Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma.

Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC50 = 1.30 µM) and inhibited the proliferation of HCCLM3 cells (IC50 = 3.1 µM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.

The Efficacy of Dietary Intake, Supplementation, and Blood Concentrations of Carotenoids in Cancer Prevention: Insights from an Umbrella Meta-Analysis.

Previous meta-analyses of multiple studies have suggested that dietary intake and blood concentrations of carotenoids, as well as dietary supplement of certain carotenoids, play a role in reducing the risk of cancer. However, the conclusions of these studies have been subject to controversy. We conducted an umbrella review of meta-analyses to comprehensively analyze and evaluate the evidence pertaining the association between carotenoids and cancer outcomes. We searched PubMed, Web of Science, Embase, and Cochrane Library databases of meta-analyses and systematic reviews up to June 2023. Our selection criteria encompassed meta-analyses of cohort and case-control studies, as well as randomized controlled clinical trials, which investigated the associations between carotenoids and cancer risk. We also determined the levels of evidence for these associations with AMSTAR 2 criteria. We included 51 eligible articles, including 198 meta-analyses for qualitative synthesis in the umbrella review. Despite the presence of moderate to high heterogeneity among the studies, dietary intake, supplementation, and blood concentrations of carotenoids were inversely associated with the risk of total cancer, and certain specific cancers of lung, digestive system, prostate, breast, head and neck, and others. Subgroup analysis also showed that individual carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, lutein, zeaxanthin, and lycopene) offer certain protection against specific types of cancers. However, high doses of carotenoid supplements, especially ß-carotene, significantly increased the risk of total cancer, lung cancer, and bladder cancer. Our umbrella meta-analysis supported that high intake of dietary carotenoids as a whole food approach could be more beneficial in reducing cancer risk. Concurrently, the findings suggest that the efficacy of single-carotenoid supplementation in cancer prevention remains a subject of controversy.

Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level.

Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.

Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities.

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.

The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC50 = 0.79 ± 0.03 µM) and antitumor activity in vitro (IC50 = 0.038 ± 0.003 µM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response.

Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as a selective activator of HsClpP. After optimization, NCA029 emerged as the most potent compound, with an EC50 of 0.2 µM against HsClpP. Molecular dynamics revealed that the affinity of NCA029 for the YYW aromatic network is crucial for its selectivity toward HsClpP. Furthermore, NCA029 displayed favorable pharmacokinetics and safety profiles and significantly inhibited tumor growth in HCT116 xenografts, resulting in 83.6% tumor inhibition. Mechanistically, NCA029 targeted HsClpP, inducing mitochondrial dysfunction and activating the ATF3-dependent integrated stress response, ultimately causing cell death in colorectal adenocarcinoma. These findings highlight NCA029 as an effective HsClpP activator with potential for colon cancer therapy.

Nickel-Catalyzed 8-Aminoquinoline Directed Reductive Dialkylcyclization/Homodialkylation of Unactivated Alkenes.

Chemo and regioselective dialkylation of alkene is an efficient protocol for constructing useful chemicals, but challenges remain in the unrestricted application of alkylating reagents. Alkyl bromide belongs to the easy-to-access and operable alkyl electrophiles that can be used in reductive coupling with alkenes. Here, we reported convenient strategies for dialkylcyclization and homodialkylation of unactivated ß,γ- and γ,δ-unsaturated alkenyl amides with 1,3-dibromoalkanes or primary alkyl bromides under nickel-catalyzed reductive conditions that exhibited high regioselectivity and functional-group tolerance.

Beneficial Effects of Dietary Flaxseed Oil through Inflammation Pathways and Gut Microbiota in Streptozotocin-Induced Diabetic Mice.

Flaxseed oil (FO) has displayed potential anti-diabetes properties by providing a high content of α-linolenic acid. However, the effects and mechanisms of FO on type 1 diabetes are still unclear. The present study aims to explore the effects of different doses of FO feeding on hepatic inflammation and gut microbiota in streptozotocin-induced diabetic mice. Forty-eight six-week-old C57BL/6J male mice were divided into a control group (CON), a diabetic group (MOD), a diabetes with 7.0% w/w FO feeding group (FO-L), and a diabetes with 10.5% w/w FO feeding group (FO-H) for six weeks. The 7.0% w/w and 10.5% w/w FO feeding groups exhibited potential recovery of the number and size of pancreas tissues. The fasting blood glucose level was significantly decreased only after 4 weeks of feeding with 10.5% w/w FO in diabetic mice. The 10.5% w/w FO feeding group significantly decreased the postprandial blood glucose level of mice in the OGTT test. Hepatic glycogen levels were dramatically upregulated in the mice fed with both 7.0% w/w and 10.5% w/w FO. FO feeding significantly attenuated hepatic LPS, TNF-α, and IL-1ß levels. In addition, we observed that 7.0% w/w and 10.5% w/w FO feedings notably downregulated hepatic gene and protein expressions of TLR4, MyD88, and P65. Furthermore, only 10.5% FO regulated fecal microbiota by increasing the relative abundance of the Bacteroidetes phylum, Lactococcus family, and Muribaculaceae and Streptococcaceae family and genus in streptozotocin-induced diabetic mice. Therefore, we conclude that FO feeding plays a role in anti-inflammation via the regulation of hepatic LPS/TLR4/MyD88 pathways and gut microbiota. In addition, different doses of FO supplementation may exhibit varying mechanisms in streptozotocin-induced mice.

Multi-study evaluation of neuroimaging-based prediction of medication class in mood disorders.

Clinicians often face a dilemma in diagnosing bipolar disorder patients with complex symptoms who spend more time in a depressive state than a manic state. The current gold standard for such diagnosis, the Diagnostic and Statistical Manual (DSM), is not objectively grounded in pathophysiology. In such complex cases, relying solely on the DSM may result in misdiagnosis as major depressive disorder (MDD). A biologically-based classification algorithm that can accurately predict treatment response may help patients suffering from mood disorders. Here we used an algorithm to do so using neuroimaging data. We used the neuromark framework to learn a kernel function for support vector machine (SVM) on multiple feature subspaces. The neuromark framework achieves up to 95.45% accuracy, 0.90 sensitivity, and 0.92 specificity in predicting antidepressant (AD) vs. mood stabilizer (MS) response in patients. We incorporated two additional datasets to evaluate the generalizability of our approach. The trained algorithm achieved up to 89% accuracy, 0.88 sensitivity, and 0.89 specificity in predicting the DSM-based diagnosis on these datasets. We also translated the model to distinguish responders to treatment from nonresponders with up to 70% accuracy. This approach reveals multiple salient biomarkers of medication-class of response within mood disorders.

PPyNT/NR/NBR Composites with Excellent Microwave Absorbing Performance in X-Band.

To meet the comprehensive demand for flexible microwave absorbing (MA) materials, a novel MA rubber containing homemade Polypyrrole nanotube (PPyNT) is produced based on the natural rubber (NR) and acrylonitrile-butadiene rubber (NBR) blends. To achieve the optimal MA performance in the X band, the PPyNT content and NR/NBR blend ratio are adjusted in detail. The 6 phr PPyNT filled NR/NBR (90/10) composite has the superior MA performance with the minimum reflection loss value of -56.67 dB and the corresponding effective bandwidth of 3.7 GHz at a thickness of 2.9 mm, which has the merits in virtue of achieving strong absorption and wide effective absorption band with low filler content and thickness compared to most reported microwave absorbing rubber materials over the same frequency. This work provides new insight into the development of flexible microwave-absorbing materials.

[IL-6 Regulates the Chemosensitivity of Drug-Resistant Multiple Myeloma Cell Lines to Bortezomib through STAT3/Notch Signaling Pathway].

OBJECTIVE: To investigate the effect of interleukin-6 (IL-6) on the chemosensitivity of drug-resistant multiple myeloma (MM) cell lines to bortezomib (BTZ) and its mechanism. METHODS: Peripheral blood samples were collected from patients with BTZ-resistant MM before and after treatment. Human MM cell lines KM3 and KM3/BTZ were cultured in vitro. ELISA was used to detect the content of IL-6 in peripheral blood of MM patients, KM3 and KM3/BTZ cells. CCK-8 assay was used to detect the drug sensitivity of KM3 and KM3 / BTZ cells to BTZ. KM3 / BTZ cells were divided into KM3/BTZ control group (normal culture for 48 h), IL-6 neutralizing antibody Anti-IL-6 group (500 ng/ml Anti-IL-6 treated for 48 h), BTZ group (300 ng/ml BTZ treated for 48 h), BTZ + Anti-IL-6 group (300 ng/ml BTZ and 500 ng/ml Anti-IL-6 treated for 48 h). The proliferation activity of KM3 / BTZ cells was detected by CCK-8 assay. The cell cycle distribution of KM3/BTZ cells was detected by flow cytometry. The apoptosis of KM3/BTZ cells was detected by Annexin V-FITC/PI double staining. The mRNA expression levels of IL-6, Notch1, signal transducer and activator of transcription 3 (STAT3) in KM3/BTZ cells were detected by real-time fluorescent quantitative PCR (qRT-PCR), and the protein expression levels of IL-6, Notch1, STAT3 in KM3/BTZ cells were detected by Western blot. RESULTS: The level of IL-6 in peripheral blood of patients with BTZ-resistant MM after treatment was significantly higher than that before treatment (P<0.05). The level of IL-6 in KM3/BTZ cells was significantly higher than that in KM3 cells (P<0.05). The sensitivity of KM3/BTZ cells to BTZ was significantly lower than that of KM3 cells (P<0.05), and the resistance index (RI) was 19.62. Anti-IL-6 and BTZ could inhibit the proliferation of KM3 / BTZ cells, block cell cycle, and induce apoptosis (P<0.05). Compared with single drug treatment, the combined effect of Anti-IL-6 and BTZ was more obvious on KM3/BTZ cells (P<0.05), and significantly down regulated the mRNA and protein expression of IL-6, Notch1 and STAT3 in KM3/BTZ cells (P<0.05). CONCLUSION: Antagonizing IL-6 can increase the chemosensitivity of MM cells to BTZ, and IL-6 may reduce the sensitivity of MM cells to BTZ through STAT3/Notch signaling pathway.

Cognition, Aryl Hydrocarbon Receptor Repressor Methylation, and Abstinence Duration-Associated Multimodal Brain Networks in Smoking and Long-Term Smoking Cessation.

Cigarette smoking and smoking cessation are associated with changes in cognition and DNA methylation; however, the neurobiological correlates of these effects have not been fully elucidated, especially in long-term cessation. Cognitive performance, percent methylation of the aryl hydrocarbon receptor repressor (AHRR) gene, and abstinence duration were used as references to supervise a multimodal fusion analysis of functional, structural, and diffusion magnetic resonance imaging (MRI) data, in order to identify associated brain networks in smokers and ex-smokers. Correlations among these networks and with smoking-related measures were performed. Cognition-, methylation-, and abstinence duration-associated networks discriminated between smokers and ex-smokers and correlated with differences in fractional amplitude of low frequency fluctuations (fALFF) values, gray matter volume (GMV), and fractional anisotropy (FA) values. Long-term smoking cessation was associated with more accurate cognitive performance, as well as lower fALFF and more GMV in the hippocampus complex. The methylation- and abstinence duration-associated networks positively correlated with smoking-related measures of abstinence duration and percent methylation, respectively, suggesting they are complementary measures. This analysis revealed structural and functional co-alterations linked to smoking abstinence and cognitive performance in brain regions including the insula, frontal gyri, and lingual gyri. Furthermore, AHRR methylation, a promising epigenetic biomarker of smoking recency, may provide an important complement to self-reported abstinence duration.

Long-Term Exposure to Fine Particulate Matter and the Risk of Chronic Liver Diseases: A Meta-Analysis of Observational Studies.

Although fine particulate matter (PM2.5) is a known carcinogen, evidence of the association between PM2.5 and chronic liver disease is controversial. In the present meta-analysis study, we reviewed epidemiological studies to strengthen evidence for the association between PM2.5 and chronic liver disease. We searched three online databases from 1990 up to 2022. The random-effect model was applied for detection of overall risk estimates. Sixteen eligible studies, including one cross-sectional study, one retrospective cohort study, and 14 prospective cohort studies, fulfilled inclusion criteria with more than 330 thousand participants from 13 countries. Overall risk estimates of chronic liver disease for 10 µg/m3 increase in PM2.5 was 1.27 (95% confidence interval (CI): 1.19−1.35, p < 0.001). We further analyzed the relationship between PM2.5 exposure and different chronic liver diseases. The results showed that increments in PM2.5 exposure significantly increased the risk of liver cancer, liver cirrhosis, and fatty liver disease (hazard ratio (HR) = 1.23, 95% CI: 1.14−1.33; HR = 1.17, 95% CI: 1.06−1.29; HR = 1.51, 95% CI: 1.09−2.08, respectively). Our meta-analysis indicated long-term exposure to PM2.5 was associated with increased risk of chronic liver disease. Moreover, future researches should be focused on investigating subtypes of chronic liver diseases and specific components of PM2.5.

IMP075 targeting ClpP for colon cancer therapy in vivo and in vitro.

ONC201 is a well-known caseinolytic protease (ClpP)activator with established benefits against multiple tumors, including colorectal cancer (CRC). In this study, we investigated the anticancer effects and associated mechanisms of the ClpP agonist IMP075, derived from ONC201. Acute toxicity and CCK-8 assayswere employed to determine the safety of IMP075. The effectiveness of IMP075 was investigated in HCT116 cells and a mouse xenograft tumor model. Additionally, the properties of IMP075 were evaluated by pharmacokinetic,CYP inhibition, and hERG inhibition assays. Finally, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), cellular thermal shift assay (CETSA), molecular dynamics simulations, point mutations, and shRNA experiments were employed to elucidate the potential mechanism of IMP075. Compared with ONC201, IMP075 exhibited similar toxicity and improved antitumor effects in vitro and in vivo. Interestingly, the affinity and agonistic effects of IMP075 on ClpP were superior to ONC201, which allowed IMP075 to disrupt respiratory chain integrity at lower doses in HCT116 cells, leading to mitochondrial dysfunction. Furthermore, molecular dynamics simulations demonstrate that IMP075 forms two pairs of hydrogen bonds with ClpP, maintaining ClpP in an agonistic state. Importantly, the antiproliferative activity of IMP075 significantly decreased following ClpP knockdown. Our findings substantiate that IMP075 exerts excellent antitumor effects against CRC by activating ClpP-mediated impairment of mitochondrial function. Due to its superior properties, IMP075 appears to be have huge prospects for application.

Discovery of a Novel Series of Imipridone Compounds as Homo sapiens Caseinolytic Protease P Agonists with Potent Antitumor Activities In Vitro and In Vivo.

Homo sapiens caseinolytic protease P (HsClpP) plays an important role in maintaining mitochondrial proteostasis. Activating HsClpP has been proved to be a potential strategy for cancer therapy. In this paper, a novel class of HsClpP agonists is designed and synthesized using a position shift strategy based on the imipridone ONC201. Among these newly synthesized imipridone derivatives, compound 16z exhibits remarkably enhanced antitumor activity (IC50 = 0.04 µM against HCT116 cells). It can improve HsClpP thermal stability and induce mitochondrial dysfunction, reactive oxygen species production, cell cycle arrest in the G0/G1 phase, and apoptosis of HCT116 cells. Moreover, compound 16z possesses excellent pharmacokinetic profiles and significantly inhibits tumor growth in HCT116 cell-inoculated xenograft nude mouse models. Our study demonstrates that 16z has potential to be an antitumor drug candidate for further development and provides insights for the design of the next generation of HsClpP agonists for cancer treatment.

Dysregulated LINC00961 Contributes to the Vitality and Migration of NSCLC Via miR-19a-3p/miR-19b-3p/miR-125b-5p.

Accumulating evidence implies that long noncoding RNAs participate in non-small cell lung cancer (NSCLC) tumorigenesis. Our current study synthetically analyzed RNA sequencing data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We identified LINC00961 significantly downregulated in NSCLC tissues. We explored the LINC00961 expression in NSCLC tumor tissues and cell lines with reverse transcription-quantitative polymerase chain reaction analysis. Lentivirus-mediated infection upregulated the expression of LINC00961 in A549 cells. The proliferation and migration capability were also measured in A549 cells. In addition, we performed luciferase reporter gene assay to investigate whether LINC00961 directly interacts with miR-19a-3p/miR-19b-3p/miR-125b-5p. A nude mice model was used to detect the potential biological process of LINC00961 on tumor growth in vivo. The results showed that LINC00961 was significantly down-egulated in NSCLC tissues and cell lines. LV-LINC00961 effectively increased the expression of LINC00961 and decreased the expression of miR-19a-3p/miR-19b-3p/miR-125b-5p. LINC00961 upregulation remarkably inhibited cell proliferation, migration, and invasion while promoting cell apoptosis in A549 cells. Luciferase reporter gene assay revealed that LINC00961 could directly sponge miR-19a-3p/miR-19b-3p/miR-125b-5p. Moreover, overexpressed miR-19a-3p/miR-19b-3p/miR-125b-5p reversed the effect of LINC00961 on cell function of A549 cells. Western blot assays revealed that LINC00961 could partially act as a tumor suppressor via affecting PI3K-AKT/MAPK/mTOR signaling pathway. In addition, overexpressed LINC00961-inhibited tumor growth was demonstrated in vivo. Overexpression of LINC00961 inhibited cell viability, invasion, and induced apoptosis in NSCLC, potentially via suppressing the expression of miR-19a-3p/miR-19b-3p/miR-125b-5p by targeting PI3K-AKT/MAPK/mTOR signaling pathways, which might provide the potential biomarker for NSCLC diagnosis and therapies.

Willis Covered Stent for Treating Intracranial Pseudoaneurysms of the Internal Carotid Artery: A Multi-Institutional Study.

OBJECTIVE: This work aimed to retrospectively analyze Willis covered stent (WCS)'s therapeutic efficacy in intracranial pseudoaneurysms (PSAs) of the internal carotid artery (ICA). METHODS: Between June 2018 and July 2021, 56 individuals with intracranial PSAs of the ICA treated with WCS in three centers were included to analyze information regarding medical records, operative parameters, imaging findings and follow-up data. RESULTS: All WCSs were successfully targeted to the ICA lesions. Total exclusion of PSA was found in 53 cases (94.6%) right upon surgery, and mild endoleak into the aneurysm remained in 3 cases (5.4%). Intraoperative thrombosis occurred in 1 case (1.8%), and tirofiban was utilized for recanalization. Follow-up by angiography showed total aneurysm occlusion in the total number of individuals, including in the 3 above cases with residual endoleak. In-stent stenosis occurred in 7 (12.5%) patients. No stent-related ischemic event was encountered. Predictive factors of late in-stent stenosis following WCS implantation in this patient group were irregular post-operative antiplatelet treatment (p = 0.015) and C4-C5 segment of the ICA (p = 0.043). CONCLUSION: WCSs are effective in treating intracranial PSAs of the ICA.

Basiliximab for steroid-refractory acute graft-versus-host disease: A real-world analysis.

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD.

Association between polymorphisms rs2228001 and rs2228000 in XPC and genetic susceptibility to preeclampsia: a case control study.

BACKGROUND: Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein that plays an important role in nucleotide excision repair and can reduce oxidative stress, which may be involved in the development of preeclampsia (PE). Therefore, the aim of this study was to explore whether XPC polymorphisms were relevant to the genetic susceptibility to PE in Chinese Han women. METHOD: A total of 1276 healthy pregnant women were included as the control group and 958 pregnant women with PE as the case group. DNA was extracted from peripheral blood samples to perform genotyping of loci rs2228001 and rs2228000 in XPC through real-time quantitative polymerase chain reaction (PCR). The relationship between XPC and susceptibility to PE was evaluated by comparing the genotypic and allelic frequencies between the two groups of pregnant women. RESULTS: Polymorphism of rs2228000 may be associated with PE risk and allele T may play a protective role (genotype, χ2 = 38.961, P < 0.001 and allele χ2 = 21.746 P < 0.001, odds ratio (OR) = 0.885, 95% confidence interval (CI) = 0.840-0.932). No significant difference was found between the two groups in rs2228001,(genotype χ2 = 3.148, P = 0.207 and allele χ2 = 0.59, P = 0.442, OR = 1.017, 95% CI = 0.974-1.062). When the frequencies of genotypes and alleles for early- and late-onset PE, mild PE and severe PE were compared with those of controls, the results were consistent with the large clinical sample. CONCLUSION: Our data suggest that the genetic variant rs2228000 in XPC may be associated with PE risk in Chinese Han women, and that pregnant women with the TT genotype have a reduced risk of PE. Further investigations are needed to confirm these findings in other regions or larger prospective populations.