Cyclopeptide RA-V from Rubia yunnanensis restores activity of Adagrasib against colorectal cancer by reducing the expression of Nrf2.

Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.

Pre-thrombolysis serum sodium concentration is associated with post-thrombolysis symptomatic intracranial hemorrhage in ischemic stroke patients.

Background and aim: Symptomatic intracranial hemorrhage (sICH) was the most serious complication associated with alteplase intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients. However, the relationship between serum sodium levels and post-thrombolysis symptomatic intracranial hemorrhage has not been investigated. Therefore, the aim of this study was to investigate the relationship between pre-thrombolysis serum sodium levels and sICH after IVT, as well as to explore the optimal pre-thrombolysis serum sodium levels for lowering the risk of sICH following IVT. Methods: From July 1, 2017 to April 30, 2023, out-of-hospital AIS patients who received IVT in the emergency department were enrolled in this study. Serum sodium levels were measured at admission prior to IVT, and National Institutes of Health Stroke Scale scores were continuously assessed during and after thrombolysis. Routine follow-up neuroimaging was performed between 22 to 36 h after IVT. Initially, three logistic regression models and restricted cubic splines (RCS) were established to investigate the relationship between serum sodium levels and post-thrombolysis sICH. Furthermore, to evaluate the predictive value of serum sodium for post-thrombolysis sICH, we compared area under the receiver operating characteristic curve (AUROC) and net reclassification improvement (NRI) before and after incorporating serum sodium into traditional models. Finally, subgroup analysis was conducted to explore interactions between serum sodium levels and other variables. Results: A total of 784 AIS patients who underwent IVT were enrolled, among whom 47 (6.0%) experienced sICH. The median serum sodium concentration for all patients was 139.10 [interquartile ranges (IQR): 137.40-141.00] mmol/L. Patients who developed sICH had lower serum sodium levels than those without sICH [138.20(IQR:136.00-140.20) vs. 139.20(IQR:137.40-141.00), p = 0.031]. Logistic regression analysis (model 3) revealed a 14% reduction in the risk of post-thrombolysis sICH for every 1 mmol/L increase in serum sodium levels after adjusting for confounding variables (p < 0.001). The risk of post-thrombolysis sICH was minimized within the serum sodium range of 139.1-140.9 mmol/L compared to serum sodium concentration below 137.0 mmol/L [odds ratio (OR) = 0.33, 95% confidence interval (CI): 0.13-0.81] in model3. Furthermore, there was a significant trend of decreasing risk for sICH as serum sodium concentrations increased across the four quartiles (P for trend = 0.036). The RCS analysis indicated a statistically significant reduction in the risk of sICH as serum sodium levels increased when the concentration was below 139.1 mmol/L. Incorporating serum sodium into traditional models improved their predictive performance, resulting in higher AUROC and NRI values. Subgroup analysis suggested that early infarct signs (EIS) appeared to moderate the relationship between serum sodium and sICH (p < 0.05). Conclusion: Lower serum sodium levels were identified as independent risk factors for post-thrombolysis sICH. Maintaining pre-thrombolysis serum sodium concentrations above 139.1 mmol/L may help reduce the risk of post-thrombolysis sICH.

Safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia. / åˆå¹¶è¡€å°æ¿å‡å°‘ç—‡çš„éžå¿ƒæºæ€§è½»åž‹è„‘å’ä¸­æ‚£è€ æ—©æœŸæŠ—è¡€å°æ¿æ²»ç–—çš„å®‰å ¨æ€§ç ”ç©¶.

OBJECTIVES: To investigate the safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia. METHODS: Data of acute ischemic stroke patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤3 and a platelet count <100×109/L were obtained from a multicenter register. Those who required anticoagulation or had other contraindications to antiplatelet therapy were excluded. Short-term safety outcomes were in-hospital bleeding events, while the long-term safety outcome was a 1-year all-cause death. The short-term neurological outcomes were evaluated by modified Rankin scale (mRS) score at discharge. RESULTS: A total of 1868 non-cardioembolic mild stroke patients with thrombocytopenia were enrolled. Multivariate regression analyses showed that mono-antiplatelet therapy significantly increased the proportion of mRS score of 0-1 at discharge (OR=1.657, 95%CI: 1.253-2.192, P<0.01) and did not increase the risk of intracranial hemorrhage (OR=2.359, 95%CI: 0.301-18.503, P>0.05), compared with those without antiplatelet therapy. However, dual-antiplatelet therapy did not bring more neurological benefits (OR=0.923, 95%CI: 0.690-1.234, P>0.05), but increased the risk of gastrointestinal bleeding (OR=2.837, 95%CI: 1.311-6.136, P<0.01) compared with those with mono-antiplatelet therapy. For patients with platelet counts ≤75×109/L and >90×109/L, antiplatelet therapy significantly improved neurological functional outcomes (both P<0.05). For those with platelet counts (>75-90)×109/L, antiplatelet therapy resulted in a significant improvement of 1-year survival (P<0.05). For patients even with concurrent coagulation abnormalities, mono-antiplatelet therapy did not increase the risk of various types of bleeding (all P>0.05) but improved neurological functional outcomes (all P<0.01). There was no significant difference in the occurrence of bleeding events, 1-year all-cause mortality risk, and neurological functional outcomes between aspirin and clopidogrel (all P>0.05). CONCLUSIONS: For non-cardioembolic mild stroke patients with thrombocytopenia, antiplatelet therapy remains a reasonable choice. Mono-antiplatelet therapy has the same efficiency as dual-antiplatelet therapy in neurological outcome improvement with lower risk of gastrointestinal bleeding.

A Novel Nomogram to Predict Symptomatic Intracranial Hemorrhage in Ischemic Stroke Patients After Intravenous Thrombolysis.

Objective: This study aimed to create and validate a novel nomogram to predict the risk of symptomatic intracranial hemorrhage (sICH) in patients with acute ischemic stroke (AIS) who underwent intravenous thrombolysis (IVT). Methods: In this retrospective study, 784 patients with AIS who received IVT were enrolled. The patients were randomly divided into two groups: a training set (n=550, 70%) and a testing set (n=234, 30%). Utilizing multivariable logistic regression analysis, relevant factors for the predictive nomogram were selected. The performance of the nomogram was evaluated using various metrics, including the area under the receiver operating characteristic curve (AUC-ROC), the Hosmer-Lemeshow goodness-of-fit test, calibration plots, and decision curve analysis (DCA). Results: Multivariable logistic regression analysis showed that specific factors, including National Institutes of Health Stroke Scale (NIHSS) scores, Early infarct signs (EIS), and serum sodium, were identified as independent predictors of sICH. Subsequently, a nomogram was constructed using these predictors. The AUC-ROC values of the nomogram were 0.864 (95% CI: 0.810-0.919) and 0.831 (95% CI: 0.770-0.891) in the training and the validation sets, respectively. Both the calibration plots and the Hosmer-Lemeshow goodness-of-fit test showed favorable agreement in both the training and the validation sets. Additionally, the DCA indicated the practical clinical utility of the nomogram. Conclusion: The novel nomogram, which included NIHSS, EIS and serum sodium as variables, had the potential for predicting the risk of sICH in patients with AIS after IVT.

A Comparison of Chemotherapy Used with and without Apatinib for Patients with Ovarian Carcinoma Who Progressed after Standard Regimens: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis was conducted to compare the therapeutic efficacy and clinical safety of the combination therapy of apatinib plus chemotherapy with that of chemotherapy alone in patients with refractory or recurrent ovarian carcinoma (OC). METHODS: Relevant randomized controlled trials (RCT) or case-control studies (CCS) were identified by searching Chinese and English databases up to October 31, 2020. The risk of methodological bias tool and Newcastle-Ottawa scale (NOS) were used to assess trial quality. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the therapeutic effects and adverse drug reactions. Subgroup analyses of study type, study sample size, dosage of apatinib, and chemotherapy regimen between treatment group and control group were performed. Publication bias was assessed by funnel plot symmetry, Begg-Mazumdar test, and Egger test. The robustness of our results was presented by removing the trial one by one. RESULTS: Fifteen eligible studies covering 1,020 patients were included in this review and meta-analysis. Among these studies, 8 were RCTs, and 7 were CCSs. Compared with chemotherapy alone, apatinib plus chemotherapy significantly increased objective response rate (OR = 3.55; 95% CI 2.31 to 5.47), disease control rate (OR = 3.04; 95% CI 2.12 to 4.36), and overall survival (OR = 5.03; 95% CI 3.16 to 6.90). CONCLUSIONS: The combination treatment of apatinib plus chemotherapy provides better clinical benefits for OC patients when compared to chemotherapy alone and should be recommended for suitable patients with OC after the failure of standard regimens. However, further investigation into future large-scale prospective randomized research is still needed.

Pristimerin synergizes with gemcitabine through abrogating Chk1/53BP1-mediated DNA repair in pancreatic cancer cells.

It has been shown that checkpoint kinase inhibitors can enhance chemosensitivity to gemcitabine by disrupting the replication stress response (RSR). In the present study, we aimed to describe the chemical synthetic lethal effects of the combination of gemcitabine and quinone-methide triterpenoid pristimerin in pancreatic cancer (PC) cells. The drug interaction assay indicated effective synergy between gemcitabine and pristimerin at sub-IC50 concentrations. Interestingly, pristimerin induced lysosomal degradation of checkpoint kinase 1 (Chk1), decreased the percentage of cells at the G1/S boundary and triggered significant double-stranded DNA breaks compared to gemcitabine treatment alone. Moreover, gemcitabine activated the phosphorylation of Chk1 and induced the formation of poly (ADP-ribose) polymers (PARs) as well as the accumulation of 53BP1, which was either partially or completely impaired by pristimerin. Meanwhile, pristimerin augmented the expression of γH2AX upon gemcitabine treatment. Finally, the combination of gemcitabine with pristimerin increased the apoptotic potential of PC cells. These results show that pristimerin acts as a naturally occurring inhibitor of RSR, and a novel therapeutic strategy of combining pristimerin and gemcitabine deserves further detailed investigation in PC models in vivo.

Induction of APOBEC3C Facilitates the Genotoxic Stress-Mediated Cytotoxicity of Artesunate.

The artemisinin class of anticancer compounds is well known for oxidative DNA-damage-mediated growth arrest, followed by cell death. However, the nature of this genotoxic stress for cancer therapeutics remains elusive. Here we show that artesunate (Art), a water-soluble artemisinin analog, triggers inducible anticancer responses directly implicated in the DNA-damage-intended therapy. We observed that the level of the antiviral enzyme APOBEC3C (apolipoprotein-B mRNA-editing catalytic polypeptide-like 3C (A3C)) preferentially increased upon the treatment with Art against tumor xenografts of p53-deficient H1299 cells. Using gain-of-function experiments, A3C could improve the therapeutic efficacy of Art, as determined by cell proliferation and colony formation assays. Furthermore, elevated A3C provoked a minor accumulation of γH2AX foci and the phosphorylation of RPA32 and Chk1, which strongly sensitized H1299 cells to Art. The employment of A3C also caused an increase in the synergistic interaction between Art and Chk1 inhibition. Besides, A3C overexpression delayed the cell cycle at the S phase, accompanied by attenuated G2/M arrest in the presence of Art. The enzymatic inactivation of A3C by the mutation of zinc-coordinating residues (C97S and C100S) indicated that A3C sensitized Art in a deaminase-dependent manner. Furthermore, we showed that using small interfering RNA against A3C can induce the chemoresistance of Art. These studies combine to suggest that upregulated A3C is involved in the Art-induced DNA damage response as a consequent event to improve the overall cytotoxic responses of Art.

Accurate Indoor Localization Based on CSI and Visibility Graph.

Passive indoor localization techniques can have many important applications. They are nonintrusive and do not require users carrying measuring devices. Therefore, indoor localization techniques are widely used in many critical areas, such as security, logistics, healthcare, etc. However, because of the unpredictable indoor environment dynamics, the existing nonintrusive indoor localization techniques can be quite inaccurate, which greatly limits their real-world applications. To address those problems, in this work, we develop a channel state information (CSI) based indoor localization technique. Unlike the existing methods, we employ both the intra-subcarrier statistics features and the inter-subcarrier network features. Specifically, we make the following contributions: (1) we design a novel passive indoor localization algorithm which combines the statistics and network features; (2) we modify the visibility graph (VG) technique to build complex networks for the indoor localization applications; and (3) we demonstrate the effectiveness of our technique using real-world deployments. The experimental results show that our technique can achieve about 96% accuracy on average and is more than 9% better than the state-of-the-art techniques.