Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities.

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

The genomic history and global migration of a windborne pest.

Many insect pests, including the brown planthopper (BPH), undergo windborne migration that is challenging to observe and track. It remains controversial about their migration patterns and largely unknown regarding the underlying genetic basis. By analyzing 360 whole genomes from around the globe, we clarify the genetic sources of worldwide BPHs and illuminate a landscape of BPH migration showing that East Asian populations perform closed-circuit journeys between Indochina and the Far East, while populations of Malay Archipelago and South Asia undergo one-way migration to Indochina. We further find round-trip migration accelerates population differentiation, with highly diverged regions enriching in a gene desert chromosome that is simultaneously the speciation hotspot between BPH and related species. This study not only shows the power of applying genomic approaches to demystify the migration in windborne migrants but also enhances our understanding of how seasonal movements affect speciation and evolution in insects.

Nicotine improves DSS-induced colitis by inhibiting NLRP3 and altering gut microbiota.

Ulcerative colitis (UC) is a chronic recurrent inflammatory disease affecting the rectum and colon. Numerous epidemiological studies have identified smoking as a protective factor for UC. Dysbiosis of intestinal microbiota and release of inflammatory factors are well-established characteristics associated with UC. Therefore, we have observed that nicotine exhibits the potential to ameliorate colitis symptoms in UC mice. Additionally, it exerts a regulatory effect on colonic microbiota dysbiosis by promoting the growth of beneficial bacteria while suppressing harmful bacteria. Combined in vivo and in vitro investigations demonstrate that nicotine primarily impedes the assembly of NLRP3, subsequently inhibiting downstream IL-1ß secretion.

Adipose tissue aging is regulated by an altered immune system.

Adipose tissue is a widely distributed organ that plays a critical role in age-related physiological dysfunctions as an important source of chronic sterile low-grade inflammation. Adipose tissue undergoes diverse changes during aging, including fat depot redistribution, brown and beige fat decrease, functional decline of adipose progenitor and stem cells, senescent cell accumulation, and immune cell dysregulation. Specifically, inflammaging is common in aged adipose tissue. Adipose tissue inflammaging reduces adipose plasticity and pathologically contributes to adipocyte hypertrophy, fibrosis, and ultimately, adipose tissue dysfunction. Adipose tissue inflammaging also contributes to age-related diseases, such as diabetes, cardiovascular disease and cancer. There is an increased infiltration of immune cells into adipose tissue, and these infiltrating immune cells secrete proinflammatory cytokines and chemokines. Several important molecular and signaling pathways mediate the process, including JAK/STAT, NFκB and JNK, etc. The roles of immune cells in aging adipose tissue are complex, and the underlying mechanisms remain largely unclear. In this review, we summarize the consequences and causes of inflammaging in adipose tissue. We further outline the cellular/molecular mechanisms of adipose tissue inflammaging and propose potential therapeutic targets to alleviate age-related problems.

Loss of Wdr5 attenuates MLL-rearranged leukemogenesis by suppressing Myc targets.

WD repeat domain 5 (WDR5) is a prominent target for pharmacological inhibition in cancer through its scaffolding role with various oncogenic partners such as MLL and MYC. WDR5-related drug discovery efforts center on blocking these binding interfaces or degradation have been devoted to developing small-molecule inhibitors or degraders of WDR5 for cancer treatment. Nevertheless, the precise role of WDR5 in these cancer cells has not been well elucidated genetically. Here, by using an MLL-AF9 murine leukemia model, we found that genetically deletion of Wdr5 impairs cell growth and colony forming ability of MLL-AF9 leukemia cells in vitro or ex vivo and attenuates the leukemogenesis in vivo as well, which acts through direct regulation of ribosomal genes. Pharmacological inhibition of Wdr5 recapitulates genetic study results in the same model. In conclusion, our current study demonstrated the first genetic evidence for the indispensable role of Wdr5 in MLL-r leukemogenesis in vivo, which supports therapeutically targeting WDR5 in MLL-rearranged leukemia by strengthening its disease linkage genetically and deepening insights into its mechanism of action.

Effects of dietary berberine on growth performance, lipid metabolism, antioxidant capacity and lipometabolism-related genes expression of AMPK signaling pathway in juvenile black carp (Mylopharyngodon piceus) fed high-fat diets.

This study aimed to investigate the effects of high-fat diet (HFD) supplemented with berberine on growth, lipid metabolism, antioxidant capacity and lipometabolism-related genes expression of AMPK signaling pathway in juvenile black carp (Mylopharyngodon piceus). Five hundred and forty healthy fish (4.04 ± 0.01 g) were randomly distributed into six groups, and fed six experimental diets: normal-fat diet (NFD, 5% fat), HFD (15% fat), and four HFDs supplemented with graded levels of berberine, respectively. The results showed that, compared with fish fed NFD, HFD had no effects on the growth of fish except for reducing survival rate, whereas HFD caused extensive lipid accumulation, oxidative stress injury and hepatic abnormalities. However, compared with the HFD group, fish fed HFD containing an appropriate berberine (98.26 or 196.21 mg/kg) improved the growth performance, increased hepatic lipid metabolism and antioxidant enzymes activities, and up-regulated the mRNA expression levels of ampk subunits and lipolysis genes such as pparα, cpt-1, acox, atgl and hsl (P < 0.05). Meanwhile, HFD supplemented with an appropriate berberine reduced crude lipid contents in liver and whole-body, decreased serum lipid contents, and ALT and AST activities, and down-regulated the mRNA expression levels of lipogenesis genes such as srebp-1, acc1, gpat, fas and pparγ, and lipid transporter genes such as fatp, fabp and fat/cd36 (P < 0.05). Thus, HFD supplemented with an appropriate berberine could improve growth of black carp, promote lipid metabolism and enhance antioxidant capacity. The lipid-lowering mechanism of berberine might be mediated by activating AMPK pathway, up-regulating lipolysis genes expression, and down-regulating lipogenesis and transport genes expression.

Microbial Response to Fungal Infection in a Fungus-Growing Termite, Odontotermes formosanus (Shiraki).

The crosstalk between gut microbiota and host immunity has emerged as one of the research foci of microbiome studies in recent years. The purpose of this study was to determine how gut microbes respond to fungal infection in termites, given their reliance on gut symbionts for food intake as well as maintaining host health. Here, we used Metarhizium robertsii, an entomopathogenic fungus, to infect Odontotermes formosanus, a fungus-growing termite in the family Termitidae, and documented changes in host gut microbiota via a combination of bacterial 16S rDNA sequencing, metagenomic shotgun sequencing, and transmission electron microscopy. Our analyses found that when challenged with Metarhizium, the termite gut showed reduced microbial diversity within the first 12 h of fungal infection and then recovered and even surpassed pre-infection flora levels. These combined results shed light on the role of gut flora in maintaining homeostasis and immune homeostasis in the host, and the impact of gut flora dysbiosis on host susceptibility to infection.

[Characteristics and Source Apportionment of Ambient VOCs in Spring in Zhengzhou].

Ambient volatile organic compounds (VOCs) samples were collected at five sites in Zhengzhou during the spring of 2018. VOCs concentrations, the ozone formation potential (OFP), the aerosol formation potential (AFP), and source apportionment using a positive matrix factorization (PMF) model were studied based on chemical composition analysis. The results showed that the averaged concentration of VOCs in Zhengzhou during spring was (30.66±13.60)×10-9, of which the proportion of alkanes was the highest (35.3%) followed by oxygenated VOCs (OVOCs, 25.3%), halocarbons (24.1%), aromatics (10.0%), and alkenes (5.2%). The total OFP was 195.53 µg·m-3 and the contributions of alkanes, alkenes, aromatics, halocarbons, and OVOCs were 25.6%, 17.8%, 38.9%, 5.8%, and 11.9%, respectively. The total AFP was 0.95 µg·m-3 with an 87.6% contribution from aromatics and 12.4% from alkanes. The correlation between major species showed that pentane, isopentane, benzene, and toluene in Qinlinglu (QLL) site and Jingkaiqu (JKQ) site were greatly influenced by motor vehicles, but these were mainly influenced by combustion sources in Zhengzhou University (ZZU) site. The five factors that were identified by the PMF model were vehicle and liquefied petroleum gas (LPG) volatilization source (30.5%), solvent coating source (27.3%), industrial process source (22.1%), aging air mass (14.4%), and biogenic source (5.7%).

A Comprehensive Survey of Vision-Based Human Action Recognition Methods.

Although widely used in many applications, accurate and efficient human action recognition remains a challenging area of research in the field of computer vision. Most recent surveys have focused on narrow problems such as human action recognition methods using depth data, 3D-skeleton data, still image data, spatiotemporal interest point-based methods, and human walking motion recognition. However, there has been no systematic survey of human action recognition. To this end, we present a thorough review of human action recognition methods and provide a comprehensive overview of recent approaches in human action recognition research, including progress in hand-designed action features in RGB and depth data, current deep learning-based action feature representation methods, advances in human⁻object interaction recognition methods, and the current prominent research topic of action detection methods. Finally, we present several analysis recommendations for researchers. This survey paper provides an essential reference for those interested in further research on human action recognition.

MicroRNA-1469, a p53-responsive microRNA promotes Genistein induced apoptosis by targeting Mcl1 in human laryngeal cancer cells.

Genistein, a plant isoflavone, is reported to have therapeutic potentials in multiple cancers, However, the molecular mechanism underlying promoting cell apoptosis in laryngeal cancer remains unclear. In this study, we report that miR-1469 was induced by genistein in laryngeal cancer. Elevated miR-1469 promoted cell apoptosis and inhibited Mcl1 expression. In addition, we also observed that tumor suppressor p53 was increased under genistein treatment. Elevation of p53 promoted miR-1469 expression, leading to miR-1469 increase and Mcl1 decrease. Therefore, our findings suggest that genistein can suppress laryngeal cancer cell survival through p53 -miR-1469-Mcl1pathway.

Decreased expression of hepatic cytochrome P450 1A2 (CYP1A2) in a chronic intermittent hypoxia mouse model.

BACKGROUND: Hepatic cytochrome P450 (CYP) isoforms, CYP1A2, is one of important enzymes for many drugs metabolism. Studies have confirmed that sustained hypoxia can influence the expression of hepatic CYP, including CYP1A2. The impact of chronic intermittent hypoxia (CIH), a marked characteristic of sleep apnea, on CYP1A2 remains unclear. The aim of the present study was to evaluate the effect of CIH on the expression of hepatic CYP1A2 in a mouse model with sleep apnea. METHODS: Twenty four old male (6-8 weeks) C57BL/6J mice (n=12 in each group) were randomly assigned to either normoxia group or CIH group. Mice in CIH group underwent 12 weeks intermittent hypoxia exposure. The different gene expression of hepatic CYP1A2 between two groups was analyzed by quantity real-time polymerase chain reaction. The protein levels of hepatic CYP1A2 in each group were observed by using western blotting and immunohistochemistry. RESULTS: After 12 weeks of exposure to intermittent hypoxia, the expression of hepatic CYP1A2, at the mRNA and protein levels was decreased more significantly in the CIH group than the normoxia group (P<0.01). CONCLUSIONS: CIH contributes to inhibiting the expression of hepatic CYP1A2. This implies that the dosage of drugs metabolized by CYP1A2, should be adjusted in patients with sleep apnea.

HMGB1-mediated autophagy confers resistance to gemcitabine in hormone-independent prostate cancer cells.

As a main treatment of prostate cancer, castration therapy has been widely applied in the clinic. However, the therapeutic strategy for hormone-independent prostate cancer (HIPC) was not satisfied. Gemcitabine is an important chemotherapeutic agent that has been approved for the treatment of numerous human solid tumors, including HIPC, whereas the gemcitabine resistance has become a serious problem in clinical chemotherapy. In the present study, the mechanisms of resistance to gemcitabine were investigated in HIPC cell lines. The results demonstrated that the autophagy markers were induced significantly in HIPC cells subsequent to gemcitabine treatment. Meanwhile, administration of gemcitabine to HIPC cells increased the expression of high mobility group box1 (HMGB1). Furthermore, the gemcitabine-induced autophagy response was attenuated in stable HIPC cells harboring HMGB1 shRNA. Notably, the HIPC cells stably transfected with HMGB1 shRNA or treated with autophagy inhibitors were more sensitive to gemcitabine compared with the control group. These data suggested that inhibition of HMGB1 increased the sensitivity to gemcitabine by decreasing autophagy response in HIPC cells. Overall, the present findings demonstrate a new mechanism for the resistance to gemcitabine in HIPC cell lines.

Knocking down glycoprotein nonmetastatic melanoma protein B suppresses the proliferation, migration, and invasion in bladder cancer cells.

Glycoprotein nonmetastatic melanoma protein B is a type 1 transmembrane protein that has been recently found to play a role in cancer cell proliferation, angiogenesis, and invasion. Due to its potential responsibility in cancer aggressiveness, the main objective of this work was to investigate its expression in bladder cancer and the biological functions in bladder cancer cells. Using immunohistochemistry, western blot, and reverse transcription polymerase chain reaction, we analyzed the expression of glycoprotein nonmetastatic melanoma protein B in bladder cancer tissues and bladder cancer cell lines. The effects of glycoprotein nonmetastatic melanoma protein B on proliferation, migration, and invasion were tested after knocking down the glycoprotein nonmetastatic melanoma protein B in bladder cancer cells with small interfering RNAs by CCK-8, Transwell, and Matrigel assays. Our results showed that glycoprotein nonmetastatic melanoma protein B protein was highly expressed in the bladder cancer tissues and cell lines. Downregulating glycoprotein nonmetastatic melanoma protein B could suppress the proliferation, migration, and invasion in bladder cancer cells. Glycoprotein nonmetastatic melanoma protein B expression was related to the poor differentiation and recurrence by immunohistochemistry analysis. The survival analysis also showed that glycoprotein nonmetastatic melanoma protein B was related to the patient prognosis. In conclusion, Glycoprotein nonmetastatic melanoma protein B protein was highly expressed in the bladder cancer, which was related to the poor prognosis in bladder cancer patients. Glycoprotein nonmetastatic melanoma protein B promoted the proliferation, migration, and invasion in bladder cancer cells.

Psychological burden, sexual satisfaction and erectile function in men whose partners experience recurrent pregnancy loss in China: a cross-sectional study.

BACKGROUND: The aim of this study was to elucidate recurrent pregnancy loss (RPL)-associated psychosocial effects and sexual functions of Chinese men whose partners experience a history of RPL. METHODS: Questionnaire data from a total of 236 men whose partners experience RPL(RPL group) and another 236 non-RPL male volunteers(control group) were analyzed. The self-administered questionnaires included anxiety and depression measures (SAS & SDS), the Index of Sexual Satisfaction (ISS) and the International Index of Erectile Function (IIEF-5) for evaluating psychological burden, sexual satisfaction and erectile function, respectively. RESULTS: The mean age of the RPL group and control group was 29.8 ± 8.6 and 28.2 ± 7.3, respectively. The incidence of erectile dysfunction was significantly higher in the RPL group than in the control group (19.07 % vs. 7.63 %, P < 0.001). Anxiety and depression were also more prevalent in RPL group than in the control group (anxiety: 36.90 % vs. 19.08 %, P < 0.001; depression: 26.30 % vs. 7.63 %, P < 0.001). Furthermore, after adjusting for age in the RPL group, negative relationships were observed between the IIEF-5 score and anxiety and depression (P < 0.001), and a positive correlation was found between the ISS and anxiety and depression (P < 0.001). In addition, history of RPL, anxiety and depressive symptoms were significantly associated with a higher risk of ED. CONCLUSIONS: Psychological functioning, sexual satisfaction and erectile function are impaired in infertile men with RPL partners. These men should be targeted for psychological consultation.

Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma.

Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.

[Factors affecting activation and transference of soil colloidal phosphorus and related analysis technologies].

Colloids play a key role in the transference process of phosphorus (P) in soil. Activation and transference of soil colloidal phosphorus have great effect on soil P pool and the surrounding water quality. This paper summarized the current studies on soil colloidal P, discussing the effects of the various factors (e. g., soil physical and chemical properties, fertilization, rainfall and soil amendments) on the transference of soil colloidal P. Some advanced analysis technologies (e.g., flow field-flow fractionation, transmission electron microscope-energy dispersive X-ray spectrometer, X-ray absorption near-edge structure and nuclear magnetic resonance) and methods of reducing soil colloidal P were also involved. This review would provide important information on the mechanism of soil colloidal P transference.

[Expression and significance of CMTM5 and epidermal growth factor receptor in prostate cancer].

OBJECTIVE: To investigate the expression patterns of CKLF-like MARVEL transmembrane domain containing 5 (CMTM5), a novel tumor suppressor, and epidermal growth factor receptor (EGFR) in prostate cancer (PCa) tissues and cells and to analyze the relationship between CMTM5 and EGFR in PCa. METHODS: The expression patterns of CMTM5 and EGFR in PCa tissues and cells were detected by immunohistochemistry and Western blot, respectively. RESULTS: CMTM5 was highly expressed in 75% (27/36) of benigh prostatic hyperplasia (BPH) tissues but 35.9% (23/64) of PCa tissues (P<0.001). There was a significant difference of CMTM5 expression between the two groups of PCa tissues with different Gleason scores (P=0.003), though its expression was not related to the age, clinical stage, and metastatic situation (P>0.05). EGFR was highly expressed in 57.8% (37/64) of PCa tissues, it had statistical significance between EGFR and CMTM5 expressions in PCa tissues. Furthermore, 23 cases (35.9%) had low CMTM5 expression and high EGFR expression. Western blot showed that CMTM5 was undetectable in PCa cells, in which the EGFR expression was upregulated. CONCLUSION: The loss of CMTM5 may participate in the progression of PCa resulting from deregulated EGFR.

The effects of Ficus carica polysaccharide on immune response and expression of some immune-related genes in grass carp, Ctenopharyngodon idella.

The present study investigated the effect of Ficus carica polysaccharide (FCP), isolated from the fruit of F. carica L., at 0%, 0.1%, 0.5% and 1.0% doses supplementation with feed on genes Interleukin 1-ß (IL-1ß), Tumor Necrosis Factor α (TNF-α) and heat shock protein 70 (HSP70) gene expression in blood, humoral innate immune parameters and resistant to Flavobacterium columnare of grass carp at weeks 1, 2 and 3. The results revealed that administration of FCP significantly (P<0.05) up regulated IL-1ß and TNF-α gene expression. HSP70 gene expression was significantly (P<0.05) lower in FCP-fed fish at the end of trial. The serum total protein, albumin and globulin did not significantly increased in any diet on the first week whereas it was significantly enhanced in 0.5% and 1.0% supplementation diets on weeks 2 and 3 when compared to control. The serum complement C3 was significantly (P<0.05) increased on weeks 1 and 2 when compared to control, however, no significant difference was found in this activity after 3 weeks of treatment. All diets significantly enhanced the serum lysozyme activity, bactericidal activity from weeks 1-2 as compared to control. Grass carp fed with FCP showed remarkably higher resistance against F. columnare (60% survival) compared to the control group (30% survival). These results confirm that FCP can up regulate immune related genes expression, stimulates immune response that per se enhances disease resistance in grass carp.

Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo.

Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (RB) phosphorylation and dramatically decreased liposarcoma cell growth. Cell-cycle analysis demonstrated arrest at G0-G1. siRNA-mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor (18)F-fluorodeoxyglucose uptake with decreased tumor biomarkers, including RB phosphorylation and bromodeoxyuridine incorporation in vivo. Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight. After prolonged continuous dosing, reestablishment of RB phosphorylation and cell-cycle progression was noted. These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function, and suggest its potential function in the regulation of survival and metabolism of liposarcoma, supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS.

Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.

PURPOSE: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. EXPERIMENTAL DESIGN: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. RESULTS: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. CONCLUSIONS: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.