A two-dimensional conjugated small molecule (SMPV1) was designed and synthesized for high performance solution-processed organic solar cells. This study explores the photovoltaic properties of this molecule as a donor, with a fullerene derivative as an acceptor, using solution processing in single junction and double junction tandem solar cells. The single junction solar cells based on SMPV1 exhibited a certified power conversion efficiency of 8.02% under AM 1.5 G irradiation (100 mW cm−2). A homo-tandem solar cell based on SMPV1 was constructed with a novel interlayer (or tunnel junction) consisting of bilayer conjugated polyelectrolyte, demonstrating an unprecedented PCE of 10.1%. These results strongly suggest solution-processed small molecular materials are excellent candidates for organic solar cells.
Traditional methods of projecting population health statistics, such as calculating future death rates, can give inaccurate results and lead to inferior or even poor policy decisions. A new “three-dimensional” method of forecasting vital health statistics is more accurate because it takes into account the delayed effects of the health risks being accumulated by today’s younger generations. Applying this forecasting technique to the US obesity epidemic suggests that future death rates and health care expenditures could be far worse than currently anticipated. We suggest that public policy makers adopt this more robust forecasting tool and redouble efforts to develop and implement effective obesity-related prevention programs and interventions.
Although mesenchymal stem cells (MSCs) have been increasingly trialed to treat a variety of diseases, the underlying mechanisms remain still elusive. In this study, human umbilical cord (UC)-derived MSCs were stimulated by hypoxia, and the membrane microvesicles (MVs) in the supernatants were collected by ultracentrifugation, observed under an electron microscope, and the origin was identified with the flow cytometric technique. The results showed that upon hypoxic stimulus, MSCs released a large quantity of MVs of ∼100 nm in diameter. The MVs were phenotypically similar to the parent MSCs, except that the majority of them were negative for the receptor of platelet-derived growth factor. DiI-labeling assay revealed that MSC-MVs could be internalized into human UC endothelial cells (UC-ECs) within 8 h after they were added into the culture medium. Carboxyfluorescein succinimidyl ester-labeling technique and MTT test showed that MSC-MVs promoted the proliferation of UC-ECs in a dose-dependent manner. Further, MVs could enhance in vitro capillary network formation of UC-ECs in a Matrigel matrix. In a rat hindlimb ischemia model, both MSCs and MSC-MVs were shown to improve significantly the blood flow recovery compared with the control medium (P<0.0001), as assessed by laser Doppler imaging analysis. These data indicate that MV releasing is one of the major mechanisms underlying the effectiveness of MSC therapy by promoting angiogenesis.
We examined the incidence trends of bladder and kidney cancers using a population-based cancer registration data.
Age-standardized incidence rates were analyzed using data from the Shanghai Cancer Registry during 1973 to 2005. Annual percentage changes and 95% confidence intervals were calculated to evaluate the incidence changes. Age-period-cohort analysis was further implemented to assess the contributions of age, period and cohort effects to the trends using the intrinsic estimator method.
In total, 12,676 bladder and 5,811 kidney cancer patients were registered in urban Shanghai. The age-standardized rates of bladder cancer in males increased from 6.39 to 7.66 per 100,000, or 0.62% per year, whereas the rates in females increased from 1.95 to 2.09 per 100,000, or 0.33% per year. For kidney cancer, the age-standardized rates in males increased from 1.20 to 5.64 per 100,000, or 6.98% per year. Similarly in females, the rates increased from 0.85 to 3.33 per 100,000, or 5.93% per year. Age-period-cohort analysis showed increasing curves of age and period effects but generally decreasing cohort effects for bladder and kidney cancers.
Our results show increasing incidence trends of bladder and kidney cancers in Chinese men and women, especially for kidney cancer.
We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal–regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase–dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress–induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress–induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide–mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.
Plant responses to developmental and environmental cues are often mediated by calcium (Ca2+) signals that are transmitted by diverse calcium sensors. The calcineurin B-like (CBL) protein family represents calcium sensors that decode calcium signals through specific interactions with a group of CBL-interacting protein kinases. We report functional analysis of Arabidopsis CBL2 and CBL3, two closely related CBL members that are localized to the vacuolar membrane through the N-terminal tonoplast-targeting sequence. While cbl2 or cbl3 single mutant did not show any phenotypic difference from the wild type, the cbl2 cbl3 double mutant was stunted with leaf tip necrosis, underdeveloped roots, shorter siliques and fewer seeds. These defects were reminiscent of those in the vha-a2
vha-a3 double mutant deficient in vacuolar H+-ATPase (V-ATPase). Indeed, the V-ATPase activity was reduced in the cbl2 cbl3 double mutant, connecting tonoplast CBL-type calcium sensors to the regulation of V-ATPase. Furthermore, cbl2 cbl3 double mutant was compromised in ionic tolerance and micronutrient accumulation, consistent with the defect in V-ATPase activity that has been shown to function in ion compartmentalization. Our results suggest that calcium sensors CBL2 and CBL3 serve as molecular links between calcium signaling and V-ATPase, a central regulator of intracellular ion homeostasis.
calcium sensor; tonoplast; V-ATPase; ion homeostasis; V-ATPase
Background & Aims
Immunosuppression-related symptom experience has not been covered thoroughly in long-term liver transplant recipients. The aim of this study was to assess the symptom experience of immunosuppressive therapy three years after liver transplantation and to correlate it with adherence to medications and sociodemographic or disease-related characteristics.
This study included 94 liver transplant recipients who had survived for more than 3 years after liver transplantation. Symptom experience was measured by the 59-Item Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) at the outpatient visits. Adherence to immunosuppressive drugs was assessed using the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS).
Itching, concentration or memory problems, and fatigue were the three most frequent or most distressing symptoms. Factors significantly associated with a higher level of symptom frequency and distress were 3- to 5-year time cohort (i.e., time post-transplantation), and younger age. At the item level, concentration or memory problems were the most frequent and distressing symptoms in the 3- to 5-year time cohort. Itching was the most frequent and distressing symptom in the 5- to 9-year time cohort. Finally, relationship was found between symptom experience and nonadherence to immunosuppressive drugs.
Symptoms related to physical complaints or impairments were more often perceived and more distressing for liver transplant recipients 3 years after transplantation. Furthermore, the 3- to 5-year time cohort and younger age were associated with a higher degree of perceived symptom occurrence and symptom distress. Finally, recipients who perceived higher levels of symptom frequency and symptom distress reported higher levels of nonadherence.
Peri-procedural myocardial injury, which is associated with worse long-term clinical outcome, is a common complication related to inflammatory pathogenetic mechanisms. Monocytes and macrophages play key roles in the initiation and progression of atherosclerosis. Recent studies have demonstrated that monocytes in human peripheral blood are heterogeneous, including CD14+CD16− monocytes and CD14+CD16+ monocytes. Several lines of evidence suggested that CD14+CD16+ monocytes might contribute to the accelerated atherosclerosis. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we hypothesized that an up-shifting subset of CD14+CD16+ monocytes might be induced by percutaneous coronary intervention (PCI), which subsequently leads to peri-procedural myocardial injury. Moreover, statins loading before PCI could exert anti-inflammatory effects partly by modulating monocyte phenotype and thus prevent peri-procedural myocardial injury.
monocyte subsets; inflammation; peri-procedural myocardial injury; statin
hMOF (MYST1), a histone acetyltransferase (HAT), forms at least two distinct multiprotein complexes in human cells. The male specific lethal (MSL) HAT complex plays a key role in dosage compensation in Drosophila and is responsible for histone H4K16ac in vivo. We and others previously described a second hMOF-containing HAT complex, the non-specific lethal (NSL) HAT complex. The NSL complex has a broader substrate specificity, can acetylate H4 on K16, K5, and K8. The WD (tryptophan-aspartate) repeat domain 5 (WDR5) and host cell factor 1 (HCF1) are shared among members of the MLL/SET (mixed-lineage leukemia/set-domain containing) family of histone H3K4 methyltransferase complexes. The presence of these shared subunits raises the possibility that there are functional links between these complexes and the histone modifications they catalyze; however, the degree to which NSL and MLL/SET influence one another's activities remains unclear. Here, we present evidence from biochemical assays and knockdown/overexpression approaches arguing that the NSL HAT promotes histone H3K4me2 by MLL/SET complexes by an acetylation-dependent mechanism. In genomic experiments, we identified a set of genes including ANKRD2, that are affected by knockdown of both NSL and MLL/SET subunits, suggested they are co-regulated by NSL and MLL/SET complexes. In ChIP assays, we observe that depletion of the NSL subunits hMOF or NSL1 resulted in a significant reduction of both H4K16ac and H3K4me2 in the vicinity of the ANKRD2 transcriptional start site proximal region. However, depletion of RbBP5 (a core component of MLL/SET complexes) only reduced H3K4me2 marks, but not H4K16ac in the same region of ANKRD2, consistent with the idea that NSL acts upstream of MLL/SET to regulate H3K4me2 at certain promoters, suggesting coordination between NSL and MLL/SET complexes is involved in transcriptional regulation of certain genes. Taken together, our results suggest a crosstalk between the NSL and MLL/SET complexes in cells.
Covalent modification of N-terminal tails of histone proteins is accomplished by a variety of chromatin modifying complexes. These complexes catalyze at least eight distinct types of histone modifications including acetylation, methylation, phosphorylation, and ubiquitination. Histone modifications may act alone or in a coordinated manner to activate or repress chromosomal processes. For example, a particular histone modification may recruit or activate chromatin modifying complexes that generate a different histone modification. Coordination between hMOF-mediated histone H4K16 acetylation and other histone modifications has been reported by several research groups. The presence of subunits shared between the hMOF-containing NSL and MLL/SET family complexes suggests there may be functional links between two complexes. Consistent with this idea, we identified a set of genes that are co-regulated by the NSL and MLL/SET complexes. Both in vitro and in vivo experimental approaches provide evidence that the NSL HAT functions in promoting histone H3K4 di-methylation activity by MLL/SET complexes. Interestingly crosstalk between hMOF/NSL HAT and MLL/SET HMT activity seems to be unidirectional since there we detected no effect of MLL/SET activity on NSL HAT, either in vitro or in cells.
In the present study, we investigated the anti-nociceptive effect and the underlying mechanism of the analgesic-antitumor peptide (AGAP), a neurotoxin from the scorpion Buthus martensii Karsch. AGAP in doses of 0.2, 1 and 5 µg was injected intraplantarly (i.pl.) before formalin injection 10 min at the same site. The suppression by intraplantar injection of AGAP on formalin-induced spontaneous nociceptive behaviors was investigated. The results show that AGAP could dose-dependently inhibit formalin-induced two-phase spontaneous flinching response. To investigate the mechanism of action of treatment with AGAP in inflammatory pain, the expressions of peripheral and spinal phosphorylated mitogen-activated protein kinases (phospho-MAPKs) including p-p38, p-ERK and p-JNK were examined. We found that formalin increased the expressions of peripheral and spinal MAPKs, which were prevented by pre-intraplantar injection of AGAP in inflammation pain model in mice. AGAP could also decrease the expression of spinal Fos induced by formalin. Furthermore, combinations the lower doses of the inhibitors of MAPKs (U0126, SP600125, or SB203580 0.1 µg) with the lower dose of AGAP (0.2 µg), the results suggested that AGAP could potentiate the effects of the inhibitors of MAPKs on the inflammatory pain. The present results indicate that pre-intraplantar injection of AGAP prevents the inflammatory pain induced by formalin through a MAPKs-mediated mechanism in mice.
Laccase is useful for various biotechnological and industrial applications. The white-rot fungus Trametes velutina 5930 and its laccase, isolated from the Shennongjia Nature Reserve in China by our laboratory, has great potential for practical application in environmental biotechnology. However, the original level of laccase produced by Trametes velutina 5930 was relatively low in the absence of any inducer. Therefore, in order to enhance the laccase production by Trametes velutina 5930 and make better use of this fungus in the field of environmental biotechnology, the regulation of laccase production and laccase gene expression in Trametes velutina 5930 were investigated in this study. Different metal ions such as Cu2+ and Fe2+ could stimulate the laccase synthesis and laccase gene transcription in Trametes velutina 5930. Some aromatic compounds structurally related to lignin, such as tannic acid, syringic acid, cinnamic acid, gallic acid and guaiacol, could also enhance the level of laccase activity and laccase gene transcription. We also found that there existed a positive synergistic effect of aromatic compound and metal ion on the laccase production and laccase gene transcription in Trametes velutina 5930. Taken together, our study may contribute to the improvement of laccase productivity by Trametes velutina 5930.
AIM: To assess diagnostic accuracy of Ras association domain family 1A (RASSF1A) promoter methylation in body fluids (serum, plasma and whole blood) for hepatocellular carcinoma (HCC).
METHODS: Relative information about study characteristics and incidence of RASSF1A methylation was collected. Quality of all included studies was evaluated by Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled using a random-effect model, and a summary receiver operating characteristic curve was used to demonstrate the overall diagnostic performance. Positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with 95%CI were also calculated. Meta-regression was applied to analyze observed heterogeneity, and Deeks’ test was performed to detect publication bias.
RESULTS: After a systematic literature review, seven studies with a total of 302 cases of HCC and 250 cases of chronic liver diseases were included in the analysis. The pooled sensitivity and specificity were 0.70 (95%CI: 0.49-0.85) and 0.72 (95%CI: 0.54-0.85), respectively. The PLR was 2.51 (95%CI: 1.64-3.86), NLR was 0.41 (95%CI: 0.25-0.68), and DOR was 6.13 (95%CI: 3.17-11.84). The χ2 values of sensitivity, specificity, PLR, NLR and DOR were 59.41 (P < 0.001), 50.50 (P < 0.001), 17.40 (P = 0.010), 31.24 (P < 0.001) and 80.51 (P < 0.001), respectively. The area under the curve was 0.77 (95%CI: 0.73-0.81). Three factors were analyzed by univariate meta-regression and none was significant to interpret the observed heterogeneity (P > 0.05). No significant publication bias was detected by Deeks’ test (P = 0.346).
CONCLUSION: We showed the potential diagnostic value of RASSF1A methylation in body fluids in HCC patients and it may improve diagnostic accuracy combined with the α-fetoprotein test.
Methylation; Ras association domain family 1A; Hepatocellular carcinoma; Biomarker; Diagnostic sensitivity; Diagnostic specificity
Using a glutathione S-transferase pull-down liquid chromatography–coupled tandem mass spectrometry approach and immunoprecipitation/immunoblot analysis, we found that heat shock cognate protein 70 (Hsc70) was involved in the complex formed by atypical protein kinase Cι (PKCι) and LC3 in the esophageal cancer cell line KYSE30. Further study indicated that Hsc70 was targeted by autophagic degradation, and knockdown of PKCι down-regulated Hsc70 by promoting autophagy. PKCι knockdown sensitized cells to oxidative stress-induced apoptosis, whereas forced PKCι expression counteracted the oxidative stress-induced apoptosis via Hsc70.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-012-0389-4) contains supplementary material, which is available to authorized users.
PKCι; Hsc70; Oxidative stress; Autophagic degradation
As the pandemic (H1N1) 2009 progressed, the Ministry of Health of China advised cases with mild symptoms to remain home for isolation and observation, which may have increased the risk for infection among other household members. Describing the transmission characteristics of this novel virus is indispensable to effectively controlling the spread of disease; thus, the aim of this study was to assess risk factors associated with household transmission of pandemic H1N1 from self-quarantined patients in Beijing, the capital city of China. A 1:2 case-control study with 54 case households and 108 control households was conducted between August 1 and September 30, 2009 in Beijing. Cases were households with a self-quarantined index patient and a secondary case, while controls were households with a self-quarantined index patient and a close contact. Controls were also matched to cases for sex and age of index case-patient. A structured interview guide was used to collect the data. Conditional logistical models were employed to estimate Odds Ratios (OR) with 95% confidence intervals (95% CI). Results indicated that higher education level (OR 0.42; 95% CI 0.22-0.83), sharing room with an index case-patient (OR 3.29; 95%CI 1.23-8.78), daily room ventilation (OR 0.28; 95%CI 0.08-0.93), and hand washing ≥3/d (OR 0.71; 95%CI 0.48-0.94) were related to the household transmission of pandemic H1N1 from self-quarantined patients. These results highlight that health education, as well as the quarantine of the index case-patient immediately after infection, frequent hand hygiene, and ventilation are critical to mitigating household spread of pandemic H1N1 virus and minimizing its impact. Household contacts should be educated to promote these in-home practices to contain transmission, particularly when household members are quarantined at home.
In recent decades, ambient air pollution has been an important public health issue in Beijing, but little is known about air pollution and health effects after the 2008 Beijing Olympics. We conduct a time-series analysis to evaluate associations between daily mortality (nonaccidental, cardiovascular and respiratory mortality) and the major air pollutants (carbon monoxide, nitrogen dioxide and particulate matter less than 10 µm in aerodynamic diameter) in Beijing during the two years (2009∼2010) after the 2008 Beijing Olympics. We used generalized additive model to analyze relationship between daily mortality and air pollution. In single air pollutant model with two-day moving average concentrations of the air pollutants, increase in their interquartile range (IQR) associated with percent increase in nonaccidental mortality, 2.55 percent [95% confidence interval (CI): 1.99, 3.11] for CO, 2.54 percent (95% CI: 2.00, 3.08) for NO2 and 1.80 percent (95% CI: 1.21, 2.40) for PM10, respectively; increases in the IQR of air pollutant concentrations associated with percent increase in cardiovascular mortality, 2.88 percent (95% CI: 2.10,3.65) for CO, 2.63 percent (95% CI: 1.87, 3.39) for NO2 and 1.72 percent (95% CI: 0.88, 2.55) for PM10, respectively; and increase in IQR of air pollutant concentrations associated with respiratory mortality, 2.39 percent (95% CI: 0.68, 4.09) for CO, 1.79 percent (95% CI: 0.11, 3.47) for NO2 and 2.07 percent (95% CI: 0.21, 3.92) for PM10, respectively. We used the principal component analysis to avoid collinearity of varied air pollutants. In addition, the association stratified by sex and age was also examined. Ambient air pollution remained a significant contributor to nonaccidental and cardiopulmonary mortalities in Beijing during 2009∼2010.
Tumor necrosis factor-α (TNFα) activates both cell death and cell survival pathways. The activation of survival pathway renders most cancer cells resistant to TNF-induced cytotoxicity. We found that pretreatment with digitoflavone, a plant flavonoid, greatly sensitized TNFα-induced apoptotic cell death in several human pancreatic cancer cells. In search of the molecular basis of the sensitization effect of digitoflavone, digitoflavone was found to inhibit TNFα-induced activation of nuclear transcription factor-kappa B (NF-κB) which is the main survival factor in TNFα signaling. NF-κB suppression occurred through inhibition of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, and NF-κB nuclear translocation. This inhibition correlated with suppression of NF-κB-dependent genes involved in antiapoptosis (mcl-1, bcl-2, bcl-xl, c-iap1, c-iap2, flip, and survivin), proliferation (c-myc, cyclin d1), and angiogenesis (vegf, cox-2, and mmp-9). In addition, digitoflavone can activate JNK through inhibition of NF-κB signaling, provide a continuous blockade of the feed-back inhibitory mechanism by JNK-induced NF-κB activation. This study found a novel function of digitoflavone and enhanced the value of digitoflavone as an anticancer agent.
SELEX-Seq is now the optimal high-throughput technique for characterizing DNA-binding specificities of transcription factors. In this study, we introduced an improved EMSA-based SELEX-Seq strategy with several advantages. The improvements of this strategy included: (1) using a FAM-labeled probe to track protein-DNA complex in polyacrylamide gel for rapidly recovering the protein-bound dsDNA without relying on traditional radioactive labeling or ethidium bromide staining; (2) monitoring the specificity of SELEX selection by detecting a positive and negative sequence doped into the input DNAs used in each round with PCR amplification; (3) using nested PCR to ensure the specificity of PCR amplification of the selected DNAs after each round; (4) using the nucleotides added at the 5′ end of the nested PCR primers as the split barcode to code DNAs from various rounds for multiplexing sequencing samples. The split barcode minimized selection times and thus greatly simplified the current SELEX-Seq procedure. The reliability of the strategy was demonstrated by performing a successful SELEX-Seq of a well-known transcription factor, NF-κB. Therefore, this study provided a useful SELEX-Seq strategy for characterizing DNA-binding specificities of transcription factors.
Intramuscular fat (IMF) is an important trait influencing meat quality, and preadipocyte differentiation is a key factor affecting IMF deposition. Here we compared the transcriptome profiles of porcine intramuscular and subcutaneous preadipocytes during differentiation to gain insight into specific molecular and cellular events associated with intramuscular stromal vascular cell (MSVC) differentiation. RNA-Seq was used to screen for differentially expressed genes (DEGs) during the in vitro differentiation of MSVC and subcutaneous stromal vascular cell (ASVC) on days 0, 2 and 4. A total of 985 DEGs were identified during ASVC differentiation and 1469 DEGs during MSVC differentiation. Among these DEGs, 409 genes were specifically expressed during ASVC differentiation, 893 genes were specifically expressed during MSVC differentiation, and 576 DEGs were co-expressed during ASVC and MSVC differentiation. The expression profiles of DEGs during ASVC or MSVC differentiation were determined by cluster analysis based on Short Time-series Expression Miner (STEM). Four significant STEM profiles (profiles 1, 4, 5, and 14) were determined during ASVC differentiation, and four significant STEM profiles (profiles 1, 4, 11, and 14) were determined during MSVC differentiation. Gene ontology (GO) analysis indicated that DEGs related to adipocyte differentiation were identified to be significantly enriched in both adipose and muscle profile 14. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs in adipose profile 14 and muscle profiles 11 and 14 (STEM clustered them into one cluster) showed that the PPAR signaling pathway was significantly enriched in these profiles and four signaling pathways were specifically enriched in muscle profiles 11 and 14. Furthermore, analysis of transcription factor binding sites (TFBS) in the gene set revealed two over-represented transcription factors (NR3C4 and NR3C1), which were specifically significantly enriched in the promoter regions of genes within muscle gene expression profiles 11 and 14.
Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor-specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited effect on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival.
Biomarkers capable of discriminating the patients who are likely to respond to certain chemotherapeutic agents could improve the clinical efficiency. The sulfatases(SULFs) play a critical role in the pathogenesis of a variety of human cancers. Here, we focused our investigation on the prognostic and predictive impact of SULF2 methylation in gastric cancer.
Promoter CpG island methylation of SULF2 was analyzed in 100 gastric cancer samples. The in vitro sensitivity to cisplatin, docetaxel, gemcitabine, irinotecan and pemetrexed were determined by histoculture drug response assay(HDRA). Additionally, 56 gastric cancer patients treated with a modified FOLFOX regimen(biweekly oxaliplatin plus 5-FU and folinic acid) were retrospectively analyzed to further evaluate the prognostic and predictive impact of SULF2 methylation in gastric cancer.
Methylated SULF2(SULF2M) was detected in 28 patients, while the remaining 72 patients showed unmethylated SULF2(SULF2U, methylation rate: 28%). Samples with SULF2U were more sensitive to cisplatin than those with SULF2M(inhibition rate: 48.80% vs. 38.15%, P = 0.02), while samples with SULF2M were more sensitive to irinotecan than SULF2U(inhibition rate: 53.61% vs. 40.92%, P = 0.01). There were no association between SULF2 methylation and in vitro sensitivity to docetaxel, gemcitabine and pemetrexed. SULF2 methylation was found to have a significant association with cisplatin efficacy(SULF2M: 57.14%, SULF2U: 80.56%, P = 0.02) and irinotecan efficacy(SULF2M: 89.29%, SULF2U: 62.50%, P = 0.01). Among the 56 patients receiving the modified FOLFOX regimen, a significant association was observed between survival and SULF2 methylation status(SULF2M: 309 days, 95% CI = 236 to 382 days; SULF2U: 481 days, 95% CI = 418 to 490 days; P = 0.02). Multivariate analysis revealed that SULF2 methylation was an independent prognostic factor of overall survival in gastric cancer patients treated with platinum-based chemotherapy.
SULF2 methylation is negatively associated with cisplatin sensitivity in vitro. SULF2 methylation may be a novel prognostic biomarker for gastric cancer patients treated with platinum-based chemotherapy.
Notch signaling plays a critical role in the maintenance of intestinal crypt epithelial cell proliferation. The aim of this study was to investigate the role of Notch signaling in the proliferation and regeneration of intestinal epithelium after intestinal ischemia reperfusion (I/R) injury.
Male Sprague-Dawley rats were subjected to sham operation or I/R by occlusion of the superior mesenteric artery (SMA) for 20 min. Intestinal tissue samples were collected at 0, 1, 2, 4, and 6 h after reperfusion. Proliferation of the intestinal epithelium was evaluated by immunohistochemical staining of proliferating nuclear antigen (PCNA). The mRNA and protein expression levels of Notch signaling components were examined using Real-time PCR and Western blot analyses. Immunofluorescence was also performed to detect the expression and location of Jagged-2, cleaved Notch-1, and Hes-1 in the intestine. Finally, the γ-secretase inhibitor DAPT and the siRNA for Jagged-2 and Hes-1 were applied to investigate the functional role of Notch signaling in the proliferation of intestinal epithelial cells in an in vitro IEC-6 culture system.
I/R injury caused increased intestinal crypt epithelial cell proliferation and increased mRNA and protein expression of Jagged-2, Notch-1, and Hes-1. The immunofluorescence results further confirmed increased protein expression of Jagged-2, cleaved Notch-1, and Hes-1 in the intestinal crypts. The inhibition of Notch signaling with DAPT and the suppression of Jagged-2 and Hes-1 expression using siRNA both significantly inhibited the proliferation of IEC-6 cells.
The Jagged-2/Notch-1/Hes-1 signaling pathway is involved in intestinal epithelium regeneration early after I/R injury by increasing crypt epithelial cell proliferation.
The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) has been reported to have both tumor-promoting and tumor-suppressing roles in tumorigenesis. However, the role of SHP-2 in tumor immunity remains unclear. Here we observed progressively lower levels of phosphorylated SHP-2 in tumor-associated CD4+ T cells during melanoma development in a murine model. Similarly, the levels of phosphorylated SHP-2 in the CD4+ T cells of human melanoma specimens revealed a decrease paralleling cancer development. The CD4+ T cell-specific deletion of SHP-2 promoted melanoma metastasis in mice. Furthermore, SHP-2 deficiency in CD4+ T cells resulted in the increased release of inflammatory cytokines, especially IL-6, and the enhanced accumulation of tumor-promoting myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. An IL-6-neutralizing antibody reduced MDSC accumulation and inhibited tumor growth in CD4+ T-cell-specific SHP-2-knockout mice. Our results suggest that SHP-2 in CD4+ T cells plays an important role in preventing melanoma progression and metastasis.