[Application of immune combination therapy in MSS/pMMR-type colorectal cancer: current status and future perspectives].

In recent years, immune checkpoint inhibitors (ICIs) have been widely used in malignant solid tumors with remarkable efficacy. However, in colorectal cancer (CRC), ICIs have shown significant therapeutic effects only in patients with highly microsatellite unstable/mismatch repair-deficient metastatic CRC and these patients are only a minority of all CRC patients. In contrast, the majority of patients, those with microsatellite stable (MSS)/mismatch repair-complete (pMMR)-type metastatic CRC, could hardly benefit from ICI monotherapies, and immune combination therapies have become the key to solveing this clinical challenge. This article introduces the common patterns and possible mechanisms of immune-combination therapies for MSS/pMMR-type CRC, the exploration and progress made in the application of immune-combination therapies, as well as the possible predictive markers of efficacy of immune therapies. The prospects and directions of ICIs in the treatment of MSS/pMMR-type CRC are also discussed.

[Study on relationship between Set gene expression and clinical manifestations in bone marrow of patients with acute myelogenous leukemia].

Objective: To explore the expression and significance of Set gene in Acute myeloid leukemia (AML) patients , and to analyze its effect for the prognosis of AML. Methods: The level of Set gene expression was detected by real-time PCR in 59 AML patients and 20 heathy people. The mutations in C-kit 8/17 gene, NPM1 gene and FLT3-TKD/ITD gene in 59 AML patients were detected by direct sequencing. Results: The level of Set gene expression[1.41(0.41-3.31)]was significantly higher in 59 AML patients.The expression of Set gene was correlated with the percentage of marrow blasts and CR in AML patients (P=0.040, P<0.001); the CR rate of Set gene high expression group was significantly lower than that of Set gene low expression group(32.1% vs 83.9%, P=0.01). In the intermediate-risk of AML patients with chromosome karyotype analysis, the CR rate of Set gene high expression group and low expression group were 34.8% and 88.9%, and there are significantly different between two groups(P<0.001); univariate and multivariate analysis showed that Set gene high expression group correlated with poor OS[4(2-15)months]and EFS[3(2-13)months])(P=0.021, P=0.017). It suggests that the Set gene maybe one of AML independent poor prognostic marker.The level of Set gene expression did not correlate with sex, age, WBC, HGB, PLT, FAB typing, chromosomal karyotype and NPM1, C-Kit8/17, CEBPa, FLT3-ITD/TKD gene mutations in AML patients(all P>0.05). Conclusions: The level of Set gene expression in bone marrow maybe play an important role in AML. The high expression of Set gene indicates poor prognosis in AML patients.

MYBA2 gene involved in anthocyanin and flavonol biosynthesis pathways in grapevine.

MYBA2 transcription factor (Myb-related gene) affects the coloring in grapevine berry and plays an important role in the biosynthesis of anthocyanin. The MYBA2 gene was cloned from Vitis vinifera L. cv. Cabernet Sauvignon and polyclonal antibodies for VvmybA2 were prepared. The VvmybA2 gene expression patterns were observed in seven tissues (the leaf, stem, flower, bud, root, berry, and tendril) and during the berry development stage at transcriptional and translational levels, respectively. The results indicated that the expression of VvmybA2 was approximately 11-fold higher in the berry than that in the other six tissues, and increased rapidly from 60 days after full bloom reaching a maximum on day 80. Furthermore, both the anthocyanin content and UDP-glucose:flavonoid-3-O-glucosyltransferase (UFGT) gene expression levels increased rapidly 60 days after full bloom. Moreover, correlation analysis indicated that the transcriptional and translational expression levels of the VvmybA2 gene were significantly positively correlated with not only UFGT and DFR genes but also with the anthocyanin content during berry development. These results suggested that VvmybA2 could not only regulate the transcription of both UFGT and DFR but also is involved in the expression of the UFGT gene associated with color determination in grape berries.

Several time indicators and Barthel index relationships at different spinal cord injury levels.

STUDY DESIGN: Retrospective chart review. OBJECTIVES: To compare different injury levels in spinal cord injury (SCI) patients with respect to operation intervention time (OIT), rehabilitation intervention time (RIT), average length of hospital stay (ALOS) and Barthel Index (BI) on admission and discharge. SETTING: China. METHODS: We retrospectively analyzed data from 95 SCI cases who received treatment in our rehabilitation center from 2010-2013. RESULTS: SCI resulted from high falls (55.79%), traffic accidents (28.42%), diseases (8.42%) and low falls (7.37%). We found no correlations between OIT, RIT, ALOS and discharge BI for all spinal segments (P>0.05). The OIT of thoracic SCI and lumbar SCI correlated negatively with RIT (P<0.01). The OIT of lumbar SCI correlated negatively with ALOS (P<0.05). CONCLUSION: BI had no correlation with OIT, RIT or ALOS for all spinal segments; the OIT of thoracic and lumbar SCI correlated negatively with RIT; and the OIT of lumbar SCI correlated negatively with ALOS.

MiRNA-1246 suppresses the proliferation and migration of renal cell carcinoma through targeting CXCR4.

OBJECTIVE: To uncover the role of miRNA-1246 in influencing the proliferative and migratory capacities of RCC by binding CXCR4 and downregulating its level. PATIENTS AND METHODS: Relative levels of miRNA-1246 and CXCR4 in 40 paired RCC tissues and adjacent normal tissues were determined. The binding relationship between miRNA-1246 and CXCR4 was confirmed by Dual-Luciferase reporter assay. Proliferative and migratory abilities of RCC regulated by miRNA-1246 and CXCR4 were assessed. RESULTS: MiRNA-1246 was downregulated in RCC tissues and cell lines. Overexpression of miRNA-1246 attenuated proliferative and migratory capacities of 786-O and 769-P cells. CXCR4 was the direct target of miRNA-1246 and its level was negatively regulated by miRNA-1246. Silence of CXCR4 inhibited RCC to proliferate and migrate. CONCLUSIONS: MiRNA-1246 attenuates proliferative and migratory abilities of RCC by downregulating CXCR4. MiRNA-1246/CXCR4 axis could be potential therapeutic target for RCC.

Effect of miR-29c on renal fibrosis in diabetic rats via the AMPK/mTOR signaling pathway.

OBJECTIVE: To explore the effect of micro-ribonucleic acid (miR)-29c on renal fibrosis in diabetic rats through the adenosine 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway, and to investigate its related mechanism by the research on the effect of miR-29c on the expression of fibrosis-related genes. MATERIALS AND METHODS: The rat model of diabetic nephropathy (DN) was established, and the levels of fasting blood glucose (FBG), 24 h urine protein (24h-Pro), blood urea nitrogen (BUN), and serum creatinine (sCr) were monitored. After the rats were executed, kidney tissues were dissected, stained with paraffin and embedded in hematoxylin and eosin (H&E). Then, Western blotting was used to detect the levels of miR-29c, phosphorylated-AMPK (p-AMPK), α-smooth muscle actin (α-SMA), tumor necrosis factor-α (TNF-α), and macrophage migration inhibitory factor (MIF). The human renal tubular epithelial HK-2 cell line was treated with high glucose (HG) to simulate DN cell status in vivo. After that, the expressions of miR-29c and the renal fibrosis marker α-SMA were examined via Western blotting. Finally, the level of α-SMA was measured by Western blotting after HG treatment combined with miR-29c silencing. RESULTS: The levels of FBG, BUN, sCr, and 24h-Pro in DN model rats were significantly higher than those in rats of control group. The data manifested that the DN model was successfully established. The expression level of miR-29c in DN model rats was markedly increased and that of the downstream protein p-AMPK also exhibited a significantly increasing trend. In addition, the levels of α-SMA, TNF-α, and MIF were elevated. The expression levels of miR-29c and α-SMA were increased markedly after the human renal tubular epithelial HK-2 cell line was treated with HG, but the expression of α-SMA was reduced after HG treatment combined with miR-29c silencing for 24 h. CONCLUSIONS: MiR-29c is probably related to the occurrence and development of DN. Besides, miR-29c silencing may inhibit the DN renal fibrosis through AMPK/mTOR signals, so miR-29c may be an effective target for the treatment of DN renal fibrosis.

MicroRNA-29a enhances autophagy in podocytes as a protective mechanism against high glucose-induced apoptosis by targeting heme oxygenase-1.

OBJECTIVE: To evaluate the effects of miR-29a on the high glucose (HG)-induced apoptosis and the correlation between miR-29a and heme oxygenase-1 (HO-1) and the underlying molecular mechanism. MATERIALS AND METHODS: The cell apoptosis was analyzed by the flow cytometry, and the cells autophagy was evaluated using the transmission electron microscopy. Luciferase reporter assay was carried out to detect the correlation between miR-29a and HO-1. Besides, reverse transcription-PCR and Western blot were applied to detect the mRNA and protein levels. RESULTS: The expression of miR-29a was significantly decreased in the HG-treated podocytes. Besides, miR-29a overexpression could promote cellular autophagy and significantly reduce HG-induced podocytes apoptosis. Moreover, HO-1 was a direct target of miR-29a and the pre-autophagy and the anti-apoptotic effects of miR-29a on HG-treated podocytes could be significantly reversed by the HO-1 siRNA administration. CONCLUSIONS: MiR-29a functionally promoted podocytes autophagy and inhibited apoptosis through the HO-1dependent pathway in the HG condition.

Enhanced glycolysis in the process of renal fibrosis aggravated the development of chronic kidney disease.

OBJECTIVE: To explore the effect of glycometabolism on renal fibrosis and its underlying mechanism. MATERIALS AND METHODS: For in vivo experiments, unilateral ureteral obstruction (UUO) mouse model was constructed to induce renal interstitial fibrosis. Fibrosis and proliferation indicators in renal tissues were detected to observe the fibroblast phenotype changes during the process of renal fibrosis. Moreover, mRNA and protein levels of key enzymes in glycometabolism were also detected. For in vitro experiments, plasmid transfection was performed to overexpress pyruvate kinase M2 (PKM2) to explore the relationship between PKM2 and renal interstitial fibrosis. Energy metabolism monitoring was performed to detect changes in aerobic glycolysis and oxidative phosphorylation during the process of TGF-ß1-induced fibroblast phenotype changes. RESULTS: Fibroblast phenotype was changed. Both fibrosis and proliferation indicators were upregulated during renal fibrosis. Meanwhile, elevated expressions of key enzymes in glycometabolism and metabolic reprogramming of fibroblasts were observed. Overexpressed PKM2 activated fibroblasts and induced renal interstitial fibrosis, accompanied by increased glycometabolism level. CONCLUSIONS: Metabolic reprogramming promoted renal interstitial fibrosis, which leads to alteration of cell energy metabolism model.

MiR-519d inhibits prostate cancer cell proliferation, cycle and invasion via targeting NRBP1.

OBJECTIVE: To investigate the effects of miR-519d on the proliferation, cycle and invasion of human prostate cancer PC3 cells and its possible molecular mechanism. MATERIALS AND METHODS: The proliferation, cycle, and invasion of human prostate cancer PC3 cells were detected via cell counting kit-8 (CCK-8) and transwell assay. The expression of NRBP1 mRNA was detected via reverse transcription-polymerase chain reaction (RT-PCR). Western blotting was used to detect the expression of NRBP1, cyclin D1, and epithelial-mesenchymal transition (EMT) markers. RESULTS: The expression of miR-519d in prostate cancer was decreased, which was correlated with tumor size, metastasis, and staging. Proliferation, cycle, and invasion of PC3 cells were significantly decreased after overexpression of miR-519d. Bioinformatics analysis and Western blotting showed that there was a potential miR-519d binding site in NRBP1 3'-UTR, and overexpression of miR-519d significantly inhibited the expression of NRBP1. The expression of E-cadherin in PC3 cells overexpressing miR-519d was up-regulated, and the expressions of N-cadherin, cyclin D1, vimentin, fibronectin, and Snail were down-regulated. CONCLUSIONS: MiR-519d can repress the proliferation, cycle, and invasion of prostate cancer PC3 cells by inhibiting NRBP1.

Erythrocyte fatty acids, plasma lipids, and cardiovascular disease in rural China.

Cardiovascular disease (CVD) mortality (coronary heart disease, hypertensive heart disease, and stroke), plasma lipids, and red blood cell fatty acid composition were examined in an ecologic study in 65 rural counties in the People's Republic of China. Means of plasma total cholesterol, triglyceride, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol concentrations were substantially lower and the ratio of HDL cholesterol to total cholesterol was higher in this Chinese population than in Western populations. Mortality rates for CVD in China were well below Western values. Within China neither plasma total cholesterol nor LDL cholesterol was associated with CVD. A strong inverse correlation between red blood cell oleate concentrations and CVD was observed. However, red blood cell oleate concentrations were not associated with plasma cholesterol but were strongly negatively associated with arachidonate concentrations, suggesting potential diminution of CVD by oleate through reduced platelet aggregability. The results indicate that geographical differences in CVD mortality within China are caused primarily by factors other than dietary or plasma cholesterol.

Facial contact dermatitis. Pathogenetic factors in China.

In 107 cases of facial contact dermatitis, routine Finn chamber epicutaneous tests with TROLAB European Standard Allergens (ESAs) were performed. Sixty-one (57%) had positive reaction. The most frequent contact allergens were paraphenylenediamine dihydrochloride (16%), followed by fragrance mix (15%), and nickel sulfate (13%). The major sensitized contactants were rims of spectacles, hair dyes, cosmetic creams, and topical medications. Among the cases caused by cosmetic cream, the positive allergens were fragrance mix, formaldehyde, wood alcohols, and balsam of Peru. In ten season-incidence cases in which ESAs and cosmetic cream epicutaneous tests were negative, the chamber and scratch-chamber tests were performed using five kinds of pollen. The results show that all chamber tests were negative, but two cases with scratch-chamber tests were positive.

Study on Chinese common allergens of contact dermatitis.

Patch tests were performed according to the European Standard Allergens (ESA) in 204 cases suspected of contact dermatitis. The reaction was positive in 58.33% of the cases. The common allergens were nickel (15.7%), fragrance mix (11.8%) p-phenylenediamine (8.8%), colophony (6.9%), benzocaine (6.4%), formaldehyde (5.9%), black rubber mix (4.9%), cobalt (4.4%), balsam of Peru (3.9%), potassium dichromate (3.4%), thiuram mix (2.9%) and mercapto mix (2.9%). In 85 cases of negative reaction to the European Standard Allergens, 36 were patch tested to suspected agents based on the individual case histories, of which 21 positively reacted. The common sensitizing agents were ampicillin and thiomersal. Of 204 cases, 107 were cases of facial contact dermatitis. Patch tests showed that the most common allergens were p-phenylenediamine (15.9%), nickel (13.1%) and fragrance mix (14.95%).

Effects of cholestanetriol on cytotoxicity and prostacyclin production in cultured rabbit aortic endothelial cells.

Rabbit aortic endothelial cells in culture were incubated with 10 micrograms/ml of either pure cholesterol or cholestane-3 beta, 5 alpha, 6 beta-triol (triol) for 12 or 24 hours. Cells incubated with triol showed an increased rate of cell death, decreased [3H]-thymidine incorporation and decreased prostacyclin production as compared to either the control or the pure cholesterol group. These effects were more marked at 24 hours than at 12 hours. Pure cholesterol had no significant effects on any of the above parameters at either time interval. These results suggest potential atherogenic mechanisms for cholestanetriol, one of the most biologically active cholesterol oxidation products.

Path test reactions to the Chinese Standard Screening Allergens in 1,135 patients investigated for allergic contact dermatitis.

BACKGROUND: The patch test has become the standard method of investigating patients with allergic contact dermatitis. Many countries have developed standard screening allergens to make patch testing more efficient. A series of the Chinese Standard Screening Allergens were studied and modified. OBJECTIVE: This study investigated the frequency of contact allergies in suspected allergic contact dermatitis and tested the practicality of the Chinese Standard Screening Patch Test Allergens. METHODS: A total of 1,135 patients suspected of having allergic contact dermatitis were patch tested. Three hundred twelve (27.5%) were men, and their age ranged from 2 to 75 years old (mean age, 34.3 years), 823 (72.5%) were women, and their age ranged from 2 to 76 years old (mean age, 33.0 years). Nanjing Medical University supplied the Chinese Standard Screening Allergens and Finn-Chamber. All patients were patch tested according to the Chinese Standard Screening Patch Test Allergens with Finn-Chamber the protocol as established by the International Contact Dermatitis Research Group (ICDRG). RESULTS: From the 1,135 patients suspected to have allergic contact dermatitis, 650 (57.3%) had at least one positive reaction. Nineteen (95%) of the Chinese Standard Screening Patch Test Allergens had positive reactions higher than 1%. Of 485 patients with negative reaction to the Standard Allergens, 106 patients were tested with other suspected contactants according to history. Thirty-nine (36.8%) had positive reactions to the contactants they provided. The total positive rate therefore increased by 3.4%. CONCLUSIONS: Our study results indicate that the Chinese Standard Screening Patch Test Allergens are suitable for use in routine clinic in China.

Role of Mycobacterium paratuberculosis in Crohn's disease: a prospective, controlled study using polymerase chain reaction.

PURPOSE: Mycobacterium paratuberculosis has been proposed as a causative agent in patients with Crohn's disease. The purpose of this study was to determine whether M. paratuberculosis was present in tissue from patients with Crohn's disease in a defined geographic area. METHODS: We prospectively evaluated, using polymerase chain reaction and culture, whether M. paratuberculosis was present in 44 specimens (37 from intestinal mucosal biopsies and 7 from surgical resections) from patients with Crohn's disease, ulcerative colitis, or normal colonic mucosa. RESULTS: Of the 25 specimens tested from the 21 Crohn's patients, only 1 positive specimen was noted, whereas the 8 specimens from the 5 ulcerative colitis patients and the 11 specimens from the 11 control patients failed to demonstrate a positive result with polymerase chain reaction. Cultures of all specimens revealed no growth of M. paratuberculosis. CONCLUSION: M. paratuberculosis was only rarely detected in biopsy or surgical specimens from patients with Crohn's disease. These results do not support a common causative role of M. paratuberculosis in Crohn's disease.