A carbohydrate-rich diet increases social immunity in ants

Increased potential for disease transmission among nest-mates means living in groups has inherent costs. This increased potential is predicted to select for disease resistance mechanisms that are enhanced by cooperative exchanges among group members, a phenomenon known as social immunity. One potential mediator of social immunity is diet nutritional balance because traits underlying immunity can require different nutritional mixtures. Here, we show how dietary protein–carbohydrate balance affects social immunity in ants. When challenged with a parasitic fungus Metarhizium anisopliae, workers reared on a high-carbohydrate diet survived approximately 2.8× longer in worker groups than in solitary conditions, whereas workers reared on an isocaloric, high-protein diet survived only approximately 1.3× longer in worker groups versus solitary conditions. Nutrition had little effect on social grooming, a potential mechanism for social immunity. However, experimentally blocking metapleural glands, which secrete antibiotics, completely eliminated effects of social grouping and nutrition on immunity, suggesting a causal role for secretion exchange. A carbohydrate-rich diet also reduced worker mortality rates when whole colonies were challenged with Metarhizium. These results provide a novel mechanism by which carbohydrate exploitation could contribute to the ecological dominance of ants and other social groups.     

Protection of palmitic acid-mediated lipotoxicity by arachidonic acid via channeling of palmitic acid into triglycerides in C2C12

Background

Excessive saturated fatty acids have been considered to be one of major contributing factors for the dysfunction of skeletal muscle cells as well as pancreatic beta cells, leading to the pathogenesis of type 2 diabetes.

Results

PA induced cell death in a dose dependent manner up to 1.5 mM, but AA protected substantially lipotoxicity caused by PA at even low concentration of 62 μM, at which monounsaturated fatty acids including palmitoleic acid (POA) and oleic acid (OA) did not protect as much as AA did. Induction of cell death by PA was resulted from mitochondrial membrane potential loss, and AA effectively blocked the progression of apoptosis. Furthermore, AA rescued significantly PA-impaired glucose uptake and -signal transduction of Akt in response to insulin.Based on the observations that polyunsaturated AA generated competently cellular droplets at low concentration within the cytosol of myotubes compared with other monounsaturated fatty acids, and AA-driven lipid droplets were also enhanced in the presence of PA, we hypothesized that incorporation of harmful PA into inert triglyceride (TG) may be responsible for the protective effects of AA against PA-induced lipotoxicity. To address this assumption, C2C12 myotubes were incubated with fluorescent probed-PA analogue 4, 4-difluoro-5, 7-dimethyl-4-boro-3a,4a-diaza-s-indacene-3-hexadecanoic acid (BODIPY FL C16) in the presence of AA and their subsequent lipid profiles were analyzed. The analyses of lipids on thin layer chromatograpy (TLC) showed that fluorescent PA analogue was rapidly channeled into AA-driven TG droplets.

Conclusion

Taken together, it is proposed that AA diverts PA into inert TG, therefore reducing the availability of harmful PA into intracellular target molecules.     

Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors

BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole‐exome sequencing of drug‐resistant BRAF^V600K melanoma cells. We further describe a new screening approach, a genome‐wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N‐terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF^L505H), is the first resistance‐conferring second‐site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF‐PLX4032 interface with a larger polar residue. Moreover, we show that BRAF^L505H, found in human prostate cancer, is itself a MAPK‐activating, PLX4032‐resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032‐resistant melanoma cells are sensitive to novel, next‐generation BRAF inhibitors, especially the ‘paradox‐blocker’ PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF‐mutations.     

Expression of insulin‐like growth factor‐1 receptor in metastatic uveal melanoma and implications for potential autocrine and paracrine tumor cell growth

We investigated the importance of the insulin‐like growth factor‐1 receptor (IGF‐1R) in hepatic metastases of uveal melanoma. The expression pattern of IGF‐1R in archival tissue samples of hepatic metastasis from 24 patients was analyzed by immunohistochemistry. All the samples of hepatic metastases stained positive for IGF‐1R. To investigate the biological role of IGF‐1R on the growth of metastatic uveal melanoma, a long‐term cell line obtained from a hepatic metastasis (TJU‐UM001) was evaluated. TJU‐UM001 expressed cell surface IGF‐1R (>90%) and proliferated in response to exogenous and endogenous insulin‐like growth factor‐1 (IGF‐1). Correlatively, anti‐IGF‐1R antibody completely blocked IGF‐1‐induced growth of TJU‐UM001 cells. IGF‐1 preferentially induced phosphorylation of Akt (S473) in quiescent TJU‐UM001 cells, and this was blocked by anti‐IGF‐1R antibody. This study suggests that autocrine and paracrine mechanisms underlie IGF‐1‐induced growth of metastatic uveal melanoma and underscore the potential benefit of IGF‐1 or IGF‐1R antagonism in treatment for metastatic uveal melanoma.     

2011～2013年血液分离葡萄球菌的临床分布及耐药性分析

目的了解临床各科发热患者（怀疑细菌感染）血培养中葡萄球菌分布及耐药性,为临床治疗提供参考依据。方法血培养采用BaeT／Alert3D全自动血培养仪（梅里埃）培养5d,采用MicroScanWalk—Away-96plus全自动微生物鉴定和药敏分析系统（西门子）进行细菌鉴定和药敏试验。结果血培养共检出葡萄球菌185株,检出最多的科室是ICU,耐甲氧西林金黄色葡萄球菌（methicillin—resistant Staphylococcus aureus,MRSA）检出率为30．4％,而耐甲氧西林凝固酶阴性葡萄球菌（methicillin—resistant coagulase-negative Staphylococci,MRCNS）的检出率高达80．7％。还检出了1株万古霉素中介的凝固酶阴性葡萄球菌。结论通过血培养检出葡萄球菌的耐药性分析发现,凝固酶阴性葡萄球菌对苯唑西林、氨苄西林、青霉素、红霉素的耐药率在70％以上,而对氯霉素、利福平、四环素的耐药率在30％以下,因此这三种药物应为我院应对凝固酶阴性葡萄球菌血流感染的常用首选药物。     

耐碳青霉烯类肺炎克雷伯菌的耐药机制研究

目的了解碳青霉烯类耐药肺炎克雷伯菌及耐药机制。方法对2012-2013年临床分离的耐碳青霉烯类肺炎克雷伯菌共计12株进行分析,药敏采用MIC方法检测,用WHONET 5.6软件进行分析,KPC表型检测采用改良Hodge试验,基因检测采用PCR方法。结果 12株碳青霉烯类耐药肺炎克雷伯菌改良Hodge试验阴性,基因测序为KPC-2型。结论 KPC-2基因是引起本院肺炎克雷伯菌耐药的主要原因。     

不同海拔地区同级别医院鲍曼不动杆菌的分布与 耐药性的连续对比性分析

目的连续对比分析不同海拔地区同级别医院非鲍曼不动杆菌的耐药性,寻找不同海拔对鲍曼不动杆菌的耐药性的影响并指导合理应用抗生素。方法回顾分析2011-2013年两家不同海拔地区同级别医院临床分离的鲍曼不动杆菌药敏结果。结果 2011年至2013年,低海拔地区医院鲍曼不动杆菌检出率为12.66%、17.01%、15.33%。高海拔的地区院鲍曼不动杆菌检出率为0.24%、1.50%、1.44%。低海拔地区医院鲍曼不动杆菌仅对美满环素仍保持较高的敏感率;除头孢哌酮/舒巴坦外,对多数常用药物耐药率均高于70%。而且保持稳定。高海拔的地区院鲍曼不动杆菌对常用抗生素的耐药率逐年下降,庆大霉素、左旋氧氟沙星、亚胺培南、头孢哌酮、头孢他啶的敏感率近两年均在60%以上。结论低海拔地区医院鲍曼不动杆菌检出率高,常用抗生素耐药率高。高海拔的地区院鲍曼不动杆菌检出率低,常用抗生素敏感率高。环境因素对微生态具有重要的影响作用。     

ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors

With the existing knowledge of ATM''s role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent ‘resistance-to-apoptosis'' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.     

Stability of gene expression and epigenetic profiles highlights the utility of patient-derived paediatric acute lymphoblastic leukaemia xenografts for investigating molecular mechanisms of drug resistance

Background

Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response.

Results

We found high correlations in DNA methylation and gene expression profiles between matching primary and xenograft tumour samples with Pearson’s correlation coefficients ranging between 0.85 and 0.98. In order to demonstrate the potential utility of epigenetic analyses in BCP-ALL xenografts, we identified DNA methylation biomarkers that correlated with prednisolone responsiveness of the original tumour samples. Differential methylation of CAPS2, ARHGAP21, ARX and HOXB6 were confirmed by locus specific analysis. We identified 20 genes showing an inverse relationship between DNA methylation and gene expression in association with prednisolone response. Pathway analysis of these genes implicated apoptosis, cell signalling and cell structure networks in prednisolone responsiveness.

Conclusions

The findings of this study confirm the stability of epigenetic and gene expression profiles of paediatric BCP-ALL propagated in mouse xenograft models. Further, our preliminary investigation of prednisolone sensitivity highlights the utility of mouse xenograft models for preclinical development of novel drug regimens with parallel investigation of underlying gene expression and epigenetic responses associated with novel drug responses.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-416) contains supplementary material, which is available to authorized users.