A Correlation Evaluation Between the Peripheral Blood Index and the Prognosis of Advanced Esophageal Squamous Cell Carcinoma Patients Treated with Camrelizumab.

Purpose: This study aimed to investigate the relationship between peripheral blood indices and the efficacy and prognosis of advanced esophageal squamous cell carcinoma (ESCC) patients treated with camrelizumab. Patients and Methods: We retrospectively analyzed 64 patients who received camrelizumab for advanced ESCC at the Second People's Hospital of Lianyungang City between July 2020 and June 2022. The study included examination of the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic inflammation index (SII), the lymph-to-monocytes ratio (LMR), the absolute lymphocyte count (ALC), and lactate dehydrogenase (LDH). We used multivariate logistic regression analysis to explore the link existing between peripheral blood and the efficacy of treatment. Determination of potential prognostic factors for Progression-free survival (PFS) and Overall survival (OS) using Cox regression analysis. The nomogram model was developed based on the results of the Cox multivariate analysis. Patients were divided into three groups according to the reduction in LDH and LDL levels before treatment, and the Kaplan-Meier survival curves for the three groups were compared and ROC curves for LDH combined with PLR were plotted. Results: Lower LDH (OR=6.237, 95% CI: 1.625-23.944) were independently associated with disease control rates(DCR). LDH was independently correlated with PFS (HR: 0.227 95% CI: 0.099-0.517). LDH and PLR were independently linked to OS. The C index of the nomogram model is 0.819, indicating good predictive performance. Kaplan-Meier Survival Curve suggested better OS in patients with reduced pretreatment LDH and PLR. The area under the ROC curve showed that the LDH index combined with the PLR index predicts patient survival better than the index alone. Conclusion: LDH combined with PLR predicted prognosis in patients with ESCC treated with camrelizumab.

Cooperative Finitely Excited Learning for Dynamical Games.

In this article, we propose a way to enhance the learning framework for zero-sum games with dynamics evolving in continuous time. In contrast to the conventional centralized actor-critic learning, a novel cooperative finitely excited learning approach is developed to combine the online recorded data with instantaneous data for efficiency. By using an experience replay technique for each agent and distributed interaction amongst agents, we are able to replace the classical persistent excitation condition with an easy-to-check cooperative excitation condition. This approach also guarantees the consensus of the distributed actor-critic learning on the solution to the Hamilton-Jacobi-Isaacs (HJI) equation. It is shown that both the closed-loop stability of the equilibrium point and convergence to the Nash equilibrium can be guaranteed. Simulation results demonstrate the efficacy of this approach compared to previous methods.

The catalytic mechanism of direction-dependent interactions for 2,3-dihydroxybenzoate decarboxylase.

Benzoic acid decarboxylases offer an elegant alternative to CO2 fixation by reverse reaction-carboxylation, which is named the bio-Kolbe-Schmitt reaction, but they are unfavorable to carboxylation. Enhancing the carboxylation efficiency of reversible benzoic acid decarboxylases is restricted by the unexplained carboxylation mechanisms. The direction of reversible enzyme catalytic reactions depends on whether catalytic residues at the active center of the enzyme are protonated, which is subjected by the pH. Therefore, the forward and reverse reactions could be separated at different pH values. Reversible 2,3-dihydroxybenzoate acid decarboxylase undergoes decarboxylation at pH 5.0 and carboxylation at pH 8.6. However, it is unknown whether the interaction of enzymes with substrates and products in the forward and reverse reactions can be exploited to improve the catalytic activity of reversible enzymes in the unfavorable direction. Here, we identify a V-shaped tunnel of 2,3-dihydroxybenzoic acid decarboxylase from Aspergillus oryzae (2,3-DHBD_Ao) through which the substrate travels in the enzyme, and demonstrate that the side chain conformation of a tyrosine residue controls the entry and exit of substrate/product during reversible reactions. Together with the kinetic studies of the mutants, it is clarified that interactions between substrate/product traveling through the enzyme tunnel in 2,3-DHBD_Ao are direction-dependent. These results enrich the understanding of the interactions of substrates/products with macromolecular reversible enzymes in different reaction directions, thereby demonstrating a possible path for engineering decarboxylases with higher carboxylation efficiency. KEY POINTS: • The residue Trp23 of 2,3-DHBD_Ao served as a switch to control the entry and exit of catechol • A V-shaped tunnel of 2,3-DHBD_Ao for decarboxylation and carboxylation reactions was identified • The results provide a promising strategy for engineering decarboxylases with direction-dependent residues inside the substrate/product traveling tunnel of the enzyme.

Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma.

Background: The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin's lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling. Methods: Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107. Results: We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells. Conclusions: Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials. Funding: Yang's laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).

Dietary γ-mangostin triggers immunogenic cell death and activates cGAS signaling in acute myeloid leukemia.

Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary γ-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34+ leukemic progenitor cells from leukemia patients. Strikingly, γ-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, γ-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8+ T cell is activated and recruited by γ-mangostin-induced chemokines in the microenvironment. Our study identifies γ-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary γ-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.

Uncover rock-climbing fish's secret of balancing tight adhesion and fast sliding for bioinspired robots.

The underlying principle of the unique dynamic adaptive adhesion capability of a rock-climbing fish (Beaufortia kweichowensis) that can resist a pull-off force of 1000 times its weight while achieving simultaneous fast sliding (7.83 body lengths per second (BL/S)) remains a mystery in the literature. This adhesion-sliding ability has long been sought for underwater robots. However, strong surface adhesion and fast sliding appear to contradict each other due to the need for high surface contact stress. The skillfully balanced mechanism of the tight surface adhesion and fast sliding of the rock-climbing fish is disclosed in this work. The Stefan force (0.1 mN/mm2) generated by micro-setae on pectoral fins and ventral fins leads to a 70 N/m2 adhesion force by conforming the overall body of the fish to a surface to form a sealing chamber. The pull-off force is neutralized simultaneously due to the negative pressure caused by the volumetric change of the chamber. The rock-climbing fish's micro-setae hydrodynamic interaction and sealing suction cup work cohesively to contribute to low friction and high pull-off-force resistance and can therefore slide rapidly while clinging to the surface. Inspired by this unique mechanism, an underwater robot is developed with incorporated structures that mimic the functionality of the rock-climbing fish via a micro-setae array attached to a soft self-adaptive chamber, a setup which demonstrates superiority over conventional structures in terms of balancing tight underwater adhesion and fast sliding.

Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist.

Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.

Investigation of the effect of different distilled water, rainwater and seawater mass ratios on coal spontaneous combustion characteristics.

When water comes into contact with coal, the risk of coal spontaneous combustion should be reassessed. In order to analyze the effect of distilled water, rainwater and seawater on the coal self-heating, thermogravimetric analysis (TGA) was applied to investigate the differences between the macroscopic oxidation properties of raw coal and water-immersed coal. The risk of coal spontaneous combustion increases after water immersion, but different types of water have different degrees of influence on the spontaneous combustion of coal. The microscopic pore structure and elemental changes on the surface of coal samples before and after water immersion were studied by Scanning Electron Microscope (SEM), low-pressure nitrogen gas adsorption (LP-N2GA) and Energy Dispersive Spectroscopy (EDS) experiments. Fourier infrared spectroscopy (FTIR) was used to investigate the change of active groups. The results show that the pore structure of coal samples immersed in water is much more developed than that of raw coal. In the low-temperature oxidation stage, moisture evaporation consumes much oxidation heat and inhibits the coal self-heating. After the stage, it promotes the coal spontaneous combustion. The content of the hydroxyl group increases, and the content of carbonyl and carboxyl decreases. The alkali metal elements can act as catalysts and active carriers of oxygen, enhancing the oxidation activity of coal. The results are helpful to understand the mechanism of different distilled water, rainwater and seawater mass ratios on coal spontaneous combustion and avoid potential self-heating after immersion.

FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway.

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2- breast cancer. However, their therapeutic effectiveness in triple-negative breast cancer (TNBC) remains controversial. Here, we observed that the expression level of fibrous sheath interacting protein 1 (FSIP1) could predict the treatment response of TNBC to CDK4/6 inhibitors. High FSIP1 expression level was related to a poor prognosis in TNBC, which was associated with the ability of FSIP1 to promote tumor cell proliferation. FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC. FSIP1 knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway. FSIP1 could form a complex with Nanog, protecting it from ubiquitination and degradation, which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors. Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.

KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes.

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.

Covalent Organic Framework Nanosheets for Fluorescence Quantification of Peptide.

Rapid and sensitive quantification of peptides plays an important role in clinical diagnosis. Fluorescence assay is one of the most promising peptide detection tools, but it relies on intrinsic fluorescence or additional derivatization, resulting in poor versatility. Covalent organic frameworks (COFs) have shown a good application prospect in the field of fluorescence detection, but their application scope is limited to heavy metal ions and some small polar organic molecules. Herein, we report the application of COFs nanosheet for fluorescence detection of peptides. Fluorescent sp2 acrylonitrile-linked COFs nanosheets (TTAN-CON) were prepared by water-assisted ultrasonic exfoliation which performed with excellent fluorescence properties with Stokes shifts of 146 nm and fluorescence quantum yield of up to 24.45%. Compared to the bulk fluorescent COFs, exfoliated CONs films performed with better stability of fluorescence signal in solution. We found the fluorescence of TTAN-CON can be effectively quenched by hydrophobic peptides at a very rapid rate (less than 5 min per sample). TTAN-CON presented good sensitivity and selectivity for hydrophobic peptides detection via the static and dynamic joint quenching mechanism. TTAN-CON was further used to detect NLLGLIEAK and ProGRP31-98, two target peptide fragments of lung cancer biomarker ProGRP. The fluorescence intensities of TTAN-CON were negative linearly correlated with the amounts of hydrophobic NLLGLIEAK over the range of 5-1000 ng/mL with the correlation coefficients over 0.99, and the limit of detection was 1.67 ng/mL, displaying higher sensitivity and convenience than traditional optical methods. What's more, the quantification of ProGRP31-98 was achieved by the quantification of hydrophobic peptides in its enzyme hydrolysis products. We anticipate COFs nanosheets to be a universal fluorescence detection work-box for peptides biomarkers with clinical significance.

KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer.

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

The effects of environmental information disclosure on stock price synchronicity in China.

Environmental information disclosure has attracted the attention of the capital market because it can convey corporate characteristic information. But there needs to be direct evidence that environmental information disclosure can improve the market's overall efficiency. This study examines whether corporate environmental information disclosure can improve the information efficiency of the capital market. This study takes Chinese listed companies from 2008 to 2021 as samples, constructs a panel fixed effect model, and adopts multiple linear, instrumental variable method and Heckman sample selection model. We find that the disclosure of environmental information in the Chinese market reduces the information efficiency of the capital market represented by the synchronicity of stock prices. The reason is that the information after greenwashing by enterprises needs to be of better quality and more obscure, which disrupts market information. Environmental information disclosure by enterprises prone to greenwashing significantly affects stock price synchronicity, such as low institutional ownership, non-state-owned, growth, and manufacturing firms. Finally, this paper discusses the impact mechanism and confirms that stock liquidity and analyst coverage are the two paths through which environmental information disclosure impacts stock price synchronicity. This study is significant in encouraging the government to strengthen market supervision, promoting enterprises to disclose high-quality environmental information, and improving the pricing efficiency of the capital market.

An herbal drug combination identified by knowledge graph alleviates the clinical symptoms of plasma cell mastitis patients: A nonrandomized controlled trial.

Background: Plasma cell mastitis (PCM) is a nonbacterial breast inflammation with severe and intense clinical manifestation, yet treatment methods for PCM are still rather limited. Although the mechanism of PCM remains unclear, mounting evidence suggests that the dysregulation of immune system is closely associated with the pathogenesis of PCM. Drug combinations or combination therapy could exert improved efficacy and reduced toxicity by hitting multiple discrete cellular targets. Methods: We have developed a knowledge graph architecture toward immunotherapy and systematic immunity that consists of herbal drug-target interactions with a novel scoring system to select drug combinations based on target-hitting rates and phenotype relativeness. To this end, we employed this knowledge graph to identify an herbal drug combination for PCM and we subsequently evaluated the efficacy of the herbal drug combination in clinical trial. Results: Our clinical data suggests that the herbal drug combination could significantly reduce the serum level of various inflammatory cytokines, downregulate serum IgA and IgG level, reduce the recurrence rate, and reverse the clinical symptoms of PCM patients with improvements in general health status. Conclusions: In summary, we reported that an herbal drug combination identified by knowledge graph can alleviate the clinical symptoms of PCM patients. We demonstrated that the herbal drug combination holds great promise as an effective remedy for PCM, acting through the regulation of immunoinflammatory pathways and improvement of systematic immune level. In particular, the herbal drug combination could significantly reduce the recurrence rate of PCM, a major obstacle to PCM treatment. Our data suggests that the herbal drug combination is expected to feature prominently in future PCM treatment. Funding: C. Liu's lab was supported by grants from the Public Health Science and Technology Project of Shenyang (grant: 22-321-32-18); Y. Yang's laboratory was supported by the National Natural Science Foundation of China (grant: 81874301), the Fundamental Research Funds for Central University (grant: DUT22YG122), and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (2021JH1/10400050). Clinical trial number: NCT05530226.

Impacts of different biomass burning emission inventories: Simulations of atmospheric CO2 concentrations based on GEOS-Chem.

Biomass burning has substantial spatiotemporal variabilities. It contributes significantly to the dynamics of global CO2 distributions and variances. Quantifying the impacts of biomass burning emissions on atmospheric CO2 concentrations is essential for global and regional carbon cycles and budgets. In this study, we performed several numerical experiments by switching and replacing inventories to estimate the impacts of four biomass burning emission inventories on atmospheric CO2 concentration simulations in 2006-2010 based on the global chemical transport model, GEOS-Chem. The results highlighted similarities and differences in the annual and seasonal variability of biomass burning emissions and simulated CO2 concentrations at global and regional scales. Based on four different biomass burning emission inventories, we found that biomass burning emissions could lead to a global CO2 concentration increase of 2.4 ppm annually. Africa contributed the largest global CO2 emissions among all continental regions, where the maximum CO2 concentration increase could reach 7.9-13.0 ppm in summer. Model evaluation results showed that simulation using the Quick Fire Emissions Database (QFED) as the model priori biomass burning emission inventory had the best performance compared with the satellite and surface observations. The sensitivity of simulated CO2 concentrations to the uncertainties in different biomass burning emission inventories was high in southern South America and most areas of the Eurasian continent, and low in central Africa and Southeast Asia. This study furthers our understanding of the critical role of biomass burning in atmospheric CO2 and indicates an urgent need to improve the accuracy of biomass burning emission estimates in CO2 simulations.

Does environmental regulation improve public health? Evidence from China's Two Control Zones policy.

Improving public health is the premise of sustainable human development and an essential condition of economic growth. However, increasing severe environmental pollution poses a threat to public health. Implementing environmental regulation policy has become a meaningful way to control environmental pollution and the basis and guarantee for achieving public health. This paper aims to study the impact of environmental regulation on public health. The Two Control Zones (TCZ) policy is the earliest and stricter environmental regulation in China. Based on the policy experiment of TCZ, this paper analyzes the role of TCZ policy in improving public health using the DID model and data from 112 cities. The study finds that the TCZ policy can significantly improve public health, and this improvement effect was continuous and lagging. The results of benchmark regression show that the implementation of the TCZ policy has reduced the incidence rate of respiratory diseases in TCZ areas by 5.7%. When considering city heterogeneity in terms of economic and geographical conditions, the study further found that the impact of improvement is largest for cities in more heavily non-provincial capital and central and western regions, respectively. In addition, the results of mediating test show that TCZ policy improves public health by reducing environmental pollution. Our research fills the gap in the literature on the micro effects of environmental regulation policy on public health in developing countries. The government should prioritize environmental pollution control through reasonable environmental regulation policies. The government should strengthen environmental information disclosure to remind the public to deal with air pollution. The government and enterprises also should take various environmental protection measures to reduce air pollution emissions.

Application of Preoperative Ultrasonography in the Percutaneous Minimally Invasive Repair of Acute Closed Achilles Tendon Rupture.

Percutaneous minimally invasive surgery involving Achilles tendon (AT) repair has the advantages of a low rerupture rate and fewer postoperative complications. However, due to the inability to operate under direct vision, the injury of the small saphenous vein (SSV) and sural nerve (SN) remains largely a high risk involving many challenges. We propose to introduce the preoperative application and advantages of ultrasonography in percutaneous minimally invasive surgery for acute AT rupture. Our results indicated that ultrasonography could locate the position of the SN more accurately and reduce the risk of iatrogenic nerve injury. Compared with the traditional surface markers, the preoperative localization and marking of AT, SSV, and SN in ultrasonography significantly reduced the risk of intraoperative accidental injury to blood vessels and nerves, which could reduce postoperative complications and promote early rehabilitation of patients. We ultimately exploit the properties of ultrasonography in percutaneous minimally invasive surgery to treat Achilles tendon rupture.

Online estimating weight of white Pekin duck carcass by computer vision.

The increasing consumption of ducks and chickens in China demands characterizing carcasses of domestic birds efficiently. Most existing methods, however, were developed for characterizing carcasses of pigs or cattle. Here, we developed a noncontact and automated weighing method for duck carcasses hanging on a production line. A 2D camera with its facilitating parts recorded the moving duck carcasses on the production line. To estimate the weight of carcasses, the images in the acquired dataset were modeled by a convolution neuron network (CNN). This model was trained and evaluated using 10-fold cross-validation. The model estimated the weight of duck carcasses precisely with a mean abstract deviation (MAD) of 58.8 grams and a mean relative error (MRE) of 2.15% in the testing dataset. Compared with 2 widely used methods, pixel area linear regression and the artificial neural network (ANN) model, our model decreases the estimation error MAD by 64.7 grams (52.4%) and 48.2 grams (45.0%). We release the dataset and code at https://github.com/RuoyuChen10/Image_weighing.

A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells.

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.