The efficacy of modified contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) using Sonazoid in diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis.

Background: The contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) is an algorithm for the diagnosis of hepatocellular carcinoma (HCC) in high-risk populations. Previous studies have shown the algorithm to have high specificity and moderate sensitivity. Nevertheless, it is designated for utilization solely with blood pool contrast agents. Sonazoid, a contrast agent that combines blood pools and Kupffer cells properties, has recently gained approval for marketing in an increased number of countries. Enhanced sensitivity in diagnosing HCC may be achieved through the distinctive Kupffer phase (KP) exhibited by Sonazoid. Certain academics have suggested the modified CEUS LI-RADS using Sonazoid. The main criteria of mild and late (≥60 seconds) washout in CEUS LI-RADS LR-5 were replaced by KP (>10 minutes) defects as the primary criteria. The purpose of this research was to evaluate the effectiveness of the modified CEUS LI-RADS using Sonazoid in diagnosing HCC. Methods: Original studies on Sonazoid and CEUS LI-RADS were searched in the PubMed, Embase, Cochrane Library, and Web of Science databases until 13 July 2023, with no restrictions on language. We enrolled studies that applied Sonazoid for CEUS in patients at high risk of HCC and modified CEUS LI-RADS for the diagnosis of intrahepatic nodules. Meta-analyses, evaluations, case studies, correspondences, remarks, and summaries of conferences were excluded. Additionally, studies that fell outside the scope of this study and contained data on the same patients were also excluded. We evaluated the quality of research by employing the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. A bivariate mixed effects model was utilized to conduct a meta-analysis, summarizing the sensitivity and specificity in the diagnosis of HCC. The investigation of potential factors contributing to study heterogeneity was conducted using meta-regression analysis. Results: Out of the 103 studies screened, 6 studies (835 lesions) were included in the final results. Modified CEUS LR-5 exhibited a sensitivity of 0.77 [95% confidence interval (CI): 0.70-0.82; I2=71.98%; P=0.00] and a specificity of 0.88 (95% CI: 0.83-0.92; I2=0.00; P=0.47) for HCC diagnosis, with heterogeneity in sensitivity. The presence of heterogeneity in the study was found to have a significant association with factors such as the study design, the number of image reviewers, the proportion of cirrhosis, the proportion of other non-HCC malignancies (OM) cases, and the type of reference standard (P≤0.05). Conclusions: The modified CEUS LI-RADS LR-5 categorization demonstrates a reasonable level of sensitivity 0.77, but an insufficient level of specificity 0.88 when diagnosing HCC. KP defects cannot be used as a primary feature in the diagnosis of HCC by CEUS LI-RADS, perhaps as an ancillary feature.

Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients' survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

Empowering hydrophobic anticancer drugs by ultrashort peptides: General Co-assembly strategy for improved solubility, targeted efficacy, and clinical application.

The current state of drug delivery systems allows for the resolution of specific issues like inadequate solubility, limited targeting capabilities, and complex preparation processes, requiring tailored designs for different drugs. Yet, the major challenge in clinical application lies in surmounting these obstacles with a universal carrier that is effective for a variety of anticancer drugs. Herein, with the help of computer simulation, we rationally design ultrashort peptides GY and CCYRGD, which can co-assemble with hydrophobic anticancer drugs into nanoparticles with enhanced solubility, targeting ability and anticancer efficacy. Taking 7-ethyl-10-hydroxy camptothecin (SN38) as a model anticancer drug, the co-assembled SN38-GY-CCYRGD nanoparticles significantly enhance the water solubility of SN38 by more than three orders of magnitude. The as-prepared nanoparticles can effectively kill cancer cells, e.g., human small cell lung cancer (A549) cells with a notable cell mortality rate of 71%. Mice experimental results demonstrate the nanoparticles' efficient targeting capability, marked reducing the toxicity to normal tissues while improving antitumor efficacy. This work presents a novel drug delivery method, integrating effective, targeted, and safe strategies into a comprehensive carrier system, designed for the administration of hydrophobic anticancer drugs.

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.

The association of the prothrombin A19911G single-nucleotide polymorphism and the risk of venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: The study employed meta-analysis to provide a comprehensive synthesis of evidence regarding the association between the prothrombin A19911G polymorphism and the risk of venous thromboembolism (VTE). METHOD: The databases were searched to identify studies investigating the association between the prothrombin A19911G polymorphism and the risk of VTE. Meta-analysis was conducted using Stata 14.0 software. RESULTS: A total of five literature studies were included, involving 14,001 participants. Meta-analysis demonstrated that prothrombin A19911G polymorphism increased the risk of VTE (G vs A: OR = 1.17, 95% CI = 1.11-1.22, p < .00001; GG + AG vs AA: OR = 1.22, 95% CI = 1.13-1.31, p < .00001; GG vs AG + AA: OR = 1.23, 95% CI = 1.14-1.33, p < .00001; AG vs AA: OR = 1.15, 95% CI = 1.06-1.25, p = .0006; GG vs AA: OR = 1.34, 95% CI = 1.22-1.48, p < .00001). CONCLUSION: The polymorphism of prothrombin A19911G enhances the susceptibility to VTE.

Rapid and multi-target genotyping of Helicobacter pylori with digital microfluidics.

Helicobacter pylori (H. pylori) infection correlates closely with gastric diseases such as gastritis, ulcers, and cancer, influencing more than half of the world's population. Establishing a rapid, precise, and automated platform for H. pylori diagnosis is an urgent clinical need and would significantly benefit therapeutic intervention. Recombinase polymerase amplification (RPA)-CRISPR recently emerged as a promising molecular diagnostic assay due to its rapid detection capability, high specificity, and mild reaction conditions. In this work, we adapted the RPA-CRISPR assay on a digital microfluidics (DMF) system for automated H. pylori detection and genotyping. The system can achieve multi-target parallel detection of H. pylori nucleotide conservative genes (ureB) and virulence genes (cagA and vacA) across different samples within 30 min, exhibiting a detection limit of 10 copies/rxn and no false positives. We further conducted tests on 80 clinical saliva samples and compared the results with those derived from real-time quantitative polymerase chain reaction, demonstrating 100% diagnostic sensitivity and specificity for the RPA-CRISPR/DMF method. By automating the assay process on a single chip, the DMF system can significantly reduce the usage of reagents and samples, minimize the cross-contamination effect, and shorten the reaction time, with the additional benefit of losing the chance of experiment failure/inconsistency due to manual operations. The DMF system together with the RPA-CRISPR assay can be used for early detection and genotyping of H. pylori with high sensitivity and specificity, and has the potential to become a universal molecular diagnostic platform.

Transcatheter closure of atrial septal defects with absent aortic rim and the predictors of right atrial reverse remodelingTranscatheter closure of atrial septal defects with absent aortic rim and the predictors of right atrial reverse remodeling: 5 years experience in China.

【Abstract】 Aim: To investigate the safety of interventional therapy in patients with secondary atrial septal defect (atrial septal defect, ASD) with complete aortic rim deficiency and explore the predictors of right atrial non-reverse remodeling. METHODS: 1011 patients with ASD who underwent transcatheter closure in the Department of Cardiology, Zhongshan Hospital affiliated to Fudan University from June 2017 to June 2022 were enrolled in the study. They were divided into a complete aortic rim deficiency group and without absent aortic rim group. Furthermore, patients who had an enlarged right atrial in the absent aortic rim group were divided into two sub-groups according to whether their right atrial reversed remodeling post-procedure. Multivariate logistic regression was used to determine the predictors of right atrial reversed remodeling. RESULTS: During the 1-year follow-up, no major operative complications occurred in all patients with the absence of an aortic rim and a normal edge. After the operation, the right heart remodeling was significantly reversed, multivariate logistic regression analysis was performed and found that preoperative without coronary heart disease, lower plasma creatinine level, and larger RA and RV dimension were predictive factors for the reverse of right atrial remodeling after treatment. CONCLUSION: Transcatheter closure of ASD with complete aortic rim deficiency is safe and feasible. The patients without coronary heart disease, the lower the creatinine value and the less tricuspid regurgitation before an operation, the more improvement of right atrial remodeling after the operation.

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

The effect of scutellaria baicalensis and its active ingredients on major depressive disorder: a systematic review and meta-analysis of literature in pre-clinical research.

Background: Scutellaria baicalensis, the dry root of scutellaria baicalensis georgi, is a traditional Chinese medicine with long. In clinic, scutellaria baicalensis is commonly used in prescription for the treatment of depression. Additionally, numerous pre-clinical studies have shown that Scutellaria baicalensis and its active constituents are effective for depression. In this study, we aims to systematically review the roles of scutellaria baicalensis in depression and summarize the possible mechanism. Methods: A systematic review and meta-analysis were conducted to analyze the existing studies on the effects of scutellaria baicalensis on depression in animal models. Briefly, we searched electronic databases including Pubmed and Embase for preclinical trial studies from inception to September 2023. The items in each study were evaluated by two independent reviewers, and meta-analyses were performed on scutellaria baicalensis-induced behavioral changes in the study. Finally, random effects model is used to collect data. Results: A total of 49 studies were identified, and 13 studies were included in the final analysis. They all reported the different antidepressant effects of scutellaria baicalensis and the underlying biological mechanisms. Among the included 13 studies, the results of eight articles SPT[SMD = -2.80, 95%CI(-4.03, -1.57), p < 0.01], the results of the nine articles OFT[SMD = -2.38, 95%CI(-3.53, -1.23), p < 0.01], and the results of two articles NSFT[SMD = -2.98, 95%CI(-3.94, -2.02), p < 0.01] were significantly different from the control group. The risk of bias was moderate in all studies, however, there was a significant heterogeneity among studies. Conclusion: These results preliminarily suggest that scutellaria baicalensis can alleviate depressive behaviors and modulate underlying mechanisms, which is expected to be a promising antidepressant.

Effects of gamma-Ray irradiation on material and electrical properties of AlN gate dielectric on 4H-SiC.

This article investigates the radiation effects on as-deposited and annealed AlN films on 4H-SiC substrates under gamma-rays. The AlN films are prepared using plasma-enhanced-atomic-layer-deposition (PEALD) on an n-type 4H-SiC substrate. The AlN/4H-SiC MIS structure is subjected to gamma-ray irradiation with total doses of 0, 300, and 600 krad(Si). Physical, chemical, and electrical methods were employed to study the variations in surface morphology, charge transport, and interfacial trapping characteristics induced by irradiation. After 300 krad(Si) irradiation, the as-deposited and annealed samples exhibit their highest root mean square values of 0.917 nm and 1.190 nm, respectively, which is attributed to N vacancy defects induced by irradiation. Under irradiation, the flatband voltage (Vfb) of the as-deposited sample shifts from 2.24 V to 0.78 V, while the annealed sample shifts from 1.18 V to 2.16 V. XPS analysis reveals the decomposition of O-related defects in the as-deposited AlN and the formation of Al(NOx)y compounds in the annealed sample. Furthermore, the Space-Charge-Limits-Conduction (SCLC) in the as-deposited sample is enhanced after radiation, while the barrier height of the annealed sample decreases from 1.12 eV to 0.84 eV, accompanied by the occurrence of the SCLC. The physical mechanism of the degradation of electrical performance in irradiated devices is the introduction of defects like N vacancies and O-related defects like Al(NOx)y. These findings provide valuable insights for SiC power devices in space applications.

Development of a 3D Brain Model to Study Sex-Specific Neuroinflammation After Hemorrhagic Stroke.

Subarachnoid hemorrhage (SAH) accounts for 5% of stroke, with women having a decreased inflammatory response compared to men; however, this mechanism has yet to be identified. One hurdle in SAH research is the lack of human brain models. Studies in murine models are helpful, but human models should be used in conjunction for improved translatability. These observations lead us to develop a 3D system to study the sex-specific microglial and neuroglial function in a novel in vitro human SAH model and compare it to our validated in vivo SAH model. Our lab has developed a 3D, membrane-based in vitro cell culture system with human astrocytes, microglia, and neurons from both sexes. The 3D cultures were incubated with male and female cerebrospinal fluid from SAH patients in the Neuro-ICU. Furthermore, microglial morphology, erythrophagocytosis, microglial inflammatory cytokine production, and neuronal apoptosis were studied and compared with our murine SAH models. The human 3D system demonstrated intercellular interactions and proportions of the three cell types similar to the adult human brain. In vitro and in vivo models of SAH showed concordance in male microglia being more inflammatory than females via morphology and flow cytometry. On the contrary, both in vitro and in vivo models revealed that female microglia were more phagocytic and less prone to damaging neurons than males. One possible explanation for the increased phagocytic ability of female microglia was the increased expression of CD206 and MerTK. Our in vitro, human, 3D cell culture SAH model showed similar results to our in vivo murine SAH model with respect to microglial morphology, inflammation, and phagocytosis when comparing the sexes. A human 3D brain model of SAH may be a useful adjunct to murine models to improve translation to SAH patients.

Tool mark prediction on the surface of large-aperture mirrors via magnetorheological finishing.

The magnetorheological finishing (MRF) of surfaces often results in tool mark errors. A prediction model can effectively guide subsequent processing, necessitating thorough research. To address this issue, this paper introduces an enhanced continuous tool influence function method. This method involves sub dwell time convolution with varying tool influence functions, enabling tool mark prediction. Numerical simulations demonstrate the proposed method's effectiveness, while the data size is estimated to confirm its economic properties. Subsequently, a MRF experiment was conducted, affirming the practicability through power spectral density evaluation. A fast algorithm is given to guide tool mark predictions on large-aperture mirrors fabrication engineering subjected to sub-aperture polishing.

Association between white matter hyperintensity and anxiety/depression.

Although previous studies have explored the associations of white matter hyperintensity with psychiatric disorders, the sample size is small and the conclusions are inconsistent. The present study aimed to further systematically explore the association in a larger sample. All data were extracted from the UK Biobank. First, general linear regression models and logistic regression models were used to assess the association between white matter hyperintensity volume and anxiety/depression. White matter hyperintensity has been classified into periventricular white matter hyperintensity and deep white matter hyperintensity. Anxiety was determined by General Anxiety Disorder-7 score (n = 17,221) and self-reported anxiety (n = 15,333), depression was determined by Patient Health Questionnaire-9 score (n = 17,175), and self-reported depression (n = 14,519). Moreover, we employed Cox proportional hazard models to explore the association between white matter hyperintensity volume and anxiety/depression. The covariates included in fully adjusted model are age, gender, body mass index, Townsend deprivation index, healthy physical activity, cigarette consumption, alcohol consumption, educational attainment, diabetes, hypertension, and coronary heart disease. The results of the fully adjusted model showed that white matter hyperintensity volume was significantly associated with General Anxiety Disorder-7 score (periventricular white matter hyperintensity: ß = 0.152, deep white matter hyperintensity: ß = 0.094) and Patient Health Questionnaire-9 score (periventricular white matter hyperintensity: ß = 0.168). Logistic regression analysis results indicated that periventricular white matter hyperintensity volume (odds ratio = 1.153) was significantly associated with self-reported anxiety. After applying the Cox proportional hazard models, we found that larger white matter hyperintensity volume was associated with increased risk of depression (periventricular white matter hyperintensity: hazard ratio = 1.589, deep white matter hyperintensity: hazard ratio = 1.200), but not anxiety. In summary, our findings support a positive association between white matter hyperintensity volume and depression.

DDR1-targeted therapies: current limitations and future potential.

Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.

Prevalence and genetic diversity of human rhinovirus among patients with acute respiratory infections in China, 2012-2021.

To understand the prevalence of rhinovirus (RV) among acute respiratory infection (ARI) patients, 10-year ARI surveillance in multiple provinces of China were conducted during 2012-2021. Of 15 645 ARI patients, 1180 (7.54%) were confirmed to have RV infection and 820 (69.49%) were children under 5 years of age. RV typing was performed on the 527 VP1 gene sequences, and species A, B, and C accounted for 73.24%, 4.93%, and 21.82%, respectively. Although no significant difference in the proportions of age groups or disease severity was found between RV species, RV-C was more frequently detected in children under 5 years of age, RV-A was more frequently detected in elderly individuals (≥60), and the proportions of pneumonia in RV-A and RV-C patients were higher than those in RV-B patients. The epidemic peak of RV-A was earlier than that of RV-C. A total of 57 types of RV-A, 13 types of RV-B, and 35 types of RV-C were identified in RV-infected patients, and two uncertain RV types were also detected. The findings showed a few differences in epidemiological and clinical features between RV species in ARI patients, and RV-A and RV-C were more prevalent than RV-B.

Multi-omics data-based analysis characterizes molecular alterations of the vesicle genes in human colorectal cancer.

The role of vesicular genes in the development of colorectal cancer (CRC) is crucial. Analyzing alterations in these genes at multi-omics can aid in understanding the molecular pathways behind colorectal carcinogenesis and identifying potential treatment targets. However, studies on the overall alteration of vesicular genes in CRC are still lacking. In this study, we aimed to investigate the relationship between vesicle genetic alterations and CRC progression. To achieve this, we analyzed molecular alterations in CRC vesicle genes at eight levels, including mRNA, protein, and epigenetic levels. Additionally, we examined CRC overall survival-related genes that were obtained from a public database. Our analysis of chromatin structural variants, DNA methylation, chromatin accessibility, and proteins (including phosphorylation, ubiquitination, and malonylation), along with RNA-seq data from the TCGA database, revealed multiple levels of alterations in CRC vesicle genes in the collected tissue samples. We progressively examined the alterations of vesicle genes in mRNA and protein levels in CRC and discovered the hub genes. Further investigation identified the probable essential transcription factors. This study contributes to a thorough knowledge of the connection between vesicle gene alterations at multiple levels and the development of CRC and offers a theoretical framework for the identification of novel treatment targets.

Alkali injury-induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation.

Inflammatory lymphangiogenesis is intimately linked to immune regulation and tissue homeostasis. However, current evidence has suggested that classic lymphatic vessels are physiologically absent in intraocular structures. Here, we show that neolymphatic vessels were induced in the iris after corneal alkali injury (CAI) in a VEGFR3-dependent manner. Cre-loxP-based lineage tracing revealed that these lymphatic endothelial cells (LECs) originate from existing Prox1+ lymphatic vessels. Notably, the ablation of iridial lymphangiogenesis via conditional deletion of VEGFR3 alleviated the ocular inflammatory response and pathological T cell infiltration. Our findings demonstrate that iridial neolymphatics actively participate in pathological immune responses following injury and suggest intraocular lymphangiogenesis as a valuable therapeutic target for the treatment of ocular inflammation.

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a ß-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy.

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Renal interstitial fibrotic assessment using non-Gaussian diffusion kurtosis imaging in a rat model of hyperuricemia.

BACKGROUND: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia. METHODS: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment. RESULTS: The HUA, AP, and AP + EM group MKOS and MKIS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MKOS and MKIS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MDOS and FAIS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively). CONCLUSION: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia.