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Abstract Idiopathic short stature (ISS) is a common childhood condition with largely unknown underlying causes. Recent research highlights the role of circulating exosomes in the pathogenesis of various disorders, but their connection to ISS remains unexplored. In the experiments, human chondrocytes are cocultured with plasma exosomes from ISS patients, leading to impaired chondrocyte growth and bone formation. Elevated levels of a specific long non‐coding RNA (lncRNA), ISSRL, are identified as a distinguishing factor in ISS, boasting high specificity and sensitivity. Silencing ISSRL in ISS plasma exosomes reverses the inhibition of chondrocyte proliferation and bone formation. Conversely, overexpression of ISSRL in chondrocytes impedes their growth and bone formation, revealing its mechanism of action through the miR‐877‐3p/GZMB axis. Subsequently, exosomes (CT‐Exo‐siISSRL‐oeGH) with precise cartilage‐targeting abilities are engineered, loaded with customized siRNA for ISSRL and growth hormone. This innovative approach offers a therapeutic strategy to address ISS by rectifying abnormal non‐coding RNA expression in growth plate cartilage and delivering growth hormone with precision to promote bone growth. This research provides valuable insights into ISS diagnosis and treatment, highlighting the potential of engineered exosomes.

BackgroundOsteosarcoma is a highly aggressive type of bone cancer with a poor prognosis. In the tumor immune microenvironment, T-cell exhaustion can occur due to various factors, leading to reduced tumor-killing ability. The purpose of this study was to construct a prognostic model based on T-cell exhaustion-associated genes in osteosarcoma.MethodsPatient data for osteosarcoma were retrieved from the TARGET and GEO databases. Consensus clustering was employed to identify two novel molecular subgroups. The dissimilarities in the tumor immune microenvironment between these subgroups were evaluated using the “xCell” algorithm. GO and KEGG analyses were conducted to elucidate the underlying mechanisms of gene expression. Predictive risk models were constructed using the least absolute shrinkage and selection operator algorithm and Cox regression analysis. To validate the prognostic significance of the risk gene expression model at the protein level, immunohistochemistry assays were performed on osteosarcoma patient samples. Subsequently, functional analysis of the key risk gene was carried out through in vitro experimentation.ResultsFour gene expression signatures (PLEKHO2, GBP2, MPP1, and VSIG4) linked to osteosarcoma prognosis were identified within the TARGET-osteosarcoma cohort, categorizing patients into two subgroups. The resulting prognostic model showed strong predictive capability, with area under the receiver operating characteristic curve (AUC) values of 0.728/0.740, 0.781/0.658, and 0.788/0.642 for 1, 3, and 5-year survival in both training and validation datasets. Notably, patients in the low-risk group had significantly higher stromal, immune, and ESTIMATE scores compared to high-risk counterparts. Additionally, a nomogram was developed, exhibiting high accuracy in predicting the survival outcome of osteosarcoma patients. Immunohistochemistry, Kaplan-Meier, and time-dependent AUC analyses consistently supported the prognostic value of the risk model within our osteosarcoma patient cohort. In vitro experiments provided additional validation by demonstrating that the downregulation of GBP2 promoted the proliferation, migration, and invasion of osteosarcoma cells while inhibiting apoptosis.ConclusionThe current study established a prognostic signature associated with TEX-related genes and elucidated the impact of the pivotal gene GBP2 on osteosarcoma cells via in vitro experiments. Consequently, it introduces a fresh outlook for clinical prognosis prediction and sets the groundwork for targeted therapy investigations in osteosarcoma.

We study the dynamical properties of a discrete-time host-parasitoid model with Holling type III functional response. It is shown that flip bifurcation and Neimark-Sacker bifurcation occur in certain parameter regimes. A sufficient condition based on the model parameters for which both populations can coexist is derived. The boundedness, existence and local stability of the unique equilibrium are proved. In addition, the numerical simulations have been done, in addition to supporting the analytical findings, more behaviors are extracted from the model in a two-dimensional parameter space. Finally, we emphasize the importance of clearly presenting biological assumptions that are inherent to the structure of a discrete model.

Abstract Background Currently, the etiology of idiopathic short stature (ISS) is still unclear. The poor understanding of the molecular mechanisms of ISS has largely restricted this strategy towards safe and effective clinical therapies. Methods The plasma exosomes of ISS children were co-cultured with normal human chondrocytes. The differential expression of exosome miRNA between ISS and normal children was identified via high-throughput microRNA sequencing and bioinformatics analysis. Immunohistochemistry, In situ hybridization, RT-qPCR, western blotting, luciferase expression, and gene overexpression and knockdown were performed to reveal the key signaling pathways that exosome miRNA of aberrant expression in ISS children impairs longitudinal bone growth. Results Chondrocytes proliferation and endochondral ossification were suppressed after coculture of ISS plasma exosomes with human normal chondrocytes. High-throughput microRNA sequencing and RT-qPCR confirmed that plasma exosome miR-26b-3p was upregulated in ISS children. Meanwhile, exosome miRNA-26b-3p showed a high specificity and sensitivity in discriminating ISS from normal children. The rescue experiment showed that downregulation of miR-26b-3p obviously improved the repression of chondrocyte proliferation and endochondral ossification caused by ISS exosomes. Subsequently, miR-26b-3p overexpression inhibited chondrocyte proliferation and endochondral ossification once again. In situ hybridization confirmed the colocalization of miR-26b-3p with AKAP2 in chondrocytes. In vitro and in vivo assay revealed exosome miRNA-26b-3p impairs longitudinal bone growth via the AKAP2 /ERK1/2 axis. Conclusions This study is the first to confirm that miR-26b-3p overexpression in ISS plasma exosomes leads to disorders in proliferation and endochondral ossification of growth plate cartilage via inhibition of AKAP2/ERK1/2 axis, thereby inducing ISS. This study provides a new research direction for the etiology and pathology of ISS and a new idea for the biological treatment of ISS. Graphical Abstract

Abstract Objective As disc fragment completely loses contact with the parent disc and can migrate in all directions of the epidural space, making it appear similar to schwannoma, it is fairly difficult to make a definitive diagnosis for mimicking tumor discs. The aim of this research is to differentially diagnose mimicking tumor discs and schwannomas using coronal magnetic resonance imaging (MRI) of three‐dimensional fast‐field echo with water‐selective excitation (CMRI). Methods Among 76 patients (38 men and 38 women; mean age, 52.88 ± 15.80 [range, 18–78 years]) who were retrospectively examined in this study, 38 were primarily diagnosed with schwannomas and pathologically diagnosed with mimicking tumor discs after surgery, and 38 were primarily diagnosed with neurogenic tumors and pathologically diagnosed with schwannomas after surgery. Open surgery was performed in all the patients between March 2016 and April 2020. The preliminary diagnosis of all patients was considered an intraspinal tumor based on conventional two‐dimensional MRI sequences. After open surgery, the final diagnosis was confirmed to mimic a tumor disc or schwannoma based on postoperative pathology reports. The sensitivity, specificity, and reliability of CMRI and conventional MRI for identifying mimicking tumor discs and schwannomas were compared. Chi‐square and McNemar tests were used for statistical analyses. Results Symptoms were considerably relieved in all the patients after surgery. Seven patients had grade 1 extensor digitorum longus, triceps surae, or quadriceps femoris muscle strength prior to surgery. No nerve root injury was observed in any of the patients. CMRI showed significantly higher sensitivity (94.74%) and specificity (94.74%) than conventional MRI (71.05% and 92.11%, respectively; p = 0.012 0.05, respectively) for differential identification between mimicking tumor discs and schwannomas. Moreover, CMRI showed a higher reliability (kappa value = 0.787) than conventional MRI (kappa value = 0.374). Conclusions CMRI is a better non‐invasive technology for the identification of intraspinal lesions, especially for differentiating between mimicking tumor discs and schwannomas.

In this paper, we consider a discrete-time SIR epidemic model. Codimension-two bifurcations associated with 1:2, 1:3 and 1:4 strong resonances are analyzed by using a series of affine transformations and bifurcation theory. Numerical simulations are carried out to verify and illustrate these theoretical results. More precisely, two kinds of high-resolution stability phase diagrams are exhibited to describe how the system's complexity unfolds with control parameters varying.

This paper presents an exploitation model with a stage structure to analyze the dynamics of a fish population, where periodic birth pulse and pulse fishing occur at different fixed time. By utilizing the stroboscopic map, we can obtain an accurate cycle of the system and investigate the stability thresholds. Through the application of the center manifold theorem and bifurcation theory, our research has shown that the given model exhibits transcritical and flip bifurcation near its interior equilibrium point. The bifurcation diagrams, maximum Lyapunov exponents and phase portraits are presented to further substantiate the complexity. Finally, we present high-resolution stability diagrams that demonstrate the global structure of mode-locking oscillations. We also describe how these oscillations are interconnected and how their complexity unfolds as control parameters vary. The two parametric planes illustrate that the structure of Arnold’s tongues is based on the Stern–Brocot tree. This implies that the periodic occurrence of birth pulse and pulse fishing contributes to the development of more complex dynamical behaviors within the fish population.

Abstract Background Developmental dysplasia of the hip (DDH) is a highly prevalent hip disease among children. However, its pathogenesis remains unclear. MicroRNAs (miRNA) are important regulators of cartilage development. In a previous study, high-throughput miRNA sequencing of tissue samples from an animal model of DDH showed a low level of miR-1-3p in the cartilage of the acetabular roof (ARC), but its role in DDH pathogenesis was not addressed. Therefore, our aim here was to investigate the effects of miR-1-3p in the ARC. Methods The diagnosis of acetabular dysplasia was confirmed with X-ray examination, while imaging and HE staining were conducted to further evaluate the ARC thickness in each animal model. FISH was employed to verify miR-1-3p expression in the ARC and chondrocytes. The miR-1-3p target genes were predicted by a bioinformatics database. A dual-luciferase reporter assay was used to confirm the targeting relationship between miR-1-3p and SOX9. The gene expression of miR-1-3p, SOX9, RUNX2 and collagen type X was evaluated by qPCR analysis. The protein expression of SOX9, RUNX2 and collagen type X was detected by western blot analysis. The levels of SOX9, RUNX2, and collagen type X in the ARC were further assessed via immunohistochemistry analysis. Finally, Alizarin Red S staining was used to observe the mineralized nodules produced by the chondrocytes. Results We observed low expression of miR-1-3p in the ARC of animals with DDH. SOX9 is a miR-1-3p target gene. Using miR-1-3p silencing technology in vitro, we demonstrated significantly reduced chondrocyte-generated mineralized nodules compared to those of the control. We also confirmed that with miR-1-3p silencing, SOX9 expression was upregulated, whereas the expression of genes associated with endochondral osteogenesis such as RUNX2 and collagen type X was downregulated. To confirm the involvement of miR-1-3p silencing in abnormal ossification through SOX9, we also performed a rescue experiment in which SOX9 silencing restored the low expression of RUNX2 and collagen type X produced by downregulated miR-1-3p expression. Finally, the elevated SOX9 levels and reduced RUNX2 and collagen type X levels in the ARC of rabbits with DDH were also verified using immunohistochemistry, RT-PCR, and western blots. Conclusion The relatively low expression of miR-1-3p in the ARC may be the cause of abnormal endochondral ossification in the acetabular roof of animals with DDH.

Idiopathic short stature (ISS) is the most common clinical cause of the short stature with an unclear aetiology and a lack of effective treatment. Circular RNAs have been shown to play a significant regulatory role through various signal transduction pathways in a variety of diseases in recent years. However, the role of circular RNAs on ISS is not yet well-understood and requires a special attention. The differentially expressed circular RNAs were screened by microarray chip analysis, and RT-qPCR was used to verify the expression of hsa_circ_0008870 in ISS patients. Subsequently, in vitro and in vivo experiments were conducted to determine the biological functions of hsa_circ_0008870 in ISS. The authors first confirmed that hsa_ circ_0008870 was downregulated in ISS children. Meanwhile, we also observed that the downregulated hsa_circ _0008870 significantly inhibited chondrocyte proliferation and endochondral ossification in vivo and in vitro. Mechanistically, hsa_circ_0008870 regulates MAPK1 expression by sponge miR-185-3p. This mechanism of action was further verified through rescue experiments. Finally, the authors revealed that the silencing of hsa_circ_0008870 induces low expression of MAPK1 by impairing the sponge action of miR-185-3p, thereby inhibiting chondrocyte proliferation, hypertrophy, and endochondral ossification, which results in a short stature phenotype. In addition to these, we also observed an interesting phenomenon that upregulated of miR-185-3p can in turn inhibit the expression of hsa_circ_0008870 in chondrocytes. This suggests that hsa_circ_0008870 could potentially serve as a therapeutic target for the treatment of ISS.

Summary: Background: The mechanism of missense alteration at EGFR L792F in patients with non-small cell lung cancer resistant to osimertinib has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation. Methods: Circulating tumor DNA-based sequencing data of 1153 patients with osimertinib resistance were collected to illustrate the prevalence of EGFR L792F mutation. Sensitivity to osimertinib was tested with constructed EGFR 19Del/T790M-cis-L792F cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR L792Fcis-induced osimertinib resistance were investigated. Possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored. Findings: The concomitant EGFR L792F was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR T790M-cis-L792F mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutation. EGFR T790M-cis-L792F mutation upregulated phosphorylation of STAT3 Tyr705 and promoted its specific binding to IL4 promoter, enhancing IL-4 expression and secretion and inducing macrophage M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed macrophage M2 polarization and regressed tumor sensitivity to osimertinib. Interpretation: Our results proved that targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC. Funding: This work was supported by the National Natural Science Foundation of China (81871889, 82072586, 81902910), Beijing Natural Science Foundation (7212084, 7214249), the China National Natural Science Foundation Key Program (81630071), the National Key Research and Development Project (2019YFC1315704), CAMS Innovation Fund for Medical Sciences (CIFMS 2021-1-I2M-012), Aiyou Foundation (KY201701) and CAMS Key Laboratory of translational research on lung cancer (2018PT31035).

The dynamics of a discrete-time SIS epidemic model are reported in this paper. Three types of codimension one bifurcation, namely, transcritical, flip, Neimark–Sacker (N-S) bifurcations, and their intersection codimension two bifurcations including 1 : 2, 1 : 3, and 1 : 4 resonances are discussed. The necessary and sufficient conditions for detecting these types of bifurcation are derived using algebraic criterion methods. Numerical simulations are conducted not only to illustrate analytical results but also to exhibit complex behaviors which include period-doubling bifurcation in period −2,−4,−8,−16 orbits, invariant closed cycles, and attracting chaotic sets. Especially, here we investigate the parameter space of the discrete model. We also investigate the organization of typical periodic structures embedded in a quasiperiodic region. We identify period-adding, Farey sequence of periodic structures embedded in this quasiperiodic region.

The hydroxylase EgIN2 contributes to triple negative breast cancers. Here, using an enzyme-substrate trapping strategy, the authors identify ASDL as a bona fide substrate of EgIN2 promoting aggressive properties of TNBC via the activation of cMYC signaling.

Hepatocellular carcinoma (HCC) is characterized by a high rate of incidence and recurrence, and resistance to chemotherapy may aggravate the poor prognosis of HCC patients. Sorafenib resistance is a conundrum to the treatment of advanced/recurrent HCC. Therefore, studies on the molecular pathogenesis of HCC and the resistance to sorafenib are of great interest. Here, we report that GINS1 was highly expressed in HCC tumors, associated with tumor grades, and predicted poor patient survival using Gene Expression Omnibus (GEO) databases exploration. Cell cycle, cell proliferation assay and in vivo xenograft mouse model indicated that knocking down GINS1 induced in G1/S phase cell cycle arrest and decreased tumor cells proliferation in vitro and in vivo. Spheroid formation assay results showed that GINS1 promoted the stem cell activity of HCC tumor cells. Furthermore, GEO database (GSE17112) analysis showed that HRAS oncogenic gene set was enriched in GINS1 high-expressed cancer cells, and quantitative real-time PCR, and Western blot results proved that GINS1 enhanced HCC progression through regulating HRAS signaling pathway. Moreover, knocking down endogenous GINS1 with shGINS1 increased the sensitivity of HCC cells to sorafenib, and restoring HRAS or stem associated pathway partly recovered the sorafenib resistance. Overall, the collective findings highlight GINS1 functions in hepatocarcinogenesis and sorafenib resistance, and indicate its potential use of GINS1 in drug-resistant HCC.

To investigate responses difference of soil potential nitrification rates (PNR) to heavy metals and antibiotics, batch toxicity experiments of Cu and sulfadiazine (SDZ) were conducted in four typical soils which were collected from different locations of China. Toxic differences of Cu and SDZ to soil PNR were evaluated based on their values of EC20 and EC50 calculated with logistic model. It was found that soil nitrification was a good indicator of Cu contamination in soils except for paddy soil. For SDZ, their ECX values were significantly higher than its concentration level (0.002 ~ 0.760 mg·kg-1) in soils. Thus, it was concluded that soil nitrification might be more sensitive to Cu than SDZ in field soil. The further Pearson correlation analysis indicated that the response of soil PNR to Cu and SDZ contamination were significantly related with soil PNR0 and pH.

Graphs have been widely used to model the complex relationships among entities. Community search is a fundamental problem in graph analysis. It aims to identify cohesive subgraphs or communities that contain the given query vertices. In social networks, a user is usually associated with a weight denoting its influence. Recently, some research is conducted to detect influential communities. However, there is a lack of research that can support personalized requirement. In this study, we propose a novel problem, named personalized influential k-ECC (PIKE) search, which leverages the k-ECC model to measure the cohesiveness of subgraphs and tries to find the influential community for a set of query vertices. To solve the problem, a baseline method is first proposed. To scale for large networks, a dichotomy-based algorithm is developed. To further speed up the computation and meet the online requirement, we develop an index-based algorithm. Finally, extensive experiments are conducted on 6 real-world social networks to evaluate the performance of proposed techniques. Compared with the baseline method, the index-based approach can achieve up to 7 orders of magnitude speedup.

Objective The complete view of the nerve root, including the extraforaminal zone, can be displayed by coronal magnetic resonance imaging (MRI) of three-dimensional (3D) fast-field echo with water-selective excitation (CMRI). However, its sensitivity, specificity, and reliability for the diagnosis of extraforaminal lumbar disc herniation are unclear. We compared the sensitivity, specificity, and reliability of conventional MRI, CMRI, and 3D MRI for the identification of extraforaminal lumbar disc herniation. Methods This study involved 140 patients (68 with extraforaminal lumbar disc herniation and 72 with paramedian disc herniation). Their mean age was 44.57 ± 14.59 years. Conventional MRI, CMRI, and 3D MRI of all patients were evaluated by five experts. The reliability, sensitivity, and specificity of the three imaging techniques for identification of extraforaminal lumbar disc herniation were compared using kappa statistics and the chi-squared test. Results CMRI showed higher agreement (0.843) than conventional MRI (0.671) and 3D MRI (0.771) for the identification of extraforaminal lumbar disc herniation. CMRI demonstrated higher sensitivity (95.6% vs. 91.2%) than conventional MRI (85.3% vs. 70.6%) and 3D MRI (92.6% vs. 86.7%) regardless of whether performed by junior or senior surgeons. Conclusions CMRI is helpful for identification of extraforaminal disc herniation by junior and senior orthopedic surgeons.

Melanoma is a global concern and accounts for the major mortality of skin cancers. Herpes simplex virus thymidine kinase gene with ganciclovir (HSV-TK/GCV) is a promising gene therapy for melanoma. Despite its low efficiency, it is well known for its bystander effect which is mainly mediated by gap junction. In this study, we found that curcumin reduced B16 melanoma cell viability in both time- and dose-dependent manner. Further study showed that curcumin improved the gap junction intercellular communication (GJIC) function, and upregulated the proteins essential to gap junction, such as connexin 32 and connexin 43, indicating the potential role in enhancing the bystander effect of HSV-TK/GCV. By co-culturing the B16TK cells, which stably expressed TK gene, with wildtype B16 (B16WT) cells, we found that co-treatment of curcumin and GCV synergistically inhibited B16 cell proliferation, but the effect could be eliminated by the gap junction inhibitor AGA. Moreover, curcumin markedly increased apoptosis rate of B16WT cells, suggesting its effect in enhancing the bystander effect of HSV-TK/GCV. In the in-vivo study, we established the xenografted melanoma model in 14 days by injecting mixture of B16TK and B16WT cell in a ratio of 3:7. The result demonstrated that, co-administration of curcumin and GCV significantly inhibited the xenograft growth, as indicated by the smaller size and less weight. The combinational effect was further confirmed as a synergistic effect. In conclusion, the results demonstrated that curcumin could enhance the killing effect and the bystander effect of HSV-TK/GCV in treating melanoma, which might be mediated by improved gap junction. Our data suggested that combination of HSV-TK/GCV with curcumin could be a potential chemosensitization strategy for cancer treatment.

Abstract This paper studies an inverse problem of determining the implied volatility in the financial products linked with gold price, which has important application in financial derivatives pricing. Based on the total variation regularization strategy, the existence and necessary condition of the minimum for the control function are addressed, and the local uniqueness of the solution is also given by a modified case. Furthermore, the stability and convergence for the regularized approach are discussed. The results obtained in this paper may be useful for those who engage in hedging or risk management.

Abstract In this paper, a discrete-time biological model and its dynamical behaviors are studied in detail. The existence and stability of the equilibria of the model are qualitatively discussed. More precisely, the conditions for the existence of a flip bifurcation and a Neimark-Sacker bifurcation are derived by using the center manifold theorem and bifurcation theory. Numerical simulations are presented not only to validate our results with the theoretical analysis, but also to exhibit the complex dynamical behaviors. We also analyze the dynamic characteristics of the system in a two-dimensional parameter space. Numerical results indicate that we can more clearly and directly observe the chaotic phenomenon, period-doubling and period-adding, and the optimal parameters matching interval can also be found easily.

Cohesive subgraph identification is a fundamental problem in bipartite graph analysis. In real applications, to better represent the co-relationship between entities, edges are usually associated with weights or frequencies, which are neglected by most existing research. To fill the gap, we propose a new cohesive subgraph model, (k,ω)-core, by considering both subgraph cohesiveness and frequency for weighted bipartite graphs. Specifically, (k,ω)-core requires each node on the left layer to have at least k neighbors (cohesiveness) and each node on the right layer to have a weight of at least ω (frequency). In real scenarios, different users may have different parameter requirements. To handle massive graphs and queries, index-based strategies are developed. In addition, effective optimization techniques are proposed to improve the index construction phase. Compared with the baseline, extensive experiments on six datasets validate the superiority of our proposed methods.

GATA binding protein 2 (GATA2) is a transcription factor that has essential roles in hematologic malignancies and progression of various solid tumors. Our previous studies suggested that high GATA2 expression is associated with recurrence of colorectal cancer (CRC). However, the influence of GATA2 single nucleotide polymorphisms (SNPs) on the survival of CRC remains unknown.We genotyped GATA2 SNP rs2335052 using Sanger sequencing after PCR amplification, and determined GATA2 expression by immunohistochemistry in a cohort of 180 CRC patients. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between the GATA2 rs2335052 genotypes and the clinical outcome of CRC.We found that there was no significant correlation between the rs2335052 genotypes and the expression of GATA2. However, the Kaplan-Meier survival analysis suggested that the carriers of the A-allele of SNP rs2335052 were significantly associated with increased risk of recurrence and reduced disease-free survival (DFS), compared with those carrying the variant genotype of GG in rs2335052 (P = 0.021). Moreover, univariate and multivariate Cox regression analyses revealed that GATA2 SNP rs2335052 was an independent risk factor for the DFS of CRC patients.Our results demonstrated that GATA2 SNP rs2335052 is an independent predictor for prognosis of CRC patients. This raised the possibility that SNP rs2335052 may serve as a potential indicator for predicting recurrence of CRC after curative colectomy.

The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy.