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Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27. These changes were associated with a significant reduction in FGFR4 transcript levels in treated cells. These decreases in H3K4me1 in the FGFR4 super enhancer were also associated with a 240-fold increase in KDM5B (JARID1B) mRNA levels. Immunoblot and immunofluorescent studies also revealed a significant increase in the KDM5B protein levels after treatment in these cells. KDM5B is the only member of KDM5 (JARID1) family of histone lysine demethylases that catalyzes demethylation of H3K4me1. These data together suggest a pleiotropic effect of DNMTi therapy in aRMS cells, converging to significantly lower FGFR4 protein levels in these cells.

The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.

Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy. We sought to extend these studies by using a clinically relevant NSC line expressing a modified human CE (hCE1m6-NSCs) to establish proof of concept and identify an intravenous dose and treatment schedule that gave maximal efficacy. Human-derived NB cell lines were significantly more sensitive to treatment with hCE1m6-NSCs and irinotecan as compared with drug alone. This was supported by pharmacokinetic studies in subcutaneous NB mouse models demonstrating tumor-specific conversion of irinotecan to SN-38. Furthermore, NB-bearing mice that received repeat treatment with intravenous hCE1m6-NSCs and irinotecan showed significantly lower tumor burden (1.4-fold, p = 0.0093) and increased long-term survival compared with mice treated with drug alone. These studies support the continued development of NSC-mediated gene therapy for improved clinical outcome in NB patients.

Drug resistance is an obstacle in the therapy of acute lymphoblastic leukemia (ALL). Whether the physical properties such as the motility of the cells contribute to the survival of ALL cells after drug treatment has recently been of increasing interest, as they could potentially allow the metastasis of solid tumor cells and the migration of leukemia cells. We hypothesized that chemotherapeutic treatment may alter these physical cellular properties. To investigate the motility of chemotherapeutics-treated B-cell ALL (B-ALL) cells, patient-derived B-ALL cells were treated with chemotherapy for 7 days and left for 12 h without chemotherapeutic treatment. Two parameters of motility were studied, velocity and migration distance, using a time-lapse imaging system. The study revealed that compared to non-chemotherapeutically treated B-ALL cells, B-ALL cells that survived chemotherapy treatment after 7 days showed reduced motility. We had previously shown that Tysabri and P5G10, antibodies against the adhesion molecules integrins α4 and α6, respectively, may overcome drug resistance mediated through leukemia cell adhesion to bone marrow stromal cells. Therefore, we tested the effect of integrin α4 or α6 blockade on the motility of chemotherapeutics-treated ALL cells. Only integrin α4 blockade decreased the motility and velocity of two chemotherapeutics-treated ALL cell lines. Interestingly, integrin α6 blockade did not affect the velocity of chemoresistant ALL cells. This study explores the physical properties of the movements of chemoresistant B-ALL cells and highlights a potential link to integrins. Further studies to investigate the underlying mechanism are warranted.

The Carboniferous strata in the northeastern Junggar Basin are an important exploration field for natural gas in the basin. However, volcanic rocks have long been the primary exploration target. In contrast, the exploration and research of clastic rocks associated with source formations have been largely overlooked, resulting in an insufficient understanding of the reservoir forming conditions and exploration potential of Carboniferous clastic rocks. Through the evaluation of Carboniferous source rocks, effective source stove characterization, clastic reservoir evaluation, oil and gas source correlation, and reservoir formation model construction in this region, three key findings have been made. First, the Carboniferous in the northeastern Junggar Basin has developed three sets of high-quality gas source rocks: the Dishuiquan Formation, the Songkalsu B Member, and the Shiqiantan Formation. These formations correspond to three hydrocarbon source centers: the Sannan–Dishuiquan Sag, the Wucaiwan Sag–Dajing area, and the Dongdao Haizi Sag–Baijiahai High. Second, the Carboniferous system in the northeast has developed multiple types of large-scale reservoirs, including sand conglomerates, sandstones, turbidites, dolomitic rocks, and shale. These reservoirs are generally characterized by low porosity to ultra-low porosity and low permeability to ultra-low permeability reservoirs. There is a dissolution pore development zone at depths of 2900–4500 m. Third, a comparison of oil and gas sources reveals that all three sets of gas source rocks contribute to the natural gas found in the northeast, with obvious characteristics of near-source reservoir formation. The Carboniferous clastic rocks host two types of natural gas reservoirs: unconventional and conventional near-source reservoirs. It is predicted that there is an orderly accumulation pattern of shale gas, tight sandstone gas, and conventional natural gas reservoirs. This study reveals that the Carboniferous clastic rock source and reservoir configuration in the northeastern Junggar Basin is highly favorable, and the natural gas reservoirs in source and near-source clastic rocks represent important exploration directions.

Abstract In recent decades, research on Extracellular Vesicles (EVs) has gained prominence in the life sciences due to their critical roles in both health and disease states, offering promising applications in disease diagnosis, drug delivery, and therapy. However, their inherent heterogeneity and complex origins pose significant challenges to their preparation, analysis, and subsequent clinical application. This review is structured to provide an overview of the biogenesis, composition, and various sources of EVs, thereby laying the groundwork for a detailed discussion of contemporary techniques for their preparation and analysis. Particular focus is given to state‐of‐the‐art technologies that employ both microfluidic and non‐microfluidic platforms for EV processing. Furthermore, this discourse extends into innovative approaches that incorporate artificial intelligence and cutting‐edge electrochemical sensors, with a particular emphasis on single EV analysis. This review proposes current challenges and outlines prospective avenues for future research. The objective is to motivate researchers to innovate and expand methods for the preparation and analysis of EVs, fully unlocking their biomedical potential.

Summary: Background: There is ongoing debate about whether intraoperative parathyroid autotransplantation effectively prevents permanent hypoparathyroidism after thyroidectomy. This study aims to examine its impact on postoperative parathyroid function and determine the best autotransplantation strategy. Methods: A retrospective analysis was conducted on 194 patients who underwent total thyroidectomy with central lymph node dissection (CLND) for papillary thyroid carcinoma (PTC). Patients were divided into four groups based on the number of parathyroid autotransplants during surgery: Group 1 (none, n = 43), Group 2 (1 transplant, n = 60), Group 3 (2 transplants, n = 67), and Group 4 (3 transplants, n = 24). Various clinical parameters were collected and compared among the groups. Results: Parathyroid autotransplantation was identified as a risk factor for temporary hypoparathyroidism (OR: 1.74; 95% CI: 1.27–2.39, P = 0.001) and a protective factor for permanent hypoparathyroidism (OR: 0.27; 95% CI: 0.14–0.55, P

The accurate estimation of soil plant analytical development (SPAD) values in cotton under various intercropping patterns with soybean is crucial for monitoring cotton growth and determining a suitable intercropping pattern. In this study, we utilized an unmanned aerial vehicle (UAV) to capture visible (RGB) and multispectral (MS) data of cotton at the bud stage, early flowering stage, and full flowering stage in a cotton–soybean intercropping pattern in the Yellow River Delta region of China, and we used SPAD502 Plus and tapeline to collect SPAD and cotton plant height (CH) data of the cotton canopy, respectively. We analyzed the differences in cotton SPAD and CH under different intercropping ratio patterns. It was conducted using Pearson correlation analysis between the RGB features, MS features, and cotton SPAD, then the recursive feature elimination (RFE) method was employed to select image features. Seven feature sets including MS features (five vegetation indices + five texture features), RGB features (five vegetation indices + cotton cover), and CH, as well as combinations of these three types of features with each other, were established. Voting regression (VR) ensemble learning was proposed for estimating cotton SPAD and compared with the performances of three models: random forest regression (RFR), gradient boosting regression (GBR), and support vector regression (SVR). The optimal model was then used to estimate and visualize cotton SPAD under different intercropping patterns. The results were as follows: (1) There was little difference in the mean value of SPAD or CH under different intercropping patterns; a significant positive correlation existed between CH and SPAD throughout the entire growth period. (2) All VR models were optimal when each of the seven feature sets were used as input. When the features set was MS + RGB, the determination coefficient (R2) of the validation set of the VR model was 0.902, the root mean square error (RMSE) was 1.599, and the relative prediction deviation (RPD) was 3.24. (3) When the features set was CH + MS + RGB, the accuracy of the VR model was further improved, compared with the feature set MS + RGB, the R2 and RPD were increased by 1.55% and 8.95%, respectively, and the RMSE was decreased by 7.38%. (4) In the intercropping of cotton and soybean, cotton growing under 4:6 planting patterns was better. The results can provide a reference for the selection of intercropping patterns and the estimation of cotton SPAD.

In order to improve the accuracy of multispectral image inversion of soil and plant analytical development (SPAD) of the cotton canopy, image segmentation methods were utilized to remove the background interference, such as soil and shadow in UAV multispectral images. UAV multispectral images of cotton bud stage canopies at three different heights (30 m, 50 m, and 80 m) were acquired. Four methods, namely vegetation index thresholding (VIT), supervised classification by support vector machine (SVM), spectral mixture analysis (SMA), and multiple endmember spectral mixture analysis (MESMA), were used to segment cotton, soil, and shadows in the multispectral images of cotton. The segmented UAV multispectral images were used to extract the spectral information of the cotton canopy, and eight vegetation indices were calculated to construct the dataset. Partial least squares regression (PLSR), Random forest (FR), and support vector regression (SVR) algorithms were used to construct the inversion model of cotton SPAD. This study analyzed the effects of different image segmentation methods on the extraction accuracy of spectral information and the accuracy of SPAD modeling in the cotton canopy. The results showed that (1) The accuracy of spectral information extraction can be improved by removing background interference such as soil and shadows using four image segmentation methods. The correlation between the vegetation indices calculated from MESMA segmented images and the SPAD of the cotton canopy was improved the most; (2) At three different flight altitudes, the vegetation indices calculated by the MESMA segmentation method were used as the input variable, and the SVR model had the best accuracy in the inversion of cotton SPAD, with R2 of 0.810, 0.778, and 0.697, respectively; (3) At a flight altitude of 80 m, the R2 of the SVR models constructed using vegetation indices calculated from images segmented by VIT, SVM, SMA, and MESMA methods were improved by 2.2%, 5.8%, 13.7%, and 17.9%, respectively, compared to the original images. Therefore, the MESMA mixed pixel decomposition method can effectively remove soil and shadows in multispectral images, especially to provide a reference for improving the inversion accuracy of crop physiological parameters in low-resolution images with more mixed pixels.

As the largest hydrocarbon-rich sag in the Junggar Basin, the limited research on geochemical characteristics, sedimentary environment and bio-precursors of source rocks in the Fukang Sag has seriously restricted the understanding of the poor proven oil and gas resources in the sag. A combined geological and geochemical analysis on the Lucaogou Formation source rocks in the Fukang Sag was conducted based on the experimental analysis results of the newly drilled source rock samples on the Fudong Slope. The results show that the Lucaogou Formation source rocks in the Fukang Sag generally belong to source rocks of medium to very good quality, with organic matter of type Ⅱ to type Ⅲ, and mainly in the thermal maturity of early mature to mature stage. Biomarker characteristics show that the organic matter of Lucaogou Formation source rocks in the Fukang Sag is a mixture of terrestrial higher plants and aquatic algae and bacteria and maybe some Dunaliella-like green algae, which is generally deposited in the anoxic to oxic, fresh to brackish, intermittent stratified water environment, showing obvious mudstone sedimentary characteristics. The geochemical characteristics of the Lucaogou Formation source rocks in the Fukang Sag vary greatly on the plane, among which, the central and northern subsags show great hydrocarbon generation potential.

Abstract Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear. Methods LC–MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC–MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype. Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis. Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.

Abstract Human activities, including urbanization, industrialization, agricultural pollution, and land use, have contributed to the increased fragmentation of natural habitats and decreased biodiversity in Zhejiang Province as a result of socioeconomic development. Numerous studies have demonstrated that the protection of ecologically significant species can play a crucial role in restoring biodiversity. Emeia pseudosauteri is regarded as an excellent environmental indicator, umbrella and flagship species because of its unique ecological attributes and strong public appeal. Assessing and predicting the potential suitable distribution area of this species in Zhejiang Province can help in the widespread conservation of biodiversity. We used the MaxEnt ecological niche model to evaluate the habitat suitability of E. pseudosauteri in Zhejiang Province to understand the potential distribution pattern and environmental characteristics of suitable habitats for this species, and used the AUC (area under the receiver operating characteristic curve) and TSS (true skill statistics) to evaluate the model performance. The results showed that the mean AUC value was 0.985, the standard deviation was 0.011, the TSS average value was 0.81, and the model prediction results were excellent. Among the 11 environmental variables used for modeling, temperature seasonality (Bio_4), altitude (Alt) and distance to rivers (Riv_dis) were the key variables affecting the distribution area of E. pseudosauteri, with contributions of 33.5%, 30% and 15.9%, respectively. Its main suitable distribution area is in southern Zhejiang Province and near rivers, at an altitude of 50–300 m, with a seasonal variation in temperature of 7.7–8 °C. Examples include the Ou River, Nanxi River, Wuxi River, and their tributary watersheds. This study can provide a theoretical basis for determining the scope of E. pseudosauteri habitat protection, population restoration, resource management and industrial development in local areas.

Abstract In order to improve the low output accuracy caused by the elastic deformations of the branch chains, a finite element-based dynamic accuracy analysis method for parallel mechanisms is proposed in this paper. First, taking a 5-prismatic-spherical-spherical (PSS)/universal-prismatic-universal (UPU) parallel mechanism as an example, the error model is established by a closed vector chain method, while its influence on the dynamic accuracy of the parallel mechanism is analyzed through numerical simulation. According to the structural and error characteristics of the parallel mechanism, a vector calibration algorithm is proposed to reduce the position and pose errors along the whole motion trajectory. Then, considering the elastic deformation of the rod, the rigid-flexible coupling dynamic equations of each component are established by combining the finite element method with the Lagrange method. The elastodynamic model of the whole machine is obtained based on the constraint condition of each moving part, and the correctness of the model is verified by simulation. Moreover, the effect of component flexibility on the dimensionless root mean square error of the displacement, velocity and acceleration of the moving platform is investigated by using a Newmark method, and the mapping relationship of these dimensionless root mean square errors to dynamic accuracy is further studied. The research work provides a theoretical basis for the design of the parameter size of the prototype.

Abstract Robot manipulators perform a point-point task under kinematic and dynamic constraints. Due to multi-degree-of-freedom coupling characteristics, it is difficult to find a better desired trajectory. In this paper, a multi-objective trajectory planning approach based on an improved elitist non-dominated sorting genetic algorithm (INSGA-II) is proposed. Trajectory function is planned with a new composite polynomial that by combining of quintic polynomials with cubic Bezier curves. Then, an INSGA-II, by introducing three genetic operators: ranking group selection (RGS), direction-based crossover (DBX) and adaptive precision-controllable mutation (APCM), is developed to optimize travelling time and torque fluctuation. Inverted generational distance, hypervolume and optimizer overhead are selected to evaluate the convergence, diversity and computational effort of algorithms. The optimal solution is determined via fuzzy comprehensive evaluation to obtain the optimal trajectory. Taking a serial-parallel hybrid manipulator as instance, the velocity and acceleration profiles obtained using this composite polynomial are compared with those obtained using a quintic B-spline method. The effectiveness and practicability of the proposed method are verified by simulation results. This research proposes a trajectory optimization method which can offer a better solution with efficiency and stability for a point-to-point task of robot manipulators.

During last two decades, transition-metal catalyzed asymmetric reactions under continuous flow system have attracted a widespread attention. With its prominent advantages including higher safety and efficiency, precise control, better heat/mass transfer, easier scale-up and better sustainability, it has impressed both the academia and related industries. However, comparing with the prosperous development of transition-metal catalyzed asymmetric reactions in batch, utilization of this type of chemistry under continuous flow is still at an early stage. To inspire more potential industrial application and further studies of this chemistry in flow, this review summarized the recent advances of transition-metal catalyzed asymmetric reactions under continuous flow. Moreover, we further discussed the encountered challenges including reactor engineering, catalyst design, catalyst deactivation, pressure drop, clogging, side reactions etc., as well as their corresponding solutions and achievements in this mini-review.

Abstract To study the characteristics of the 5-prismatic–spherical–spherical (PSS)/universal–prismatic–universal (UPU) parallel mechanism with elastically active branched chains, the dynamics modeling and solutions of the parallel mechanism were investigated. First, the active branched chains and screw sliders were considered as spatial beam elements and plane beam element models, respectively, and the dynamic equations of each element model were derived using the Lagrange method. Second, the equations of the 5-PSS/UPU parallel mechanism were obtained according to the kinematic coupling relationship between the active branched chains and moving platform. Finally, based on the parallel mechanism dynamic equations, the natural frequency distribution of the 5-PSS/UPU parallel mechanism in the working space and elastic displacement of the moving platform were obtained. The results show that the natural frequency of the 5-PSS/UPU parallel mechanism under a given motion situation is greater than its operating frequency. The maximum position error is − 0.096 mm in direction Y, and the maximum orientation error is − 0.29° around the X-axis. The study provides important information for analyzing the dynamic performance, dynamic optimization design, and dynamic control of the 5-PSS/UPU parallel mechanism with elastically active branched chains.

ABT-737 is a pan-Bcl-2 inhibitor that has a wide range of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. A relationship between expression of myeloid cell leukemia 1 (Mci-i), an antiapoptotic member of the Bci-2 family of proteins, and resistance to ABT-737 has been reported for various cancers. The synthetic cytotoxic retinoid N-(4-hydroxyphenyi)retinamide (4-HPR) is known to generate reactive oxygen species (ROS), and ROS have been shown to activate c-Jun kinase (JNK), which in turn phosphorylates and inhibits Mci-i. Thus, we investigated whether 4-HPR-mediated inactivation of Mci-i could act synergistically with ABT-737 to promote leukemia cell death. Cytotoxicity was determined using the fluorescence-based DIMSCAN assay. Synergy was defined as a combination index (CIN) less than 1. The expression of Bcl-2 family messenger RNAs was measured by real-time reverse transcription-polymerase chain reaction, and caspase activity was measured enzymati- cally. Changes in Bcl-2 family proteins and release of mitochondrial cytochrome cwere detected by immu- noblotting. ROS, apoptosis, mitochondrial membrane depolarization, and phospho-JNK were measured by flow cytometry. Gene silencing was by small interfering RNA (siRNA). All statistical tests were two-sided. ABT-737 decreased Mci-i protein expression in ABT-737--sensitive ALL cell lines but not in ABT-737-resistant lines. Using the antioxidant ascorbic acid and siRNA-mediated knockdown of JNK, we showed that 4-HPR decreased Mci-i via ROS generation (that phosphorylates JNK) in ABT-737-resistant cell lines. Combining ABT-737 with 4-HPR enhanced the mitochondrial apoptotic cascade (percentage of cells with depolarized mitochondrial membrane at 6 hours, ABT-737 vs ABT-737 plus 4-HPR: 24.5% vs 45.5%, difference = 20.1%, 95% Cl = 18.9% to i3.9%; P< .001) arid caused caspase-dependent, synergistic multilog cytotoxicity in all seven ALL cell lines examined (mean CIN = 0.57, 95% Cl = 0.37 to 0.87), with minimal cytotoxicity for nor- mal lymphocytes. An increase of Mci-i protein in response to ABT-737 is one mechanism of ABT-737 resistance that can be overcome by 4-HPR, resulting in synergistic cytotoxicity of ABT-737 combined with 4-HPR in ALL cell lines. [ABSTRACT FROM AUTHOR]

Background Genes that are overexpressed in multidrug-resistant neuroblastomas relative to drug-sensitive neuroblastomas may provide targets for modulating drug resistance. Methods We used microarrays to compare the gene expression profile of two drug-sensitive neuroblastoma cell lines with that of three multidrug-resistant neuroblastoma cell lines. RNA expression of selected overexpressed genes was quantified in 17 neuroblastoma cell lines by reverse transcription—polymerase chain reaction (RT-PCR). Small-interfering RNAs (siRNAs) were used for silencing gene expression. Cytotoxicity of melphalan, carboplatin, etoposide, and vincristine and cytotoxic synergy (expressed as combination index calculated by CalcuSyn software, where combination index < 1 indicates synergy and >1 indicates antagonism) were measured in cell lines with a fluorescence-based assay of cell viability. All statistical tests were two-sided. Results A total of 94 genes were overexpressed in the multidrug-resistant cell lines relative to the drug-sensitive cell lines. Nine genes were selected for RT-PCR analysis, of which four displayed higher mRNA expression in the multidrug-resistant lines than in the drug-sensitive lines: histone deacetylase 1 (HDAC1; 2.3-fold dif- ference, 95% confidence interval [CI] = 1.0-fold to 3.5-fold, P = .025), nuclear transport factor 2-like export factor (4.2-fold difference, 95% CI = 1.7-fold to 7.6-fold, P = .0018), heat shock 27-kDa protein 1(2.5-fold difference, 95% CI = 1.0-fold to 87.7-fold, P = .028), and TAF12 RNA polymerase II, TATA box—binding protein—associated factor, 20 kDa (2.2-fold, 95% CI = 0.9-fold to 6.0-fold, P = .051). siRNA knockdown of HDAC1 gene expression sensitized CHLA-136 neuroblastoma cells to etoposide up to fivefold relative to the parental cell line or scrambled siRNA—transfected cells (P<.001). Cytotoxicity of the histone deacetylase inhibitor depsipeptide was tested in combination with melphalan, carboplatin, etoposide, or vincristine in five multidrug-resistant neuroblastoma cell lines, and synergistic cytotoxicity was demonstrated at a 90% cell kill of treated cells (combination index < 0.8) in all cell lines. Conclusion High HDAC1 mRNA expression was correlated with multidrug resistance in neuroblastoma cell lines, and inhibition of HDAC1 expression or activity enhanced the cytotoxicity of chemotherapeutic drugs in multidrug—resistant neuroblastoma cell lines. Thus, HDAC1 is a potential therapeutic target in multidrug—resistant neuroblastoma. [ABSTRACT FROM AUTHOR]