TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Genome-Wide CRISPR/Cas9 Screening Identifies That Mitochondrial Solute Carrier SLC25A23 Attenuates Type I IFN Antiviral Immunity via Interfering with MAVS Aggregation.

Activation of the mitochondrial antiviral signaling (MAVS) adaptor, also known as IPS-1, VISA, or Cardif, is crucial for antiviral immunity in retinoic acid-inducible gene I (RIG-I)-like receptor signaling. Upon interacting with RIG-I, MAVS undergoes K63-linked polyubiquitination by the E3 ligase Trim31, and subsequently aggregates to activate downstream signaling effectors. However, the molecular mechanisms that modulate MAVS activation are not yet fully understood. In this study, the mitochondrial solute carrier SLC25A23 was found to attenuate type I IFN antiviral immunity using genome-wide CRISPR/Cas9 screening. SLC25A23 interacts with Trim31, interfering with its binding of Trim31 to MAVS. Indeed, SLC25A23 downregulation was found to increase K63-linked polyubiquitination and subsequent aggregation of MAVS, which promoted type I IFN production upon RNA virus infection. Consistently, mice with SLC25A23 knockdown were more resistant to RNA virus infection in vivo. These findings establish SLC25A23 as a novel regulator of MAVS posttranslational modifications and of type I antiviral immunity.

Cardioprotective effects of asiaticoside against diabetic cardiomyopathy: Activation of the AMPK/Nrf2 pathway.

Diabetic cardiomyopathy (DCM) is a chronic microvascular complication of diabetes that is generally defined as ventricular dysfunction occurring in patients with diabetes and unrelated to known causes. Several mechanisms have been proposed to contribute to the occurrence and persistence of DCM, in which oxidative stress and autophagy play a non-negligible role. Diabetic cardiomyopathy is involved in a variety of physiological and pathological processes. The 5' adenosine monophosphate-activated protein kinase/nuclear factor-erythroid 2-related factor 2 (AMPK/Nrf2) are expressed in the heart, and studies have shown that asiaticoside (ASI) and activated AMPK/Nrf2 have a protective effect on the myocardium. However, the roles of ASI and AMPK/Nrf2 in DCM are unknown. The intraperitoneal injection of streptozotocin (STZ) and high-fat feed were used to establish the DCM models in 100 C57/BL mice. Asiaticoside and inhibitors of AMPK/Nrf2 were used for intervention. Cardiac function, oxidative stress, and autophagy were measured in mice. DCM mice displayed increased levels of oxidative stress while autophagy levels declined. In addition, AMPK/Nrf2 was activated in DCM mice with ASI intervention. Further, we discovered that AMPK/Nrf2 inhibition blocked the protective effect of ASI by compound C and treatment with ML-385. The present study demonstrates that ASI exerts a protective effect against DCM via the potential activation of the AMPK/Nrf2 pathway. Asiaticoside is a potential therapeutic target for DCM.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Integrative score based on CDK6, PD-L1 and TMB predicts response to platinum-based chemotherapy and PD-1/PD-L1 blockade in muscle-invasive bladder cancer.

BACKGROUND: Cyclin-dependent kinase 6 (CDK6) was proved to be an important regulator in the progression of cell cycle and has been a promising therapeutic target in cancer treatment. However, the clinical significance of CDK6 in muscle-invasive bladder cancer (MIBC) remains obscure. Herein, we attempt to explore the clinical relevance of CDK6 and assess the feasibility of the integrative model to predict immune checkpoint blockade (ICB) response. METHODS: This study enrolled 933 patients with muscle-invasive bladder cancer (MIBC) from Zhongshan Hospital (ZSHS), The Cancer Genome Atlas (TCGA), Chemo, IMvigor210 and UC-GENOME cohorts. Kaplan-Meier survival and Cox regression analyses were performed to assess clinical outcomes based on CDK6 expression. RESULTS: High CDK6 expression conferred poor prognosis and superior response to platinum-based chemotherapy but inferior response to ICB in MIBC. Furthermore, the integrative model named response score based on CDK6, PD-L1 and TMB could better predict the response to ICB and chemotherapy. Patients with higher response scores were characterised by inflamed immune microenvironment and genomic instability. CONCLUSIONS: CDK6 expression was correlated with prognosis and therapy response in MIBC. Integration of CDK6, PD-L1 and TMB could better identify patients who were most likely to benefit from ICB and chemotherapy.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Realization of Gapped and Ungapped Photonic Topological Anderson Insulators.

It is commonly believed that topologically nontrivial one-dimensional systems support edge states rather than bulk states at zero energy. In this work, we find an unanticipated case of topological Anderson insulator (TAI) phase where two bulk modes are degenerate at zero energy, in addition to degenerate edge modes. We term this "ungapped TAI" to distinguish it from the previously known gapped TAIs. Our experimental realization of both gapped and ungapped TAIs relies on coupled photonic resonators, in which the disorder in coupling is judiciously engineered by adjusting the spacing between the resonators. By measuring the local density of states both in the bulk and at the edges, we demonstrate the existence of these two types of TAIs, together forming a TAI plateau in the phase diagram. Our experimental findings are well supported by theoretical analysis. In the ungapped TAI phase, we observe stable coexistence of topological edge states and localized bulk states at zero energy, highlighting the distinction between TAIs and traditional topological insulators.

Neuroprotective effects of melatonin-mediated mitophagy through nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 in neonatal hypoxic-ischemic brain damage.

Hypoxia-ischemia (HI) is a major cause of brain damage in neonates. Mitochondrial dysfunction acts as a hub for a broad spectrum of signaling events, culminating in cell death triggered by HI. A neuroprotective role of melatonin (MT) has been proposed, and mitophagy regulation seems to be important for cell survival. However, the molecular mechanisms underlying MT-mediated mitophagy during HI treatment are poorly defined. Nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 (NLRX1) has emerged as a critical regulator of mitochondrial dynamics and neuronal death that participates in the pathology of diverse diseases. This study aimed to clarify whether NLRX1 participates in the regulation of mitophagy during MT treatment for hypoxic-ischemic brain damage (HIBD). We demonstrated that MT protected neonates from HIBD through NLRX1-mediated mitophagy in vitro and in vivo. Meanwhile, MT upregulated the expression of NLRX1, Beclin-1, and autophagy-related 7 (ATG7) but decreased the expression of the mammalian target of rapamycin (mTOR) and translocase of the inner membrane of mitochondrion 23 (TIM23). Moreover, the neuroprotective effects of MT were abolished by silencing NLRX1 after oxygen-glucose deprivation (OGD). In addition, the downregulation of mTOR and upregulation of Beclin-1 and ATG7 by MT were inhibited after silencing NLRX1 under OGD. In summary, MT modulates mitophagy induction through NLRX1 and plays a protective role in HIBD, providing insight into potential therapeutic targets for MT to exert neuroprotection.

CD226 deficiency attenuates cardiac early pathological remodeling and dysfunction via decreasing inflammatory macrophage proportion and macrophage glycolysis in STZ-induced diabetic mice.

Diabetic cardiomyopathy (DCM) is one of the main complications in type I diabetic patients. Activated macrophage is critical for directing the process of inflammation during the development of DCM. The present study focused on the roles of CD226 on macrophage function during the DCM progression. It has been found that the number of cardiac macrophages in the hearts of streptozocin (STZ)-induced diabetes mice was significantly increased compared with that in non-diabetes mice, and the expression level of CD226 on cardiac macrophages in STZ-induced diabetes mice was higher than that in non-diabetes mice. CD226 deficiency attenuated the diabetes-induced cardiac dysfunction and decreased the proportion of CD86+ F4/80+ macrophages in the diabetic hearts. Notably, adoptive transfer of Cd226-/- - bone marrow derived macrophages (BMDMs) alleviated diabetes-induced cardiac dysfunction, which may be due to the attenuated migration capacity of Cd226-/- -BMDM under high glucose stimulation. Furthermore, CD226 deficiency decreased the macrophage glycolysis accompanying by the downregulated hexokinase 2 (HK2) and lactate dehydrogenase A (LDH-A) expression. Taken together, these findings revealed the pathogenic roles of CD226 played in the process of DCM and provided a basis for the treatment of DCM.

Transapical concomitant transseptal transcatheter closure of a giant mitral paravalvular leak under three-dimensional printing guidance.

A mitral paravalvular leak (PVL) is a significant complication of surgical valve replacement that has a profound impact on the health and survival of patients. Transcatheter closure of PVL has emerged as a promising treatment option. We present the case of a 65-year-old patient who experienced exertional dyspnea, chest tightness, and peripheral edema (New York Heart Association functional class Ⅵ) following surgical aortic and mitral valve replacement. Echocardiography and computed tomography performed on admission revealed a giant mitral PVL (1 bundle, volume 25.0 mL, area 13.0 cm²). Due to the patient's high surgical risk and complex anatomical characteristics, a patient-specific three-dimensional printed model was utilized to visualize anatomical structures and simulate the main procedures. After careful consideration, the surgical team opted to perform transcatheter closure of the giant mitral PVL via a transapical concomitant transseptal approach using two carefully selected devices of different sizes (14-mm and 16-mm Amplatzer Vascular Plug II). The procedure was carried out successfully. During the 1-month follow-up, the patient remained asymptomatic (New York Heart Association functional class Ⅰ). Transcatheter closure of a giant and complex mitral PVL utilizing three-dimensional printing guidance has proven to be a feasible approach.

Transcatheter tricuspid valve replacement for functional tricuspid regurgitation after left-sided valve surgery: A single-center experience.

BACKGROUND: Functional tricuspid regurgitation (FTR) following left-sided valve surgery (LSVS) is of clinical significance due to its high recurrence and mortality rates. Transcatheter therapy presents a potential solution to address this issue. AIMS: The study aimed to assess the safety and efficacy of transcatheter tricuspid valve replacement using the Lux-Valve system in a single center for patients with FTR after LSVS. METHODS: From June 2020 to April 2023, 20 patients with symptomatic severe FTR after LSVS were referred to our center. A multidisciplinary cardiac team evaluated these patients for suitability for transcatheter tricuspid valve replacement with Lux-Valve systems. Primary efficacy and safety endpoints were immediate postoperative tricuspid regurgitation severity ≤ moderate and major adverse events during follow-up. RESULTS: Twenty patients (average age 65.7 ± 7.4 years; 65.0% women) successfully underwent Lux-Valve system implantation after LSVS. All patients achieved ≤ moderate tricuspid regurgitation immediately after the procedure. Only one patient (5.0%) experienced a procedure-related major adverse event, leading to in-hospital mortality due to pulmonary infection. At the 6-month follow-up, 17 patients (89.5%) improved to New York Heart Association functional class I to II (p < 0.001). The overall Kansas City Cardiomyopathy Questionnaire score significantly improved (35.9 ± 6.7 points to 58.9 ± 5.8 points, p < 0.001). CONCLUSION: The Lux-Valve system was found to be safe and effective for treating FTR after LSVS. It resulted in positive early outcomes, including a significant reduction in FTR, improved functional status, and enhanced quality of life, especially in high-risk patients.

Polymersomes in Drug Delivery─From Experiment to Computational Modeling.

Polymersomes, composed of amphiphilic block copolymers, are self-assembled vesicles that have gained attention as potential drug delivery systems due to their good biocompatibility, stability, and versatility. Various experimental techniques have been employed to characterize the self-assembly behaviors and properties of polymersomes. However, they have limitations in revealing molecular details and underlying mechanisms. Computational modeling techniques have emerged as powerful tools to complement experimental studies and enabled researchers to examine drug delivery mechanisms at molecular resolution. This review aims to provide a comprehensive overview of the state of the art in the field of polymersome-based drug delivery systems, with an emphasis on insights gained from both experimental and computational studies. Specifically, we focus on polymersome morphologies, self-assembly kinetics, fusion and fission, behaviors in flow, as well as drug encapsulation and release mechanisms. Furthermore, we also identify existing challenges and limitations in this rapidly evolving field and suggest possible directions for future research.

Mesocarnivores vary in their spatiotemporal avoidance strategies at communications hubs of an apex carnivore.

Mesocarnivores face interspecific competition and risk intraguild predation when sharing resources with apex carnivores. Within a landscape, carnivores across trophic levels may use the same communication hubs, which provide a mix of risks (injury/death) and rewards (gaining information) for subordinate species. We predicted that mesocarnivores would employ different strategies to avoid apex carnivores at shared communication hubs, depending on their trophic position. To test our prediction, we examined how different subordinate carnivore species in the Santa Cruz Mountains of California, USA, manage spatial overlap with pumas (Puma concolor), both at communication hubs and across a landscape-level camera trap array. We estimated species-specific occurrence, visitation rates, temporal overlap, and Avoidance-Attraction Ratios from camera traps and tested for differences between the two types of sites. We found that mesocarnivores generally avoided pumas at communication hubs, and this became more pronounced when pumas scent-marked during their most recent visit. Coyotes (Canis latrans), the pumas' closest subordinate competitor in our system, exhibited the strongest avoidance at communication hubs. Gray foxes (Urocyon cinereoargenteus) avoided pumas the least, which may suggest possible benefits from pumas suppressing coyotes. Overall, mesocarnivores exhibited various spatiotemporal avoidance strategies at communication hubs rather than outright avoidance, likely because they benefit from information gained while 'eavesdropping' on puma activity. Variability in avoidance strategies may be due to differential predation risks, as apex carnivores often interact more aggressively with their closest competitors. Combined, our results show how apex carnivores trigger complex species interactions across the entire carnivore guild and how trophic position determines behavioral responses and subsequent space use of subordinate mesocarnivores across the landscape.

Design, bioactivity and mechanism of N'-phenyl pyridylcarbohydrazides with broad-spectrum antifungal activity.

Succinate dehydrogenase inhibitors (SDHIs) as one of the fastest-growing fungicide categories for plant protection. In this study, a series of N'-phenyl pyridylcarbohydrazides as analogues of commercial SDHIs were designed and evaluated for inhibition activity on phytopathogenic fungi to search for potential novel SDHIs. The determination of antifungal activity in vitro and in vivo led to the discovery of a series of compounds with high activity and broad-spectrum property. Especially, N'-(4-fluorophenyl)picolinohydrazide (1c) and N'-(3,4-fluorophenyl)picolinohydrazide (1ae) showed 0.041-1.851 µg/mL of EC50 values on twelve fungi, superior to positive controls carbendazim and boscalid. In vivo activity, 1c at 50 µg/mL showed 61% of control efficacy at the post-treatment 9th day for the infection of P. piricola on apples, slightly smaller than 70% of carbendazim. In terms of action mechanism, 1c showed strong inhibition activity with IC50 of 0.107 µg/mL on SDH in Alternaria brassicae, superior to positive SDHI boscalid (IC50 0.182 µg/mL). Molecular docking indicated that 1c can well bind with the ubiquinone-binding region of SDH mainly by hydrogen bond, carbon hydrogen bond, π-alkyl, amide-π stacking, F-N and F-H interactions. Furthermore, scanning and transmission electron micrographs showed that 1c was able to obviously change the structure of mycelia and cell membrane. Fluorescence staining analysis showed that 1c could increase both the intracellular reactive oxygen species level and mitochondrial membrane potential. Finally, seed germination test, seedling growth test and cytotoxicity assay showed that 1c had very low toxicity to plant growth and mammalian cells. Thus, N'-phenyl pyridylcarbohydrazides especially 1c and 1ae can be considered promising fungicide alternatives for plant protection.

Exosome-Mediated Communication in Thyroid Cancer: Implications for Prognosis and Therapeutic Targets.

Thyroid cancer (THCA) is one of the most common malignancies of the endocrine system. Exosomes have significant value in performing molecular treatments, evaluating the diagnosis and determining tumor prognosis. Thus, the identification of exosome-related genes could be valuable for the diagnosis and potential treatment of THCA. In this study, we examined a set of exosome-related differentially expressed genes (DEGs) (BIRC5, POSTN, TGFBR1, DUSP1, BID, and FGFR2) by taking the intersection between the DEGs of the TCGA-THCA and GeneCards datasets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the exosome-related DEGs indicated that these genes were involved in certain biological functions and pathways. Protein‒protein interaction (PPI), mRNA‒miRNA, and mRNA-TF interaction networks were constructed using the 6 exosome-related DEGs as hub genes. Furthermore, we analyzed the correlation between the 6 exosome-related DEGs and immune infiltration. The Genomics of Drug Sensitivity in Cancer (GDSC), the Cancer Cell Line Encyclopedia (CCLE), and the CellMiner database were used to elucidate the relationship between the exosome-related DEGs and drug sensitivity. In addition, we verified that both POSTN and BID were upregulated in papillary thyroid cancer (PTC) patients and that their expression was correlated with cancer progression. The POSTN and BID protein expression levels were further examined in THCA cell lines. These findings provide insights into exosome-related clinical trials and drug development.

Analysis of risk factors for failed closed reduction in pediatric Gartland Type III supracondylar humerus fracture.

PURPOSE: Gartland Type III supracondylar humerus fractures are commonly treated using closed reduction followed by percutaneous pin fixation. However, conversion to open reduction may be necessary if closed reduction fails. This study aimed to identify risk factors associated with failed closed reduction and provide a theoretical basis for clinical decision-making in the treatment of Gartland Type III fractures. METHODS: A retrospective analysis was conducted on children with Gartland Type III supracondylar humerus fracture who underwent surgical treatment between April 2017 and June 2018. Based on whether or not the closed reduction was successful, patients were split into the open reduction group and the closed reduction group. Within the closed reduction group, subgroup analysis based on surgery duration was carried out. Data were collected from medical records and X-ray images. Univariate and multivariate regression analyses were utilized to evaluate the relationship between variables and failed closed reduction. RESULTS: The study included 36 patients in the open reduction group and 135 patients in the closed reduction group. Multivariate analysis revealed that the presence of angle (P=0.024, OR=3.199), rotation (P=0.000, OR=6.359), skin creases (P=0.013, OR=4.077), anterior-posterior displacement ratio (P=0.011, OR=4.337), fracture angle in the anteroposterior view (P=0.014, OR=0.939), and fracture distal displacement direction (P=0.002, OR=5.384) were independent risk factors for failed closed reduction. Subgroup analysis showed that fracture distal displacement direction (P=0.013), skin folds (P=0.013), lateral displacement ratio (P=0.016), and anterior-posterior displacement value (P=0.005) significantly influenced the duration of closed reduction surgery. CONCLUSION: The presence of sharp angle or rotation at the fracture ends, skin folds on the anterior elbow, minor anterior-posterior displacement of the fracture, higher medial inclination of the fracture plane, and distal fracture displacement towards the radial side are independent risk factors for failed closed reduction in pediatric Gartland Type III supracondylar humerus fracture.

Development of a novel human stratum corneum mimetic phospholipid -vesicle-based permeation assay models for in vitro permeation studies.

OBJECTIVES: To develop and evaluate a novel human stratum corneum (SC) mimetic phospholipid vesicle-based permeation assay (PVPASC) model for in vitro permeation studies. SIGNIFICANCE: Due to the increasing restrictions on the use of human and animal skins, artificial skin models have attracted substantial interest in pharmaceuticals and cosmetic industries. In this study, a modified PVPASC model containing both SC lipids and proteins was developed. METHODS: The PVPASC model was optimized by altering the lipid composition and adding keratin in the formulation of large liposomes. The barrier properties were monitored by measuring the electrical resistance (ER) and permeability of Rhodamine B (RB). The modified PVPASC model was characterized in terms of the surface topography, solvent influence and storage stability. The permeation studies of the active components in Compound Nanxing Zhitong Plaster (CNZP) were performed to examine the capability of PVPASC in the application of skin penetration. RESULTS: The ER and Papp values of RB obtained from the optimized PVPASC model indicated a similar barrier property to porcine ear skin. Scanning electron microscope analysis demonstrated a mimic 'brick-and-mortar' structure. The PVPASC model can be stored for three weeks at -20 °C, and withstand the presence of different receptor medium for 24 h. The permeation studies of the active components demonstrated a good correlation (r2 = 0.9136) of Papp values between the drugs' permeation through the PVPASC model and porcine ear skin. CONCLUSION: Keratin contained composite phospholipid vesicle-based permeation assay models have been proven to be potential skin tools in topical/transdermal permeation studies.

[Charcoal-frying process and quality markers of Sanguisorbae Radix based on hemostatic effect].

Studies have reported that the hemostatic effect of Sanguisorbae Radix(SR) is significantly enhanced after processing with charcoal. However, the standard components(tannins and gallic acid) specified in the Chinese Pharmacopeia decrease in charcoal-fried Sanguisorbae Radix(CSR), which is contrast to the enhancement of the hemostatic effect. Therefore, this study aimed to optimize the charcoal-frying process of SR based on its hemostatic efficacy and comprehensively analyze the components of SR and its processed products, thus exploring the material basis for the hemostatic effect. The results indicated that SR processed at 250 ℃ for 14 min(14-min CSR) not only complied with the description in the Chinese Pharmacopeia but also demonstrated improved blood-coagulating and blood-adsorbing effects compared with raw SR(P<0.05). Moroever, 14-min CSR reduced the bleeding time in the rat models of tail snipping, liver bleeding, and muscle injury, surpassing both raw and excessively fried SR(16 min processed) as well as tranexamic acid(P<0.05). Ellagitannin, ellagic acid, methyl gallate, pyrogallic acid, protocatechuic acid, Mg, Ca, Mn, Cu, and Zn contributed to the hemostatic effect of CSR over SR. Among these substances, ellagitannin, ellagic acid, Mg, and Ca had high content in the 14 min CSR, reaching(106.73±14.87),(34.86±4.43),(2.81±0.23), and(1.21±0.23) mg·g~(-1), respectively. Additionally, the color difference value(ΔE~*ab) of SR processed to different extents was correlated with the content of the aforementioned hemostatic substances. In summary, this study optimized the charcoal-frying process as 250 ℃ for 14 min for SR based on its hemostatic effect. Furthermore, ellagic acid and/or the powder chromaticity are proposed as indicators for the processing and quality control of CSR.

Prediction of the effects of small molecules on the gut microbiome using machine learning method integrating with optimal molecular features.

BACKGROUND: The human gut microbiome (HGM), consisting of trillions of microorganisms, is crucial to human health. Adverse drug use is one of the most important causes of HGM disorder. Thus, it is necessary to identify drugs or compounds with anti-commensal effects on HGM in the early drug discovery stage. This study proposes a novel anti-commensal effects classification using a machine learning method and optimal molecular features. To improve the prediction performance, we explored combinations of six fingerprints and three descriptors to filter the best characterization as molecular features. RESULTS: The final consensus model based on optimal features yielded the F1-score of 0.725 ± 0.014, ACC of 82.9 ± 0.7%, and AUC of 0.791 ± 0.009 for five-fold cross-validation. In addition, this novel model outperformed the prior studies by using the same algorithm. Furthermore, the important chemical descriptors and misclassified anti-commensal compounds are analyzed to better understand and interpret the model. Finally, seven structural alerts responsible for the chemical anti-commensal effect are identified, implying valuable information for drug design. CONCLUSION: Our study would be a promising tool for screening anti-commensal compounds in the early stage of drug discovery and assessing the potential risks of these drugs in vivo.

Altered Mycobiota Signatures and Enriched Pathogenic Aspergillus rambellii Are Associated With Colorectal Cancer Based on Multicohort Fecal Metagenomic Analyses.

BACKGROUND & AIMS: The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC. METHODS: We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated in vitro and in vivo. RESULTS: Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%). CONCLUSIONS: This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.