Gut microbial fatty acid isomerization modulates intraepithelial T cells.

The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.

Elevated THBS3 predicts poor overall survival for clear cell renal cell carcinoma and identifies LncRNA/RBP/THBS3 mRNA networks.

This study was used to assess THBS3's overall survival (OS) prognostic values in clear cell renal cell carcinoma (ccRCC) as well as to determine the LncRNA/RNA binding protein (RBP)/THBS3 interactions. Clinical data and RNA sequencing data were gathered from the TCGA dataset. Significant pathways associated with THBS3 were identified by gene set enrichment analysis (GSEA). Cox regression analyses, both univariate and multivariate, were applied to assess factors with independent prognostic abilities. We also discussed THBS3's relationship to immunity. We discovered that THBS3 expression was increased in ccRCC samples, as well as shorter OS in the TCGA dataset (P<0.05). External verification results in GSE6344, ICGC, ArrayExpress, UALCAN datasets, and qRT-PCR remained consistent (all P<0.05). Cox regression analyses, both univariate and multivariate, identified THBS3 as a factor with independent prognostic ability (both P<0.001). THBS3 expression as well as several clinicopathological variables were included in the nomogram OS prognosis prediction method as well. GSEA identified four THBS3-related signal pathways and THBS3 was revealed to be significantly associated with MSI, TMB, neoantigen, and immunity (all P<0.05). We also identified several LncRNA/RBP/THBS3 mRNA networks as potentially THBS3-related mechanisms. For THBS3-related drug sensitivities, THBS3 was negatively associated with Actinomycin D, Cobimetinib, Eribulin mesilate, Geldanamycin analog, and Vinblastine, while it was positively related to Erlotinib drug sensitivity. In addition to being an independent prognostic factor for ccRCC, THBS3 had a close connection to immunity, with identifying LncRNA/RBPs/THBS3 mRNA networks. Verifications of our findings in vivo and in vitro should be done in the future.

Nanoporous Graphene Oxide-Based Quartz Crystal Microbalance Gas Sensor with Dual-Signal Responses for Trimethylamine Detection.

This paper presents a straightforward method to develop a nanoporous graphene oxide (NGO)-functionalized quartz crystal microbalance (QCM) gas sensor for the detection of trimethylamine (TMA), aiming to form a reliable monitoring mechanism strategy for low-concentration TMA that can still cause serious odor nuisance. The synthesized NGO material was characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy to verify its structure and morphology. Compared with the bare and GO-based QCM sensors, the NGO-based QCM sensor exhibited ultra-high sensitivity (65.23 Hz/µL), excellent linearity (R2 = 0.98), high response/recovery capability (3 s/20 s) and excellent repeatability (RSD = 0.02, n = 3) toward TMA with frequency shift and resistance. Furthermore, the selectivity of the proposed NGO-based sensor to TMA was verified by analysis of the dual-signal responses. It is also proved that increasing the conductivity did not improve the resistance signal. This work confirms that the proposed NGO-based sensor with dual signals provides a new avenue for TMA sensing, and the sensor is expected to become a potential candidate for gas detection.

Nucleolar protein NOP2 could serve as a potential prognostic predictor for clear cell renal cell carcinoma.

As an indispensable part for cancer precision medicine, biomarkers and signatures for predicting cancer prognosis and therapeutic benefits were urgently required. The purpose of this study was to investigate the prognostic roles of NOP2 in renal clear cell carcinoma (ccRCC) for overall survival (OS) and its relationships with immunity. NOP2-related gene expression matrix associated with clinical information was obtained from the Cancer Genome Atlas (TCGA) ccRCC dataset and NOP2-related pathways were identified by gene set enrichment analysis (GSEA). Associations among the NOP2 expression and MSI, TMB, TNB, and immunity were also explored. Both the NOP2 mRNA and protein/phosphoprotein had a higher expression in ccRCC tumor tissues than in normal kidney tissues (both P < 0.001) and elevated NOP2 expression was associated with poor OS (P < 0.001). Logistic regression analysis revealed the NOP2 expression was significantly linked to stage, age, grade, N stage, T stage, and M stage (all P < 0.05). Univariate/multivariate Cox hazard regression analysis results indicated that NOP2 was an independent prognostic factor for OS in ccRCC and GSEA revealed five NOP2-related signaling pathways. Nomogram based on NOP2 and eight clinical characteristic parameters (grade, age, stage, gender, T stage, race, M stage, N stage) was constructed and carefully evaluated. Furthermore, NOP2 gene expression was also found to be significantly related to MSI, TMB, and immunity. Our findings revealed that NOP2 might be a potential prognostic factor for OS in ccRCC and it was significantly associated with immunity, MSI, and TMB.

Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells.

PURPOSE: Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. EXPERIMENTAL DESIGN: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. RESULTS: The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. CONCLUSIONS: Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

Disseminated Cryptococcosis revealed by transverse myelitis in Immunocompetent patient: a case report and review of the literature.

BACKGROUND: Transverse myelitis (TM) is due to inflammatory spinal cord injury with bilateral neurologic involvement, which is sensory, motor, or autonomic in nature. It may be associated with autoimmune disease, vaccination, intoxication and infections. The most common infection cause of TM is Coxsackie virus and Mycoplasma pneumoniae. The cryptococcosis is rare. We present the case of disseminated cryptococcosis revealed by transverse myelitis in an immunocompetent 55-year-old male patient. The literature review is also stated. CASE PRESENTATION: The 55-year-old man suffered from gradual numbness, weakness in both lower limbs and finally paralyzed in the bed. The thoracic spine Computed tomography (CT) was normal, but multiple nodules in the lung were accidentally discovered. Thoracic Magnetic Resonance Imaging (MRI) showed diffused thoracic spinal cord thickening and extensively intramedullary T2 hyper intensity areas. Gadolinium contrast enhanced T1WI showed an intramedullary circle-enhanced nodule at 9th thoracic level. Diagnosis was made by histological examination of the bilateral lung biopsy. The patient was treated successfully with systemic amphotericin B liposome and fluconazole and intrathecal dexamethasone and amphotericin B liposome. CONCLUSIONS: This is a patient with disseminated cryptococcosis involving the lung, spinal cord and adrenal glands, which is rare in the absence of immunodeficiency.

Spectral Characterization and Molecular Dynamics Simulation of Pesticides Based on Terahertz Time-Domain Spectra Analyses and Density Functional Theory (DFT) Calculations.

This work provides the experimental and theoretical fundamentals for detecting the molecular fingerprints of six kinds of pesticides by using terahertz (THz) time-domain spectroscopy (THz-TDS). The spectra of absorption coefficient and refractive index of the pesticides, chlorpyrifos, fipronil, carbofuran, dimethoate, methomyl, and thidiazuron are obtained in frequencies of 0.1⁻3.5 THz. To accurately describe the THz spectral characteristics of pesticides, the wavelet threshold de-noising (WTD) method with db 5 wavelet fucntion, 5-layer decomposition, and soft-threshold de-noising was used to eliminate the spectral noise. The spectral baseline correction (SBC) method based on asymmetric least squares smoothing was used to remove the baseline drift. Spectral results show that chlorpyrifo had three characteristic absorption peaks at 1.47, 1.93, and 2.73 THz. Fipronil showed three peaks at 0.76, 1.23, and 2.31 THz. Carbofuran showed two peaks at 2.72 and 3.06 THz. Dimethoate showed three peaks at 1.05, 1.89, and 2.92 THz. Methomyl showed five peaks at 1.01, 1.65, 1.91, 2.72, and 3.20 THz. Thidiazuron showed four peaks at 0.99, 1.57, 2.17, and 2.66 THz. The density functional theory (DFT) of B3LYP/6-31G+(d,p) was applied to simulate the molecular dynamics for peak analyzing of the pesticides based on isolated molecules. The theoretical spectra are in good agreement with the experimental spectra processed by WTD + SBC, which implies the validity of WTD + SBC spectral processing methods and the accuracy of DFT spectral peak analysis. These results support that the combination of THz-TDS and DFT is an effective tool for pesticide fingerprint analysis and the molecular dynamics simulations.

Rapid Determination of Thiabendazole Pesticides in Rape by Surface Enhanced Raman Spectroscopy.

Thiabendazole is widely used in sclerotium blight, downy mildew and black rot prevention and treatment in rape. Accurate monitoring of thiabendazole pesticides in plants will prevent potential adverse effects to the Environment and human health. Surface Enhanced Raman Spectroscopy (SERS) is a highly sensitive fingerprint with the advantages of simple operation, convenient portability and high detection efficiency. In this paper, a rapid determination method of thiabendazole pesticides in rape was conducted combining SERS with chemometric methods. The original SERS were pretreated and the partial least squares (PLS) was applied to establish the prediction model between SERS and thiabendazole pesticides in rape. As a result, the SERS enhancing effect based on silver Nano-substrate was better than that of gold Nano-substrate, where the detection limit of thiabendazole pesticides in rape could reach 0.1 mg/L. Moreover, 782, 1007 and 1576 cm−1 could be determined as thiabendazole pesticides Raman characteristic peaks in rape. The prediction effect of thiabendazole pesticides in rape was the best ( R p 2 = 0.94, RMSEP = 3.17 mg/L) after the original spectra preprocessed with 1st-Derivative, and the linear relevance between thiabendazole pesticides concentration and Raman peak intensity at 782 cm−1 was the highest (R² = 0.91). Furthermore, five rape samples with unknown thiabendazole pesticides concentration were used to verify the accuracy and reliability of this method. It was showed that prediction relative standard deviation was 0.70–9.85%, recovery rate was 94.71–118.92% and t value was −1.489. In conclusion, the thiabendazole pesticides in rape could be rapidly and accurately detected by SERS, which was beneficial to provide a rapid, accurate and reliable scheme for the detection of pesticides residues in agriculture products.

Expression of lncRNA MIR222HG co-transcribed from the miR-221/222 gene promoter facilitates the development of castration-resistant prostate cancer.

Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa) (HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222. Upon promoter activation, a set of polyadenylated long non-coding RNA (lncRNA) MIR222HGs was transcribed from this promoter region. Over-expression of these MIR222HGs increased androgen-independent cell growth and repressed the expression of androgen receptor-regulated dihydrotestosterone (DHT)-induced KLK3, TMPRSS2, and FKBP5 in HSPC LNCaP cells, hallmarks of the CRPC phenotype. Clinically, increased expression of MIR222HG is associated with PCa progression to CRPC. In primary tumors, expression levels of MIR222HG and miR-221/222 inversely correlate with Gleason score and androgen receptor (AR) pathway activity. Interestingly, MIR222HG is Argonaute 2-bound and its expression is Dicer 1-dependent, suggesting its functional association with the RNA-induced silencing complex. Further studies led to the hypothesis that MIR222HG may potentially affect miR-mediated expression silencing, subsequently leading to AR reprogramming. Our study highlights an essential role of a non-coding RNA in CRPC development and that differential activation of a single promoter can up-regulate two different types of non-coding RNAs, miR-221/222 and lncRNA MIR222HG, in CRPC. Additionally, this study reveals a novel function of lncRNAs as a modulator of Argonaute-mediated RNA-induced silencing complex.

Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer.

PURPOSE: We evaluated the association of PSA and androgen receptor splice variant-7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate and/or enzalutamide treatment in castration-resistant prostate cancer (CRPC) patients. EXPERIMENTAL DESIGN: RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using droplet digital-PCR in retrospective cohorts treated with abiraterone acetate (N = 81) or enzalutamide (N = 51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses. RESULTS: PSA transcripts were detected in 57% of abiraterone acetate-treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients [adjusted HR = 2.27 (95% confidence interval (CI) 1.26-4.10) and 2.60 (95% CI, 1.19-5.69); P = 0.006 and 0.017 in abiraterone acetate and enzalutamide cohorts, respectively]. Patients with a higher-AR-V7 transcript level had a shorter TTF with abiraterone acetate and enzalutamide in univariate analysis (median 8.0 months vs. 15.6 months, P = 0.046 in abiraterone acetate-cohort and 3.6 months vs. 5.6 months; P = 0.050 in enzalutamide cohort). In multivariable models, the association with TTF remained significant in the enzalutamide cohort (adjusted HR = 2.02; 95% CI, 1.01-4.05; P = 0.048), but statistically insignificant in the abiraterone acetate cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS. CONCLUSIONS: PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with abiraterone acetate or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells. Clin Cancer Res; 23(3); 726-34. ©2016 AACR.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.

Association of SLCO2B1 Genotypes With Time to Progression and Overall Survival in Patients Receiving Androgen-Deprivation Therapy for Prostate Cancer.

PURPOSE: To validate the association of three previously demonstrated SLCO2B1 germline variants with time to progression (TTP) in patients receiving androgen-deprivation therapy (ADT), and to evaluate if the SLCO2B1 genetic variants impacted overall survival (OS) for prostate cancer (PC). PATIENTS AND METHODS: Three single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in an independent validation cohort of 616 patients with PC who were treated with ADT at the Dana-Farber Cancer Institute from 1996 to 2013. Multivariable Cox proportional hazards regression adjusting for known prognostic factors estimated the association of these genetic variants with TTP and OS in patients receiving ADT. The expression of SLCO2B1 was examined in prostatectomy samples, and the impact of SLCO2B1 expression level on DHEAS (dehydroepiandrosterone sulfate) uptake was evaluated in cell lines. RESULTS: The association between exonic SNP rs12422149 and TTP in patients treated with ADT was confirmed in univariable (P = .019) and multivariable analyses (adjusted hazard ratio, 1.31; 95% CI, 1.00 to 1.72 for GG v AA/AG; P = .049). Because OS had not been previously evaluated, we examined the association in the combined initial and validation cohorts (N = 1,094). The intronic SNP rs1077858 was associated with OS in both univariable (P = .009; Bonferroni's method adjusted P = .027) and multivariable analyses (adjusted hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for GG v AA/AG; P = .012). SLCO2B1 expression in normal prostate tissue and in 22RV1 cells carrying the major allele of SNP rs1077858 was significantly lower than in cells carrying the risk allele. We show in vitro that SLCO2B1 expression levels correlated with DHEAS uptake by PC cells. CONCLUSION: The association of SNP rs1077858 with OS may be a result of differential SLCO2B1 expression and the consequent increased uptake of DHEAS and subsequent resistance to ADT, which, in turn, may contribute to decreased OS.

Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage.

The intestinal epithelial barrier plays a critical role in the mucosal immunity. However, it remains largely unknown how the epithelial barrier is maintained after damage. Here we show that growth factor FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium. FGF2 or IL-17 deficiency resulted in impaired epithelial proliferation, increased pro-inflammatory microbiota outgrowth, and consequently worse pathology in a DSS-induced colitis model. The dysregulated microbiota in the model induced transforming growth factor beta 1 (TGFß1) expression, which in turn induced FGF2 expression mainly in regulatory T cells. Act1, an essential adaptor in IL-17 signaling, suppressed FGF2-induced ERK activation through binding to adaptor molecule GRB2 to interfere with its association with guanine nucleotide exchange factor SOS1. Act1 preferentially bound to IL-17 receptor complex, releasing its suppressive effect on FGF2 signaling. Thus, microbiota-driven FGF2 and IL-17 cooperate to repair the damaged intestinal epithelium through Act1-mediated direct signaling cross-talk.

Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection.

BACKGROUND: Ductular reactions (DRs) are well documented in many acute and chronic liver disease.The DRs are thought to be the transit amplifying cells deriving from activation of the stem/progenitor cell compartments of the liver. The aim of this study was to examine the presence of proliferative index of DR (PI-DR) and HPC markers' expression in HCCs after curative hepatectomy, as well as their relationship with clinicopathological features and prognosis. RESULTS: Tissue microarray with peritumoral and intratumoral tissue samples of 120 HCCs after hepatectomy was analysed for peritumoral expression of proliferating cell nuclear antigen for PI-DR. Peritumoral and intratumoral expression status of HPC markers including EpCAM, OV6, CD133 and c-kit were also examined by immunohistochemistry. TMA analysis of HCCs revealed that peritumoral PI-DR strongly correlated with the degree of inflammation and fibrosis. The peritumoral PI-DR positively correlated with peritumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Moreover, there were highly significant correlations between peritumoral PI-DR and intratumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Further, multivariate analysis showed that peritumoral PI-DR was the independent prognostic factor for overall survival (HR; 3.316, P < 0.001), and peritumoral PI-DR had a better power to predict disease-free survival (HR; 2.618, P < 0.001). CONCLUSIONS: Peritumoral PI-DR, as a valid surrogate for peritumoral and intratumoral expression of HPC markers, could be served as a potential prognostic marker for recurrence and survival in HCC after hepatectomy.

Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.

The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix αC. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix αC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop.

Mesenchymal stem cells: a new trend for cell therapy.

Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.