Electrically pumped topological laser with valley edge modes.

Quantum cascade lasers are compact, electrically pumped light sources in the technologically important mid-infrared and terahertz region of the electromagnetic spectrum1,2. Recently, the concept of topology3 has been expanded from condensed matter physics into photonics4, giving rise to a new type of lasing5-8 using topologically protected photonic modes that can efficiently bypass corners and defects4. Previous demonstrations of topological lasers have required an external laser source for optical pumping and have operated in the conventional optical frequency regime5-8. Here we demonstrate an electrically pumped terahertz quantum cascade laser based on topologically protected valley edge states9-11. Unlike topological lasers that rely on large-scale features to impart topological protection, our compact design makes use of the valley degree of freedom in photonic crystals10,11, analogous to two-dimensional gapped valleytronic materials12. Lasing with regularly spaced emission peaks occurs in a sharp-cornered triangular cavity, even if perturbations are introduced into the underlying structure, owing to the existence of topologically protected valley edge states that circulate around the cavity without experiencing localization. We probe the properties of the topological lasing modes by adding different outcouplers to the topological cavity. The laser based on valley edge states may open routes to the practical use of topological protection in electrically driven laser sources.

Exploring Chemical Reaction Space with Machine Learning Models: Representation and Feature Perspective.

Chemical reactions serve as foundational building blocks for organic chemistry and drug design. In the era of large AI models, data-driven approaches have emerged to innovate the design of novel reactions, optimize existing ones for higher yields, and discover new pathways for synthesizing chemical structures comprehensively. To effectively address these challenges with machine learning models, it is imperative to derive robust and informative representations or engage in feature engineering using extensive data sets of reactions. This work aims to provide a comprehensive review of established reaction featurization approaches, offering insights into the selection of representations and the design of features for a wide array of tasks. The advantages and limitations of employing SMILES, molecular fingerprints, molecular graphs, and physics-based properties are meticulously elaborated. Solutions to bridge the gap between different representations will also be critically evaluated. Additionally, we introduce a new frontier in chemical reaction pretraining, holding promise as an innovative yet unexplored avenue.

CMNPD: a comprehensive marine natural products database towards facilitating drug discovery from the ocean.

Marine organisms are expected to be an important source of inspiration for drug discovery after terrestrial plants and microorganisms. Despite the remarkable progress in the field of marine natural products (MNPs) chemistry, there are only a few open access databases dedicated to MNPs research. To meet the growing demand for mining and sharing for MNPs-related data resources, we developed CMNPD, a comprehensive marine natural products database based on manually curated data. CMNPD currently contains more than 31 000 chemical entities with various physicochemical and pharmacokinetic properties, standardized biological activity data, systematic taxonomy and geographical distribution of source organisms, and detailed literature citations. It is an integrated platform for structure dereplication (assessment of novelty) of (marine) natural products, discovery of lead compounds, data mining of structure-activity relationships and investigation of chemical ecology. Access is available through a user-friendly web interface at https://www.cmnpd.org. We are committed to providing a free data sharing platform for not only professional MNPs researchers but also the broader scientific community to facilitate drug discovery from the ocean.

Tailorable infrared emission of microelectromechanical system-based thermal emitters with NiO films for gas sensing.

Infrared gas sensors hold great promise in the internet of things and artificial intelligence. Making infrared light sources with miniaturized size, reliable and tunable emission is essential but remains challenging. Herein, we present the tailorability of radiant power and the emergence of new emission wavelength of microelectromechanical system (MEMS)-based thermal emitters with nickel oxide (NiO) films. The coating of NiO on emitters increases top surface emissivity and induces the appearance of new wavelengths between 15 and 19 µm, all of which have been justified by spectroscopic methods. Furthermore, a sensor array is assembled for simultaneous monitoring of concentrations of carbon dioxide (CO2), methane (CH4), humidity, and temperature. The platform shows selective and sensitive detection at room temperature toward CO2 and CH4 with detection limits of around 50 and 1750 ppm, respectively, and also shows fast response/recovery and good recyclability. The demonstrated emission tailorability of MEMS emitters and their usage in sensor array provide novel insights for designing and fabricating optical sensors with good performance, which is promising for mass production and commercialization.

Chemical Space, Scaffolds, and Halogenated Compounds of CMNPD: A Comprehensive Chemoinformatic Analysis.

The comprehensive marine natural products database (CMNPD) is a new free access and comprehensive database developed originally by Lyu's team of our research group, including more than 30 000 marine natural products (MNPs) reported from the 1960s. In this article, we aimed to present CMNPD's value in drug discovery and to present several characteristics of MNPs based on our new comprehensive data. We used chemoinformatic analysis methods to report the molecular properties, chemical space, and several scaffold assessments of CMNPD compared with several databases. Then, we reported the characteristics of MNPs from the aspect of halogens, comparing MNPs with terrestrial natural products (TNPs) and drugs. We found that CMNPD had a low proportion (2.91%) of scaffolds utilized by drugs, and high similarities between CMNPD and NPAtlas (a microbial natural products database), which are worth further investigation. The proportion of bromides in MNPs is outstandingly higher (11.0%) in contrast to other halogens. Furthermore, the results showed great differences in halogenated structures between MNPs and drugs, especially brominated substructures. Finally, we found that many marine species (2.52%) reported only halogenated compounds. It can be concluded from these results that CMNPD is a promising source for drug discovery and has many scientific issues relative to MNPs that need to be further investigated.

Radiological Society of North America/Quantitative Imaging Biomarker Alliance Shear Wave Speed Bias Quantification in Elastic and Viscoelastic Phantoms.

OBJECTIVES: To quantify the bias of shear wave speed (SWS) measurements between different commercial ultrasonic shear elasticity systems and a magnetic resonance elastography (MRE) system in elastic and viscoelastic phantoms. METHODS: Two elastic phantoms, representing healthy through fibrotic liver, were measured with 5 different ultrasound platforms, and 3 viscoelastic phantoms, representing healthy through fibrotic liver tissue, were measured with 12 different ultrasound platforms. Measurements were performed with different systems at different sites, at 3 focal depths, and with different appraisers. The SWS bias across the systems was quantified as a function of the system, site, focal depth, and appraiser. A single MRE research system was also used to characterize these phantoms using discrete frequencies from 60 to 500 Hz. RESULTS: The SWS from different systems had mean difference 95% confidence intervals of ±0.145 m/s (±9.6%) across both elastic phantoms and ± 0.340 m/s (±15.3%) across the viscoelastic phantoms. The focal depth and appraiser were less significant sources of SWS variability than the system and site. Magnetic resonance elastography best matched the ultrasonic SWS in the viscoelastic phantoms using a 140 Hz source but had a - 0.27 ± 0.027-m/s (-12.2% ± 1.2%) bias when using the clinically implemented 60-Hz vibration source. CONCLUSIONS: Shear wave speed reconstruction across different manufacturer systems is more consistent in elastic than viscoelastic phantoms, with a mean difference bias of < ±10% in all cases. Magnetic resonance elastographic measurements in the elastic and viscoelastic phantoms best match the ultrasound systems with a 140-Hz excitation but have a significant negative bias operating at 60 Hz. This study establishes a foundation for meaningful comparison of SWS measurements made with different platforms.

Target Prediction Model for Natural Products Using Transfer Learning.

A large proportion of lead compounds are derived from natural products. However, most natural products have not been fully tested for their targets. To help resolve this problem, a model using transfer learning was built to predict targets for natural products. The model was pre-trained on a processed ChEMBL dataset and then fine-tuned on a natural product dataset. Benefitting from transfer learning and the data balancing technique, the model achieved a highly promising area under the receiver operating characteristic curve (AUROC) score of 0.910, with limited task-related training samples. Since the embedding distribution difference is reduced, embedding space analysis demonstrates that the model's outputs of natural products are reliable. Case studies have proved our model's performance in drug datasets. The fine-tuned model can successfully output all the targets of 62 drugs. Compared with a previous study, our model achieved better results in terms of both AUROC validation and its success rate for obtaining active targets among the top ones. The target prediction model using transfer learning can be applied in the field of natural product-based drug discovery and has the potential to find more lead compounds or to assist researchers in drug repurposing.

Far-field controllable excitation of phonon polariton via nanostructure engineering.

Hexagonal boron nitride (h-BN) as a natural mid-infrared (mid-IR) hyperbolic material which supports a strong excitation of phonon polariton (PhP) has enabled a new class of photonic devices with unprecedented functionalities. The hyperbolic property of h-BN has not only brought in new physical insights but also spurred potential applications. However, most of the current h-BN devices are designed repying on near-field excitation and manipulation of PhP. For fully realizing the potentials of h-BN, research on far-field controllable excitation and control of PhP is important for future integrated photonic devices. In this work, we exploit the designs of controllable far-field excitation of PhP in nanostructure-patterned h-BN thin film for deep subwavelength focusing (FWHM∼λ0/14.9) and interference patterns of 1D (FWHM∼λ0/52) and 2D standing waves (FWHM∼λ0/36.8) which find great potential for super-resolution imaging beyond diffraction limit. These polaritonic patterns could be easily tuned remotely by manipulating the polarization and phase of incident laser. This approach provides a novel platform for practical IR nanophotonic devices and potential applications in mid-IR bio-imaging and sensing.

Effects of Artesunate on the Expressions of Insulin-Like Growth Factor-1, Osteopontin and C-Telopeptides of Type II Collagen in a Rat Model of Osteoarthritis.

OBJECTIVE: The study aims to explore the effects of artesunate on insulin-like growth factor-1 (IGF-1), Osteopontin (OPN), and C-telopeptides of type II collagen (CTX-II) in serum, synovial fluid (SF), and cartilage tissues of rats with osteoarthritis (OA). METHODS: OA models were established. Normal model, artesunate, and Viatril-S groups (20 rats respectively) were set. Enzyme-linked immunosorbent assay, IHC staining, and quantitative real-time polymerase chain reaction were conducted to calculate IGF-1, OPN, and CTX-II levels in serum, SF, and cartilage tissues of rats. The pathological changes in cartilage tissues were evaluated with Mankin score and Hematoxylin-Eosin staining. RESULTS: Compared with the normal group, the model group showed increased IGF-1 level; decreased OPN, CTX-II levels in the serum and SF; and contrary results were seen in the cartilage tissues. A gradual ascending IGF-1 level and descending OPN and CTX-II levels existed in the serum and SF in the artesunate and Viatril-S groups after 2 weeks. The model group showed the most obvious pathological changes and highest Mankin score compared with the other groups. Higher IGF-1 level and lower OPN, CTX-II levels were exhibited in the cartilage tissue in the artesunate and Viatril-S groups but not in the model group. CONCLUSION: Artesunate and Viatril-S inhibit OA development by elevating IGF-1 level and reducing OPN and CTX-II levels.

RNA-binding Protein UNR Promotes Glioma Cell Migration and Regulates the Expression of Ribosomal Protein L9.

Objective To investigate the role of RNA binding protein─upstream-of-N-Ras (UNR) in the development of glioma and its molecular mechanism.Methods First, bioinformatics analysis of CGGA database was performed to detect UNR expression level and prognosis of patients with glioma. Western blot and real-time PCR were used to detect UNR expression level in glioma cell lines and tissues. Next, UNR siRNAs were transfected in glioma cells, and MTS assay and scratch wound-healing assay were used to detect changes in cell proliferation and migration. Then, the candidate UNR target mRNAs were identified by analyzing the sequencing data of UNR iCLIP-seq, RNA sequencing and ribosome profiling databases of human melanoma. RNA immunoprecipitation and biotin pull-down assays were used to identify the UNR target mRNAs in glioma cells. Finally, western blot was used to detect the effect of UNR knockdown on ribosomal protein L9 (RPL9) and RPL9 protein expression level in glioma cell lines. RPL9 siRNA was transfected in A172 and T98G and the expression of vimentin in the cells was detected with western blot.Results Bioinformatics analysis showed that UNR mRNA expression level was significantly higher in high-grade glioma [Grade 2 (n=126), Grade 3 (n=51), Grade 4 (n=128), P<0.001]. UNR high expression levels were associated with poor prognosis (P=0.0177). UNR had high expression level in glioma cell lines and patient samples compared with normal cell lines and normal brain samples (P<0.01). Knockdown of UNR inhibited glioma cells migration (P<0.05), but did not inhibit glioma cells growth in three glioma cell lines. UNR binded the 3' untranslated region (UTR) of PTEN and RPL9 mRNAs. RPL9 protein was significantly highly expressed in most glioma cell lines (n=9) and knockdown of UNR resulted in a downregulation of RPL9 protein expression. Epithelial-mesenchymal transition (EMT)-related marker─vimentin was positively regulated by RPL9.Conclusions UNR could bind to the 3'UTR of PTEN and RPL9 in glioma cell lines, therefore promoting glioma cell migration and regulating the expression of RPL9. Here, we establish a link between UNR and RPL9 protein, which will provide new ideas for the further study of glioma.

Coherent emission from integrated Talbot-cavity quantum cascade lasers.

We report experimental realization of phase-locked quantum cascade laser (QCL) array using a monolithically integrated Talbot cavity. An array with six laser elements at a wavelength of ~4.8 µm shows a maximum peak power of ~4 W which is more than 5 times higher than that of a single ridge laser element and a slope efficiency of 1 W/A at room temperature. Operation of in-phase coherent supermode has been achieved over the whole dynamic range of the Talbot-cavity QCL. The structure was analysed using a straightforward theoretical model, showing quantitatively good agreement with the experimental results. The reduced thermal resistance makes the structure an attractive approach to achieve high beam quality continuous wave QCLs.

Enhanced light-matter interaction in atomically thin MoS2 coupled with 1D photonic crystal nanocavity.

Engineering the surrounding electromagnetic environment of light emitters by photonic engineering, e.g. photonic crystal cavity, can dramatically enhance its spontaneous emission rate through the Purcell effect. Here we report an enhanced spontaneous emission rate of monolayer molybdenum disulfide (MoS2) by coupling it to a 1D silicon nitride photonic crystal. A four times stronger photoluminescence (PL) intensity of MoS2 in a 1D photonic crystal cavity than un-coupled emission is observed. Considering the relative ease of fabrication and the natural integration with a silicon-based system, the high Purcell factor renders this device as a highly promising platform for applications such as visible solid-state cavity quantum electrodynamics (QED).

Microwave ablation versus hepatic resection for the treatment of hepatocellular carcinoma and oesophageal variceal bleeding in cirrhotic patients.

PURPOSE: The aim of this study was to compare the results of microwave ablation (MWA) and hepatic resection (HR) when combined with pericardial devascularisation plus splenectomy (PCDV) for the treatment of patients with cirrhosis complicated by small hepatocellular carcinoma (HCC) and oesophageal variceal bleeding (EVB). MATERIALS AND METHODS: Between 2001 and 2013, 73 patients (median age 53.2 years, 67% male) with small HCC and concomitant EVB who underwent MWA or HR for HCC and PCDV for cirrhotic portal hypertension were selected retrospectively for inclusion in this study. The overall survival curves and recurrence-free survival curves were calculated using the Kaplan-Meier method and compared using log-rank tests. Multivariate analysis was performed using the Cox regression model. RESULTS: The 1-, 3- and 5-year overall survival rates were 95.2%, 71.4% and 38.1% and 96.7%, 53.3% and 43.3% for the HR and MWA groups, respectively; these did not differ significantly between the two groups. However, patients in the HR group had more post-operative complications (52.3% vs. 13.7%; p = 0.002). Multivariate analysis identified albumin and bilirubin levels and tumour size to be statistically significant and independent prognostic factors for overall survival, while BCLC stage was associated with poor recurrence-free survival. Furthermore, albumin levels were shown to be an independent predictive factor for post-operative complications. CONCLUSIONS: For patients with small HCC and concomitant EVB, MWA plus PCDV may reduce the incidence of post-operative complications relative to and provide similar therapeutic benefits as HR plus PCDV, especially for patients with low albumin levels.

Automated T-wave analysis can differentiate acquired QT prolongation from congenital long QT syndrome.

BACKGROUND: Prolongation of the QT on the surface electrocardiogram can be due to either genetic or acquired causes. Distinguishing congenital long QT syndrome (LQTS) from acquired QT prolongation has important prognostic and management implications. We aimed to investigate if quantitative T-wave analysis could provide a tool for the physician to differentiate between congenital and acquired QT prolongation. METHODS: Patients were identified through an institution-wide computer-based QT screening system which alerts the physician if the QTc ≥ 500 ms. ECGs were retrospectively analyzed with an automated T-wave analysis program. Congenital LQTS was compared in a 1:3 ratio to those with an identified acquired etiology for QT prolongation (electrolyte abnormality and/or prescription of known QT prolongation medications). Linear discriminant analysis was performed using 10-fold cross-validation to statistically test the selected features. RESULTS: The 12-lead ECG of 38 patients with congenital LQTS and 114 patients with drug-induced and/or electrolyte-mediated QT prolongation were analyzed. In lead V5 , patients with acquired QT prolongation had a shallower T wave right slope (-2,322 vs. -3,593 mV/s), greater T-peak-Tend interval (109 vs. 92 ms), and smaller T wave center of gravity on the x axis (290 ms vs. 310 ms; p < .001). These features could distinguish congenital from acquired causes in 77% of cases (sensitivity 90%, specificity 58%). CONCLUSION: T-wave morphological analysis on lead V5 of the surface ECG could successfully differentiate congenital from acquired causes of QT prolongation.

High-mobility group protein box1 expression correlates with peritumoral macrophage infiltration and unfavorable prognosis in patients with hepatocellular carcinoma and cirrhosis.

BACKGROUND: High-mobility group protein box1 (HMGB1) is a pivotal factor in the development and progression of many types of tumor. Its role in hepatocellular carcinoma (HCC), and especially its correlation with intratumoral and peritumoral macrophage infiltration, remains obscure. We analyzed the potential roles and prognostic value of HMGB1 and explored the correlation between HMGB1 and macrophage infiltration in HCC using clinical samples. METHODS: We reviewed clinicopathological and follow-up data on a cohort of 149 patients with HCC complicated with Hepatitis B-related cirrhosis. We measured the expression of HMGB1 and CD68 in tumoral and peritumoral liver tissues after curative resection and assessed the impacts of the tumor-associated macrophage (TAM) count and HMGB1 expression on clinicopathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). RESULTS: Ninety-four of the patients had elevated tumoral HMGB1 expression and 59 of the patients had elevated peritumoral HMGB1 expression, compared to only 4 patients with elevated peritumoral HMGB1 expression in 36 pateints with Hepatitis B virus (HBV)-negative HCC without liver cirrhosis (p < 0.001). The peritumoral HMGB1 expression levels were correlated with tumor invasiveness, BCLC stage, and recurrence. The degree of TAM infiltration was higher in peritumoral tissues with high HMGB1 expression than in peritumoral tissues with low HMGB1 expression (p < 0.001). There was no significant difference in TAM infiltration between tumoral tissues with high and low HMGB1 expression. Kaplan-Meier analysis showed that intratumoral HMGB1 overexpression was associated with poor OS, but not with RFS. High peritumoral HMGB1expression and TAM count, which correlated positively with tumor size and BCLC stage, were independent prognostic factors for OS (p < 0.001 and p = 0.017, respectively) and RFS (p = 0.002 and p = 0.024, respectively). Multivariate analyses indicated peritumoral HMGB1 expression (p = 0.014) and TAM count (p = 0.037), as well as tumor differentiation (p = 0.026), to be independent significant prognostic factors for RFS. CONCLUSIONS: High HMGB1 expression in peritumoral liver tissues correlated with peritumoral macrophage infiltration and had prognostic value in HCC, suggesting that peritumoral HMGB1 might show promise as a new biomarker to predict HCC progression.

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

INTRODUCTION: Initiation of class III anti-arrhythmic medications requires telemetric monitoring for ventricular arrhythmias and QT prolongation to reduce the risk of torsades de pointes (TdP). Heart rate-corrected QT interval (QTc) is an indicator of risk, however it is imperfect, and subtle abnormalities of repolarization have been linked with arrhythmogenesis. PURPOSE: Identification of electrocardiographic predictors of torsadogenic risk through the application of a novel T wave analysis tool. METHODS: Among all patients admitted to Mayo Clinic for initiation of dofetilide or sotalol, we identified 13 cases who developed drug-induced TdP and 26 age and sex matched controls that did not develop TdP. The immediate pre-TdP ECG of those with TdP was compared to the last ECG performed prior to hospital discharge in controls using a novel T wave program that quantified subtle changes in T wave morphology. RESULTS: The QTc and 12 T wave parameters successfully distinguished TdP cases from controls. The top performing parameters were the QTc in lead V3 (mean case vs control 480 vs 420 msec, p < 0.001, r = 0.72) and T wave right slope in lead I (mean case vs control -840.29 vs -1668.71 mV/s, p = 0.002, r = 0.45). The addition of T wave right slope to QTc improved prediction accuracy from 79 to 88 %. CONCLUSION: Our data demonstrate that, in addition to QTc, the T wave right slope is correlated strongly with TdP risk. This suggests that a computer-based repolarization measurement tool that integrates additional data beyond the QTc may identify patients with the greatest torsadogenic potential.

Characterization of material properties of soft solid thin layers with acoustic radiation force and wave propagation.

Evaluation of tissue engineering constructs is performed by a series of different tests. In many cases it is important to match the mechanical properties of these constructs to those of native tissues. However, many mechanical testing methods are destructive in nature which increases cost for evaluation because of the need for additional samples reserved for these assessments. A wave propagation method is proposed for characterizing the shear elasticity of thin layers bounded by a rigid substrate and fluid-loading, similar to the configuration for many tissue engineering applications. An analytic wave propagation model was derived for this configuration and compared against finite element model simulations and numerical solutions from the software package Disperse. The results from the different models found very good agreement. Experiments were performed in tissue-mimicking gelatin phantoms with thicknesses of 1 and 4 mm and found that the wave propagation method could resolve the shear modulus with very good accuracy, no more than 4.10% error. This method could be used in tissue engineering applications to monitor tissue engineering construct maturation with a nondestructive wave propagation method to evaluate the shear modulus of a material.

Deep-Learning-Driven Discovery of SN3-1, a Potent NLRP3 Inhibitor with Therapeutic Potential for Inflammatory Diseases.

The NLRP3 inflammasome plays a central role in the pathogenesis of various intractable human diseases, making it an urgent target for therapeutic intervention. Here, we report the development of SN3-1, a novel orally potent NLRP3 inhibitor, designed through a lead compound strategy centered on deep-learning-based molecular generative models. Our strategy enables rapid fragment enumeration and takes into account the synthetic accessibility of the compounds, thereby significantly enhancing the optimization of lead compounds and facilitating the discovery of potent inhibitors. X-ray crystallography provided insights into the SN3-1 inhibitory mechanism. SN3-1 has shown a favorable safety profile in both acute and chronic toxicity assessments and exhibits robust pharmacokinetic properties. Furthermore, SN3-1 demonstrated significant therapeutic efficacy in various disease models characterized by NLRP3 activation. This study introduces a potent candidate for developing NLRP3 inhibitors and significantly expands the repertoire of tools available for the discovery of novel inhibitors.

Design, synthesis, and pharmacological characterization of sulfonylurea-based NLRP3 inhibitors: Towards an effective therapeutic strategy for Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.

Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice.

BACKGROUND & AIMS: Antiangiogenic agents can sometimes promote tumor invasiveness and metastasis, but little is known about the effects of the antiangiogenic drug sorafenib on progression of hepatocellular carcinoma (HCC). METHODS: Sorafenib was administered orally (30 mg · kg(-1) · day(-1)) to mice with orthotopic tumors grown from HCC-LM3, SMMC7721, or HepG2 cells. We analyzed survival times of mice, along with tumor growth, metastasis within liver and to lung, and induction of the epithelial-mesenchymal transition. Polymerase chain reaction arrays were used to determine the effects of sorafenib on gene expression patterns in HCC cells. We analyzed regulation of HIV-1 Tat interactive protein 2 (HTATIP2) by sorafenib and compared levels of this protein in tumor samples from 75 patients with HCC (21 who received sorafenib after resection and 54 who did not). RESULTS: Sorafenib promoted invasiveness and the metastatic potential of orthotopic tumors grown from SMMC7721 and HCC-LM3 cells but not from HepG2 cells. In gene expression analysis, HTATIP2 was down-regulated by sorafenib. HCC-LM3 cells that expressed small hairpin RNAs against HTATIP2 (knockdown) formed less invasive tumors in mice following administration of sorafenib than HCC-LM3 without HTATIP2 knockdown. Alternatively, HepG2 cells that expressed transgenic HTATIP2 formed more invasive tumors in mice following administration of sorafenib. Sorafenib induced the epithelial-mesenchymal transition in HCC cell lines, which was associated with expression of HTATIP2. Sorafenib regulated expression of HTATIP2 via Jun-activated kinase (JAK) and signal transducer and activator of transcription (STAT)3 signaling. Sorafenib therapy prolonged recurrence-free survival in patients who expressed lower levels of HTATIP2 compared with higher levels. CONCLUSIONS: Sorafenib promotes invasiveness and the metastatic potential of orthotopic tumors from HCC cells in mice, down-regulating expression of HTATIP2 via JAK-STAT3 signaling.