Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway.

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 µM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

A Domino Protocol toward High-performance Unsymmetrical Dibenzo[d,d']thieno[2,3-b;4,5-b']dithiophenes Semiconductors.

Unsymmetric organic semiconductors have many advantages such as good solubility, rich intermolecular interactions for potential various optoelectronic applications. However, their synthesis is more challenging due to intricate structures thus normally suffering tedious synthesis. Herein, we report a trisulfur radical anion (S3⋅-) triggered domino thienannulation strategy for the synthesis of dibenzo[d,d']thieno[2,3-b;4,5-b']dithiophenes (DBTDTs) using readily available 1-halo-2-ethynylbenzenes as starting materials. This domino protocol features no metal catalyst and the formation of six C-S and one C-C bonds in a one-pot reaction. Mechanistic study revealed a unique domino radical anion pathway. Single crystal structure analysis of unsymmetric DBTDT shows that its unique unsymmetric structure endows rich and multiple weak S⋅⋅⋅S interactions between molecules, which enables the large intermolecular transfer integrals of 86 meV and efficient charge transport performance with a carrier mobility of 1.52 cm2 V-1 s-1. This study provides a facile and highly efficient synthetic strategy for more high-performance unsymmetric organic semiconductors.

Non-Contact Adaptive Voltage Sensor Based on Electric Field Coupling Principle.

Non-contact voltage sensors based on the principle of electric field coupling have the advantages of simple loading and unloading, high construction safety, and the fact that they are not affected by line insulation. They can accurately measure line voltage without the need to connect to the measured object. Starting from the principle of non-contact voltage measurement, this article abstracts a non-contact voltage measurement model into the principle of capacitive voltage sharing and deduces its transfer relationship. Secondly, it is theoretically inferred that the edge effect of the traditional symmetric structure sensor plate will cause the actual capacitance value between the sensor plates to be greater than the theoretically calculated capacitance value, resulting in a certain measurement error. Therefore, the addition of an equipotential ring structure is proposed to eliminate the edge additional capacitance caused by the edge effect in order to design the sensor structure. In addition, due to the influence of sensor volume, material dielectric constant, and other factors, the capacitance value of the sensor itself is only at pF level, resulting in poor low-frequency performance and imbuing the sensor with a low voltage division ratio. In this regard, this article analyzes the measurement principle of non-contact voltage sensors. By paralleling ceramic capacitors between the two electrode plates of the sensor, the capacitance of the sensor itself is effectively increased, improving the low-frequency performance of the sensor while also increasing the sensor's voltage division ratio. In addition, by introducing a single pole double throw switch to switch parallel capacitors with different capacitance values, the sensor can have different voltage division ratios in different measurement scenarios, giving it a certain degree of adaptability. The final sensor prototype was made, and a high and low voltage experimental platform was built to test the sensor performance. The experimental results showed that the sensor has good linearity and high measurement accuracy, with a ratio error of within ±3%.

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis.

Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline-fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one-step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity.

OBJECTIVE: Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC). DESIGN: Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses. RESULTS: A negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades. CONCLUSIONS: CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

Contactless AC/DC Wide-Bandwidth Current Sensor Based on Composite Measurement Principle.

With the accelerated construction of the smart grid, new energy sources such as photovoltaic and wind power are connected to the grid. In addition to power frequency, the current signal of power grid also includes several DC signals, as well as medium-high and high-frequency transient signals. Traditional current sensors for power grids are bulky, have a narrow measurement range, and cannot measure both AC and DC at the same time. Therefore, this paper designs a non-intrusive, AC-DC wide-bandwidth current sensor based on the composite measurement principle. The proposed composite current detection scheme combines two different isolation detection technologies, namely tunneling reluctance and the Rogowski coil. These two current sensing techniques are complementary (tunneling magnetoresistive sensors have good low-frequency characteristics and Rogowski coils have good high-frequency characteristics, allowing for a wide detection bandwidth). Through theoretical and simulation analysis, the feasibility of the composite measurement scheme was verified. The prototype of composite current sensor was developed. The DC and AC transmission characteristics of the sensor prototype were measured, and the sensitivity and linearity were 11.96 mV/A, 1.14%, respectively. Finally, the sweep current method and pulse current method experiments prove that the designed composite current sensor can realize the current measurement from DC to 17 MHz.

[Research Progress in Immunosuppressive Tumor Microenvironment of Gastrointestinal Cancer].

Gastrointestinal (GI) cancer, a common malignant tumor with a high incidence in China, is showing a trend of rising incidence and is afflicting increasingly younger patients. Meanwhile, there have been constant development and innovations in new therapeutic technologies, among which, immunotherapy is now leading in a new era in the treatment of GI cancer. However, the complexity and diversity of immunosuppressive tumor microenvironment (TME) bring many obstacles to the immunotherapy of solid tumors in the GI tract. In this paper, focusing on solid tumors in the GI tract, we reviewed the main factors affecting the formation of immunosuppressive TME, and summarized strategies for targeted immunosuppressive TME-based therapies. Moreover, we analyzed the synergistic mechanism of various combination immunotherapies and reported on the latest progress in and future direction of immunotherapy for GI cancer, intending to provide new perspectives for treating solid tumors in the GI tract with immumotherapy.

Automatic model for cervical cancer screening based on convolutional neural network: a retrospective, multicohort, multicenter study.

BACKGROUND: The incidence rates of cervical cancer in developing countries have been steeply increasing while the medical resources for prevention, detection, and treatment are still quite limited. Computer-based deep learning methods can achieve high-accuracy fast cancer screening. Such methods can lead to early diagnosis, effective treatment, and hopefully successful prevention of cervical cancer. In this work, we seek to construct a robust deep convolutional neural network (DCNN) model that can assist pathologists in screening cervical cancer. METHODS: ThinPrep cytologic test (TCT) images diagnosed by pathologists from many collaborating hospitals in different regions were collected. The images were divided into a training dataset (13,775 images), validation dataset (2301 images), and test dataset (408,030 images from 290 scanned copies) for training and effect evaluation of a faster region convolutional neural network (Faster R-CNN) system. RESULTS: The sensitivity and specificity of the proposed cervical cancer screening system was 99.4 and 34.8%, respectively, with an area under the curve (AUC) of 0.67. The model could also distinguish between negative and positive cells. The sensitivity values of the atypical squamous cells of undetermined significance (ASCUS), the low-grade squamous intraepithelial lesion (LSIL), and the high-grade squamous intraepithelial lesions (HSIL) were 89.3, 71.5, and 73.9%, respectively. This system could quickly classify the images and generate a test report in about 3 minutes. Hence, the system can reduce the burden on the pathologists and saves them valuable time to analyze more complex cases. CONCLUSIONS: In our study, a CNN-based TCT cervical-cancer screening model was established through a retrospective study of multicenter TCT images. This model shows improved speed and accuracy for cervical cancer screening, and helps overcome the shortage of medical resources required for cervical cancer screening.

Research on UAV Three-Phase Transmission Line Tracking and Localization Method Based on Electric Field Sensor Array.

The tracking and positioning of transmission lines is a key element for UAVs (Unmanned Aerial Vehicles) to achieve autonomous inspection of transmission lines. Current methods are vulnerable to weather and environmental factors, have high costs, and have difficulties in data processing. Therefore, this paper proposes a transmission line tracking and localization method based on the electric field sensor array, which calculates the current UAV's heading angle deflection angle, the distance between the transmission line and the UAV, and the elevation angle, providing a new idea to solve the problem of UAV inspection of transmission lines. At the same time, the electric field distribution of different arrangements of three-phase transmission lines was analyzed using COMSOL to determine the flight area of the UAV. By comparing the electric field distribution of the UAV flight area and single-phase transmission lines, it was verified that the current method is also applicable in the three-phase transmission line scenario, and it was further verified that the sensor array used can sense the change of the UAV position in the flight area, indicating that the electric field sensor array can realize the transmission line tracking and localization of transmission lines. The experimental results showed that, in the three-phase transmission line scenario, when the sensor array moves along the transmission straight wire, the maximum absolute error of the heading angle deflection angle calculated according to this method was 8.2°, the maximum absolute error of the distance between the array and the transmission line was 19.3 cm, and the maximum absolute error of the elevation angle was 11.37°; the error was within a reasonable range and can be used for the UAV to realize autonomous inspection.

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy.

Small heat shock proteins (sHSPs) are ubiquitous ATP-independent chaperones that play essential roles in response to cellular stresses and protein homeostasis. Investigations of sHSPs reveal that sHSPs are ubiquitously expressed in numerous types of tumors, and their expression is closely associated with cancer progression. sHSPs have been suggested to control a diverse range of cancer functions, including tumorigenesis, cell growth, apoptosis, metastasis, and chemoresistance, as well as regulation of cancer stem cell properties. Recent advances in the field indicate that some sHSPs have been validated as a powerful target in cancer therapy. In this review, we present and highlight current understanding, recent progress, and future challenges of sHSPs in cancer development and therapy.

Research and Experiments on an External Miniaturized VFTO Measurement System.

Disconnect switch and circuit breakers operations in gas insulated switchgear (GIS) systems may produce very fast transient overvoltage (VFTO). Detecting VFTO is the first step for researchers to reduce the damage to other equipment of the substation caused by VFTO. Most of the existing sensors used for VFTO are generally bulky, complex to install, and require modification of the GIS structure. In this paper, a miniaturized measurement system that uses capacitive voltage divider and differentiating-integrating circuit is proposed. A special sensor structure and optimized differentiating-integrating circuit components arrangement were designed to increase the bandwidth of the measurement system. The frequency-domain, time-domain and voltage divide calibration experiment was performed, and a comparison experiment with an internal VFTO sensor was conducted. The measurement system was applied in the 500 kV GIS substation, and the VFTO measurement under specific conditions was carried out. The measured time domain and frequency domain waveforms conformed to the definition of standard VFTO according to IEC 60,071. It was found that the proposed measurement system meets VFTO measurement requirements and can be applied to actual VFTO measurements.

Ag Modified SnS2 Monolayer as a Potential Sensing Material for C4F7N Decompositions: A Density Functional Theory Study.

As the field of 2D materials rapidly evolves, substances such as graphene, metal dichalcogenides, MXenes, and MBenes have garnered extensive attention from scholars in the gas sensing domain due to their unique and superior properties. Based on first-principles calculations, this work explored the adsorption characteristics of both intrinsic and silver (Ag) doped tin disulfide (SnS2) toward the decomposition components of the insulating medium C4F7N (namely, CF4, C3F6, and COF2), encompassing the adsorption energy, charge transfer, density of state (DOS), band structure, and adsorption stability. The results indicated that Ag-doped SnS2 exhibited an effective and stable adsorption for C3F6 and COF2, whereas its adsorption for CF4 was comparatively weaker. Additionally, the potential for Ag-SnS2 in detecting C3F6 was highlighted, inferred from the contributions of the band gap variations. This research provides theoretical guidance for the application of Ag-SnS2 as a sensing material in assessing the operational status of gas-insulated equipment.

Reduced graphene oxide-encaged submicron-silicon anode interfacially stabilized by Al2O3 nanoparticles for efficient lithium-ion batteries.

Silicon-carbon composites have been recognized as some of the most promising anode candidates for advancing new-generation lithium-ion batteries (LIBs). The development of high-efficiency silicon/graphene anodes through a simple and cost-effective preparation route is significant. Herein, by using micron silicon as raw material, we designed a mesoporous composite of silicon/alumina/reduced graphene oxide (Si/Al2O3/RGO) via a two-step ball milling combined annealing process. Commercial Al2O3 nanoparticles are introduced as an interlayer due to the toughening effect, while RGO nanosheets serve as a conductive and elastic coating to protect active submicron silicon particles during lithium alloying/dealloying reactions. Owing to the rational porous structure and dual protection strategy, the core/shell structured Si/Al2O3/RGO composite is efficient for Li+ storage and demonstrates improved electrical conductivity, accelerated charge transfer and electrolyte diffusion, and especially high structural stability upon charge/discharge cycling. As a consequence, Si/Al2O3/RGO yields a high discharge capacity of 852 mA h g-1 under a current density of 500 mA g-1 even after 200 cycles, exhibiting a high capacity retention of ∼85%. Besides, Si/Al2O3/RGO achieves excellent cycling reversibility and superb high-rate capability with a stable specific capacity of 405 mA h g-1 at 3000 mA g-1. Results demonstrate that the Al2O3 interlayer is synergistic with the indispensable RGO nanosheet shells, affording more buffer space for silicon cores to alleviate the mechanical expansion and thus stabilizing active silicon species during charge/discharge cycles. This work provides an alternative low-cost approach to achieving high-capacity silicon/carbon composites for high-performance LIBs.

Advances in 2D Materials Based Gas Sensors for Industrial Machine Olfactory Applications.

The escalating development and improvement of gas sensing ability in industrial equipment, or "machine olfactory", propels the evolution of gas sensors toward enhanced sensitivity, selectivity, stability, power efficiency, cost-effectiveness, and longevity. Two-dimensional (2D) materials, distinguished by their atomic-thin profile, expansive specific surface area, remarkable mechanical strength, and surface tunability, hold significant potential for addressing the intricate challenges in gas sensing. However, a comprehensive review of 2D materials-based gas sensors for specific industrial applications is absent. This review delves into the recent advances in this field and highlights the potential applications in industrial machine olfaction. The main content encompasses industrial scenario characteristics, fundamental classification, enhancement methods, underlying mechanisms, and diverse gas sensing applications. Additionally, the challenges associated with transitioning 2D material gas sensors from laboratory development to industrialization and commercialization are addressed, and future-looking viewpoints on the evolution of next-generation intelligent gas sensory systems in the industrial sector are prospected.

Triboelectric Mechanism of Oil-Solid Interface Adopted for Self-Powered Insulating Oil Condition Monitoring.

The liquid-solid contact electrification mechanism has been explored in the aqueous solution system, but there are few systematic studies on oil-solid triboelectrification. Herein, an oil droplet triboelectric nanogenerator (Oil-droplet TENG) is designed as the probe to investigate the charge transfer properties at oil-solid interface. The charge transfer kinetics process is disclosed by the electrical signals produced, showing that the electron species initially predominated the oil-solid triboelectrification. The molecular structure and electronic properties of oil also affect triboelectric performance. Further, the charge transfer principle in multi-component liquid mixture during the electric double layer (EDL) development process is proposed to explain the component competition effect. As a proof of concept, a tubular-TENG is designed as a self-powered sensor for transformer oil trace water detection. The device demonstrates high water sensitivity with a detection limit of 10 µL L-1 and a response range of 10-100 µL L-1 . This work not only reveals the oil-solid triboelectric and charge transfer competition mechanism in EDL, but also open up a new channel for real-time online monitoring of trace water in transformer oil, which holds promise for information perception and intelligent operation of transformers in the power industry.

Higher ETCOc predicts longer phototherapy treatment in neonatal hyperbilirubinemia.

Objective: This study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia. Methods: A prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission. Results: The mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h (n = 87) and >72 h (n = 16) groups. Infants who received phototherapy for >72 h had significantly higher ETCOc (2.45 vs. 1.60, P = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value. Conclusion: ETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient.

SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair.

BACKGROUND: Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy. RESULTS: We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo. CONCLUSIONS: SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.

Compatibility and Interaction Mechanism between the C4F7N/CO2/O2 Gas Mixture and FKM and NBR.

The C4F7N/CO2/O2 gas mixture received a great deal of attention for its potential use in eco-friendly gas-insulated equipment (GIE). The evaluation of the compatibility between C4F7N/CO2/O2 and sealing rubber is necessary and significant considering the high working pressure (0.14-0.6 MPa) of GIE. Herein, we explored the compatibility between C4F7N/CO2/O2 and fluororubber (FKM) and nitrile butadiene rubber (NBR) for the first time by analyzing the gas components, rubber morphology, elemental composition, and mechanical properties. The interaction mechanism of the gas-rubber interface was further investigated based on the density functional theory. We found that C4F7N/CO2/O2 is compatible with FKM and NBR at 85 °C, while the surface morphology changed at 100 °C, with white granular and agglomerated lumps appearing on FKM and multi-layer flakes being generated on NBR. The accumulation of the fluorine element occurred, and the compressive mechanical properties of NBR deteriorated after the gas-solid rubber interaction. Overall, the compatibility between FKM and C4F7N/CO2/O2 is superior, which could be employed as the sealing material for C4F7N-based GIE.

Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1.

Cisplatin resistance remains a major obstacle limiting the effectiveness of chemotherapy in cervical cancer. However, the underlying mechanism of cisplatin resistance is still unclear. In this study, we demonstrate that vacuolar protein sorting 13 homolog C (VPS13C) deficiency promotes cisplatin resistance in cervical cancer. Moreover, through an RNA sequencing screen, VPS13C deficiency was identified as negatively correlated with the high expression of glutathione S-transferase pi gene (GSTP1). Mechanistically, loss of VPS13C contributes to cisplatin resistance by influencing the expression of GSTP1 and inhibiting the downstream c-Jun N-terminal kinase (JNK) pathway. In addition, targeting GSTP1 with the inhibitor NBDHEX effectively rescued the cisplatin resistance induced by VPS13C deficiency. Overall, our findings provide insights into the underlying mechanisms of VPS13C in cisplatin resistance and identify VPS13C as a promising candidate for the treatment of chemoresistance in cervical cancer.

WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer.

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/ß-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.