECTIVES: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL. METHODS: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line. RESULTS: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone. CONCLUSION: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

High-Speed Self-Powered PdSe2/Si 2D-3D PIN-like Photodetector with Broadband Response Based on PdSe2 Quantum Island Structure.

As a two-dimensional (2D) material, palladium diselenide (PdSe2) has attracted extensive research attention due to its unique asymmetric crystal structure and extraordinary optoelectronic properties, showing great potential in electronic, optoelectronic, and other application fields. Thinner PdSe2 exhibits semiconductor properties, while the photoresponse of the photodetectors based on this film is weaker. Although increasing the thickness of the PdSe2 film can improve the photoresponse, thicker PdSe2 exhibits metallic-like properties, which is not conducive to the formation of the heterojunction. In this work, a PdSe2 2D material with a quantum island structure is prepared by a simple thermal-assisted conversion method. A new type of photodetector with a PdSe2/n--Si/n+-Si vertical PIN-like structure is innovatively proposed. Broad spectral absorption from 532 to 2200 nm and a high rectification ratio (106) of the device are achieved. The introduced n--Si layer concentrates the electric field in the depletion region, thereby shortening the transit time and accelerating the separation and collection of the carriers, resulting in the enhancement of the responsivity and 3 dB frequency compared to the traditional device with a PN structure. A recorded highest 3 dB frequency of ∼25 kHz is achieved for the PdSe2 2D-3D PIN-like device.

Efficacy, Safety, and Early Relapse After Cessation of Upadacitinib Versus Dupilumab in Adolescents with Moderate-to-Severe Atopic Dermatitis: A Real-World Study in China.

Background: The efficacy and safety of upadacitinib and dupilumab for atopic dermatitis (AD) in adolescent patients have been proven in clinical trials. However, few daily practice studies comparing agents have been conducted in this patient population. Objectives: This single-center retrospective cohort study aimed to investigate the efficacy, safety, and early relapse after cessation of upadacitinib and dupilumab for moderate-to-severe AD in Chinese adolescents. Methods: A retrospective study collected data on a cohort of 83 adolescent patients receiving upadacitinib or dupilumab from October 2021 to October 2023. This study comprised two main emphases. The first main emphasis involved the treatment phase, where the efficacy and safety of the two treatments were evaluated. Primary endpoints included the proportion of patients achieving an improvement of ≥50%, ≥75%, and ≥90% in Eczema Area and Severity Index (EASI) from baseline (EASI-50, EASI-75, EASI-90) and the proportion of patients achieving Validated Investigator Global Assessment (vIGA) 0/1 at week 4 and week 40. In the second main emphasis, AD recurrence after treatment discontinuation was assessed in the two treatment groups. The median time to relapse was calculated. Results: A total of 83 patients were enrolled. At week 4, the proportion of patients achieving the primary endpoints, including EASI-75 and EASI-90, was substantially higher with upadacitinib than with dupilumab (51.5% vs 14.0% [P < 0.001], 18.2% vs 2.0% [P < 0.05]). However, at week 40, higher proportion of patients on dupilumab were reaching EASI-50 and EASI-75 and vIGA 0/1. After the discontinuation of dupilumab or upadacitinib therapy, the Kaplan-Meier survival curve showed that the median time to relapse was 270 days in the dupilumab group and 18 days in the upadacitinib group. Conclusions: This study demonstrated that upadacitinib has superior short-term efficacy over dupilumab in adolescents with moderate-to-severe AD, whereas dupilumab trends toward better long-term remission over upadacitinib under the condition of treatment discontinuation in some patients.

Diagnostic performance of EfficientNetV2-S method for staging liver fibrosis based on multiparametric MRI.

Problem: Previous studies had confirmed that some deep learning models had high diagnostic performance in staging liver fibrosis. However, training efficiency of models predicting liver fibrosis need to be improved to achieve rapid diagnosis and precision medicine. Aim: The deep learning framework of EfficientNetV2-S was noted because of its faster training speed and better parameter efficiency compared with other models. Our study sought to develop noninvasive predictive models based on EfficientNetV2-S framework for staging liver fibrosis. Methods: Patients with chronic liver disease who underwent multi-parametric abdominal MRI were included in the retrospective study. Data augmentation methods including horizontal flip, vertical flip, perspective transformation and edge enhancement were applied to multi-parametric MR images to solve the data imbalance between different liver fibrosis groups. The EfficientNetV2-S models were used for the prediction of liver fibrosis stages F1-2, F1-3, F3, F4 and F3-4. We evaluated the diagnostic performance of our models in training, validation, and test sets by using receiver operating characteristic curve (ROC) analysis. Results: The total training time of EfficientNetV2-S was about 6 h. For differentiating of F1-2 vs F3, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 96.2 %, 96.4 % and 96.0 % in the test set. The AUC in test set was 0.559. The accuracy, sensitivity and specificity were 82.1 %, 74.5 % and 89.6 % in the test set by using EfficientNetV2-S model to differentiate F1-2 vs F3-4, and the AUC in test set were 0.763. For differentiating F1-3 vs F4, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 71.5 %, 73.4 % and 69.5 % in the test set. The AUC was 0.553 in test set. For differentiating F1-2 vs F4, the accuracy, sensitivity and specificity of our model were 84.3 %, 80.2 % and 88.3 % in the test set, and the AUC was 0.715, respectively. For differentiating F3 vs F4, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 92.5 %, 89.1 % and 95.6 % in the test set, and the AUC was 0.696 in the test set. Conclusions: The EfficientNetV2-S models based on multi-parametric MRI had the feasibility for staging of liver fibrosis because they showed high training speed and diagnostic performance in our study.

Reduction of eEF2 kinase alleviates the learning and memory impairment caused by acrylamide.

BACKGROUND: The impact of acrylamide (ACR) on learning and memory has garnered considerable attention. However, the targets and mechanisms are still unclear. RESULTS: Elongation factor 2 (eEF2) was significantly upregulated in the results of serum proteomics. Results from in vitro and in vivo experiments indicated a notable upregulation of Eukaryotic elongation factor 2 kinase (eEF2K), the sole kinase responsible for eEF2 phosphorylation, following exposure to ACR (P < 0.05). Subsequent in vitro experiments using eEF2K siRNA and in vivo experiments with eEF2K-knockout mice demonstrated significant improvements in abnormal indicators related to ACR-induced learning and memory deficits (P < 0.05). Proteomic analysis of the hippocampus revealed Lpcat1 as a crucial downstream protein regulated by eEF2K. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that eEF2K may play a role in the process of ACR-induced learning and memory impairment by affecting ether lipid metabolism. CONCLUSIONS: In summary, eEF2K as a pivotal treatment target in the mechanisms underlying ACR-induced learning and memory impairment, and studies have shown that it provides robust evidence for potential clinical interventions targeting ACR-induced impairments.

Strong and ductile Resinvar alloys with temperature- and time-independent resistivity.

Materials with well-defined electrical resistivity that does not change with temperature or time are important in robotics, communication and automation. However, the challenge of designing such materials has remained elusive due to the temperature-dependent electron-phonon scattering. Moreover, resistive electrical conductors used in flexible and mobile systems under high mechanical loads must possess both high strength and ductility. Achieving such multi-properties presents a fundamental challenge. Here, we solve this problem by combining multicomponent alloy design with atomic-scale chemistry tuning. We term the resultant material 'Resinvar' alloy, due to its invariable resistivity (148 µΩ·cm) over wide temperature ranges from room temperature to 723 K. The alloy also has high tensile strength (948 MPa) at large tensile elongation (53%). The distorted lattice, chemical short-range order and ordered coherent nanoprecipitates in the material enable the invariant resistivity via promoting temperature-independent inelastic electron scattering, and contribute to the excellent strength-ductility synergy by manipulating dislocation slip.

Species recognition and the divergences in the chemical and ultrasonic signals between two coexisting Rattus species.

The ability to recognize and differentiate between conspecifics and heterospecifics as well as their signals is critical for the coexistence of closely related species. In the genus Rattus, species are morphologically similar and multiple species often coexist. Here, we investigated the interspecific recognition and signal differentiation of two sympatric rat species, the brown rat (Rattus norvegicus, RN) and the Asian house rat (Rattus tanezumi, RT). In a two-way choice test, both RN and RT females showed a preference for conspecific male rats to heterospecific ones. RT females showed a significant preference for accessible urine of males of same species to those of other species, but not for the inaccessible urine. On the other hand, there were significant differences in the structural characteristics of the ultrasonic vocalization emitted by males of these two rat species. Sodium dodecyl sulphate‒polyacrylamide gel electrophoresis (SDS‒PAGE) and isoelectric focusing electrophoresis unveiled that major urinary proteins (MUPs) in voided urine were more highly expressed in RN males versus RT males. The interspecific differences of urinary volatile compounds were also discussed. In conclusion, female rats had the ability to distinguish between males of either species.

Genetically proxied appendicular lean mass and stroke risk: A two-step mendelian randomization study.

BACKGROUND AND PURPOSE: Prior observational studies have suggested a strong correlation between sarcopenia and stroke, but the causal link between them remains uncertain. This study aims to investigate the associations between genetically predicted sarcopenia-related traits and stroke using a two-step Mendelian randomization (MR) approach. METHODS: Genome-wide association study (GWAS) summary data for sarcopenia-related traits were acquired from the UK Biobank. Genetic associations for ischemic stroke (IS) and its subtypes were selected from the MEGASTROKE consortium comprising European ancestry participants. GWAS summary data for cerebral hemorrhage were obtained from the FinnGen consortium, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). MR estimates were calculated using the inverse-variance weighted (IVW) method. The robustness of results was assessed for heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs). RESULTS: Higher appendicular lean mass (ALM) exhibited a potential causal association with a reduced incidence of large artery atherosclerosis (LAA) (odds ratio [OR] = 0.81, 95% confidence interval [CI]:0.71-0.93; P = 0.003) and small vessel disease (SVD) (OR = 0.83, 95% CI:0.74-0.94; P = 0.002). The associations of ALM with IS and ICH were compromised after adjusting for body fat and physical activity with multivariable MR. Two-step MR mediation analysis explored 33 candidate mediators, among which hypertension and SBP accounted for more than 10% of the mediation proportion in the relationship between ALM and stroke and its subtypes. CONCLUSION: Our research findings indicate that lower ALM is associated with a increased risk of stroke . It is necessary to explore the specific protective mechanisms of higher ALM for preventing stroke occurrence.

Fragile Guts Make Fragile Brains: Intestinal Epithelial Nrf2 Deficiency Exacerbates Neurotoxicity Induced by Polystyrene Nanoplastics.

Oral ingestion is the primary route for human exposure to nanoplastics, making the gastrointestinal tract one of the first and most impacted organs. Given the presence of the gut-brain axis, a crucial concern arises regarding the potential impact of intestinal damage on the neurotoxic effects of nanoplastics (NPs). The intricate mechanisms underlying NP-induced neurotoxicity through the microbiome-gut-brain axis necessitate further investigation. To address this, we used mice specifically engineered with nuclear factor erythroid-derived 2-related factor 2 (Nrf2) deficiency in their intestines, a strain whose intestines are particularly susceptible to polystyrene NPs (PS-NPs). We conducted a 28-day repeated-dose oral toxicity study with 2.5 and 250 mg/kg of 50 nm PS-NPs in these mice. Our study delineated how PS-NP exposure caused gut microbiota dysbiosis, characterized by Mycoplasma and Coriobacteriaceae proliferation, resulting in increased levels of interleukin 17C (IL-17C) production in the intestines. The surplus IL-17C permeated the brain via the bloodstream, triggering inflammation and brain damage. Our investigation elucidated a direct correlation between intestinal health and neurological outcomes in the context of PS-NP exposure. Susceptible mice with fragile guts exhibited heightened neurotoxicity induced by PS-NPs. This phenomenon was attributed to the elevated abundance of microbiota associated with IL-17C production in the intestines of these mice, such as Mesorhizobium and Lwoffii, provoked by PS-NPs. Neurotoxicity was alleviated by in vivo treatment with anti-IL-17C-neutralizing antibodies or antibiotics. These findings advanced our comprehension of the regulatory mechanisms governing the gut-brain axis in PS-NP-induced neurotoxicity and underscored the critical importance of maintaining intestinal health to mitigate the neurotoxic effects of PS-NPs.

Chinese guidelines for integrated diagnosis and treatment of intestinal microecology technologies in tumor application (2024 Edition).

ABSTRACT: Intestinal microecology (IM) is the largest and most important microecological system of the human body. Furthermore, it is the key factor for activating and maintaining the physiological functions of the intestine. Numerous studies have investigated the effects of the gut microbiota on the different tissues and organs of the human body as well as their association with various diseases, and the findings are gradually being translated into clinical practice. The gut microbiota affects the occurrence, progression, treatment response, and toxic side effects of tumors. The deepening of research related to IM and tumors has opened a new chapter in IM research driven by methods and technologies such as second-generation sequencing and bioinformatics. The IM maintains the function of the host immune system and plays a pivotal role in tumor-control drug therapy. Increasing evidence has proven that the efficacy of tumor-control drugs largely depends on the IM balance, and strategies based on the IM technology show promising application prospects in the diagnosis and treatment of tumor. The Tumor and Microecology Professional Committee of the Chinese Anti-cancer Association gathered relevant experts to discuss and propose the "Chinese guidelines for integrated diagnosis and treatment of IM technologies in tumor application (2024 Edition)," which was established based on the research progress of the application of the IM technology in tumor to provide a basis for the standardization of the diagnosis and treatment of the IM technology in the tumor.

[Mechanism of Modified Huoluo Xiaoling Pills against colorectal cancer based on network pharmacology, molecular docking, and experimental validation].

This study aims to predict the possible targets and related signaling pathways of Modified Huoluo Xiaoling Pills against colorectal cancer(CRC) by both network pharmacology and molecular docking and verify the mechanism of action by experiments. TCMSP was used to obtain the active ingredients and targets of Modified Huoluo Xiaoling Pills, and GeneCards, DrugBank, OMIM, and TTD were employed to acquire CRC-related targets. Cytoscape software was utilized to construct the drug-active ingredient-target network, and the STRING database was applied to establish the protein-protein interaction(PPI) network. DAVID platform was adopted to investigate the targets in terms of GO function and KEGG pathway enrichment analysis. Molecular docking was performed in AutoDock Vina. HCT 116 cells were intervened by different concentrations of Modified Huoluo Xiaoling Pills-containing serum, and CCK-8 was used to detect the proliferation inhibition of HCT 116 cells in each group. Transwell was employed to show the invasive abi-lity of HCT 116 cells, and Western blot was taken to reveal the expression levels of ß-catenin, cyclinD1, c-Myc, as well as epithelial-mesenchymal transition(EMT) marker proteins E-cadherin, N-cadherin, vimentin, MMP2, MMP7, MMP9, and TWIST in HCT 116 cells. The network pharmacological analysis yielded 242 active ingredients of Modified Huoluo Xiaoling Pills, 1 844 CRC targets, and 127 overlapping targets of CRC and Modified Huoluo Xiaoling Pills, and the signaling pathways related to CRC involved PI3K-Akt, TNF, HIF-1, IL-17, Wnt, etc. Molecular docking showed that the key active ingredients had a stable binding conformation with the core proteins. CCK-8 indicated that Modified Huoluo Xiaoling Pills significantly inhibited the proliferation of HCT 116 cells. Transwell assay showed that with increasing concentration of Modified Huoluo Xiaoling Pills containing serum, the invasive ability of HCT 116 cells was more obviously inhibited. The expression of ß-catenin, cyclinD1, c-Myc, N-cadherin, vimentin, MMP2, MMP7, MMP9, and TWIST proteins were suppressed, and the expression of E-cadherin was improved by the intervention of drug-containing serum. Thus, it can be seen that Modified Huoluo Xiaoling Pills restrains the proliferation, invasion, and metastasis of CRC cells through multiple components, multiple targets, and multiple pathways, and the mechanism of action may be related to the inhibition of the activation of the Wnt/ß-catenin signaling pathway, thereby affecting the occurrence of EMT.

Anti-Type II Diabetic Effects of Coix Seed Prolamin Hydrolysates: Physiological and Transcriptomic Analyses.

Previous studies have demonstrated that enzymatically prepared coix seed prolamin hydrolysates (CHPs) contain several bioactive peptides that efficiently inhibit the activity of target enzymes (α-glucosidase and dipeptidyl kinase-IV) in type 2 diabetes mellitus (T2DM). However, the anti-T2DM effects and potential mechanisms of CHPs as a whole in vivo have not yet been systematically explored. Therefore, we evaluated the preventive, therapeutic, and modifying effects of CHPs on T2DM by combining physiological and liver transcriptomics with a T2DM mouse model. The results showed that sustained high-fructose intake led to prediabetic symptoms in mice, with abnormal fluctuations in blood glucose and blood lipid levels. Intervention with CPHs effectively prevented weight loss; regulated abnormal changes in blood glucose; improved impaired glucose tolerance; inhibited the abnormal expression of total cholesterol, triglycerides, and low-density lipoproteins; alleviated insulin resistance; and restored pancreatic islet tissue function in mice fed a high-fructose diet. In addition, we found that CHPs also play a palliative role in the loss of liver function and protect various organ tissues (including the liver, kidneys, pancreas, and heart), and are effective in preventing damage to the liver and pancreatic islet cells. We also found that the intake of CHPs reversed the abnormally altered hepatic gene profile in model mice and identified 381 differentially expressed genes that could serve as key genes for preventing the development of T2DM, which are highly correlated with multiple glycolipid metabolic pathways. We demonstrated that CHPs play a positive role in the normal functioning of the insulin signalling pathway dominated by the IRS-1/PI3K/AKT (insulin receptor substrates-1/phosphoinositide 3-kinase/protein kinase B) pathway. In summary, CHPs can be used as effective food-borne glucose-modifying components of healthy foods.