A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter.

The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency

Relationship between the expression of hTERT and EYA4 mRNA in peripheral blood mononuclear cells with the progressive stages of carcinogenesis of the esophagus

<p>Abstract</p> <p>Objective</p> <p>To establish a relationship between esophageal squamous cell diseases and the expression of human telomerase reverse transcriptase (hTERT) and Eyes absent 4 (EYA4) mRNA in peripheral blood mononuclear cells.</p> <p>Methods</p> <p>Subjects were 50 patients with esophageal squamous cell carcinoma (ESCC), 50 with dysplasia (ESCD), 50 with basal cell hyperplasia (BCH) and 50 controls. All subjects were residents of Feicheng County, Shandong Province, China , diagnosed by histopathology. Expression of hTERT and EYA4 mRNA in peripheral blood was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).</p> <p>Results</p> <p>The hTERT and EYA4 mRNA positive expression increased according to disease severity. At the cut-off value of ≥ 0.2, the positive expression rates of EYA4 were 14% for controls, 20.0% for BCH, 26% for ESCD and 52% for ESCC, respectively. At the cut-off value of ≥ 0.8, the positive expression rates of hTERT in the four groups were 24%, 30.0%, 52% and 80%, respectively. Using a positive value of 0.47 for EYA4, the testing sensitivities in the ESCD and ESCC groups were 4% and 16%, respectively, and the testing specificity increased to 100%. Using a positive value of 1.0 for hTERT, the testing sensitivities in the ESCD and ESCC groups were 48% and 60%, respectively, and the testing specificity increased to 72%. The testing sensitivities in the predicting ESCD and ESCC in the discriminant model including EYA4 and hTERT and the five traditional risk factors (sex, age, smoking, alcohol drinking, and family history of esophageal cancer) were 70% and 80%, and testing specificities were 76% and 88% respectively. However, the testing sensitivities and specificities in the predicting ESCD and ESCC in the model only including the above five traditional risk factors were lower than that in the former case.</p> <p>Conclusion</p> <p>EYA4 and hTERT mRNA expression increased with the severity of esophageal pathological changes and may be useful for identifying high-risk endoscopy candidates or for monitoring changes in premalignant esophageal lesions.</p

The association between serum levels of oxLDL-lgG and oxLDL-lgM autoantibody with adult acute myeloblastic leukaemia

<p>Abstract</p> <p>Aim</p> <p>To evaluate the relationship between serum antibodies against ox-LDL levels and adult acute myeloblastic leukemia (AML).</p> <p>Methods</p> <p>Forty three patients with AML and 52 normal controls were enrolled in this study in the Department of Hematology, Tumor Center of Qilu Hospital of Shandong University from Feb. 2008 to Mar.2009. Serum lgG and lgM antibodies versus the oxLDL levels were evaluated by ELISA method. Data was analyzed by covariance and binary Logistic regression.</p> <p>Results</p> <p>Serum mean levels of oxLDL-lgG in patients (38.92 ± 21.1259 ug/ml) were significantly lower than in control subjects (78.88 ± 9.3705 ug/ml); Meanwhile, Serum mean levels of oxLDL-lgM in patients (20.53 ± 10.2990 IU/L) were significantly higher than in control subjects (10.29 ± 10.5771 IU/L). Binary logistic regression showed the odds ratios of association of oxLD-lgG and oxLD-lgM with adult AML were 0.72(95%CI: 0.55-0.94) and 1.11(95%CI: 1.01-1.21) respectively after adjusted for potential confounders.</p> <p>Conclusion</p> <p>In the preliminary investigation we found a descensive oxLDL- lgG and an elevated oxLDL-lgM serum levels for the adult AML. Future studies need to confirm the hypothesis whether they related to the development and progression of adult AML.</p

The effect of oxidized low-density lipoprotein combined with adriamycin on the proliferation of Eca-109 cell line

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to identify the affect on the proliferation Eca-109 cells treated with oxidized low-density lipoprotein (ox-LDL) combined with adriamycin (ADM).</p> <p>Methods</p> <p>Eca-109 cell were cultured in the presence of oxLDL/ADM, and cell proliferation tested by MTT and cell apoptosis was monitored by the proportion of apoptosis and cell cycle by flow cytomester. We simultaneously evaluated the level of associated- apoptosis Bcl-2, Bax, and Caspase-3 gene mRNA and protein.</p> <p>Results</p> <p>OxLDL were cytotoxic and activate apoptosis. OxLDL combined with ADM significant enhanced the proportion rate of apoptosis on a time and dose dependency. The expressions of the inhibiting apoptosis Bcl-2 gene mRNA and protein were down regulated, whereas, the expressions of the promoting apoptosis Bax, and Caspase-3 genes mRNA and protein were up regulation.</p> <p>Conclusion</p> <p>These results suggested that oxLDL have cytotoxicity and activate apoptosis on the Eca-109 cells. OxLDL combined with ADM have a synergistic effect on the apoptosis induced Eca-109 cells. Furthermore, oxLDL may contribute to the improvement of clinical chemotherapy of cancer need to make further investigation.</p

Analysis of gut microbiota and immune-related genes during sea cucumber (<em>Apostichopus japonicus</em>) response to dietary supplementation with <em>Codonopsis pilosula</em>

The gut microbiota composition of sea cucumber (Apostichopus japonicas) was investigated using high-throughput sequencing techniques. The mRNA expression of complement component 3 and lysozyme genes was evaluated using quantitative fluorescence PCR. Sea cucumbers were fed with a basal diet (control group) and an experimental diet supplemented with Codonopsis pilosula (experimental group) for 30 days. The results showed that the alpha diversity of the gut microbiota was changed in different indices, including Chao1, the abundance-based coverage estimator, the Shannon index, and Good's coverage. Dietary C. pilosula promoted the proliferation of the Flavobacteriaceae family of the Proteobacteria phylum and reduced the relative abundance of the Verrucomicrobiaceae family of the Verrucomicrobia phylum. We concluded that dietary C. pilosula supplementation could alter the network interactions among different microbial functional groups by changing the ecological network's microbial community composition and biological evolution. A positive effect on A. japonicus immune responses in the gut was seen via increasing the mRNA expression of the complement component 3 and lysozyme genes. It seems to happen via modulating the balance in gut microbiota

Effect of weaning age on growth performance, feed efficiency, nutrient digestibility and blood-biochemical parameters in Droughtmaster crossbred beef calves

Objective The objective of this study was to determine the effect of weaning age on intake, performance, nutrition metabolism and serum parameters of beef calves. Methods Sixty Droughtmaster crossbred calves were assigned to 5 groups with 12 calves in each group. The calves in control group remained with the dams till the 22-week age, while the calves weaned at 28 d (4 wk), 42 d (6 wk), 56 d (8 wk), and 70 d (10 wk) of age were sent to group 4 wk, group 6 wk, group 8 wk, and group 10 wk, respectively, and then were fed on milk replacer till the 22-week age. Feed intake and body weight and size were record and blood metabolites were measured. And 24 calves of them (6 in each group) were picked randomly for digestion and metabolism trail. Feed, feces and urine sample were taken and measured. Results Dry matter intake of calves in group 4 wk was significantly lower than those in the remaining groups from wk 17 to 22 (p0.05) but was higher than that of group 4 wk (p<0.05). Calves in group 6 wk had higher final body weight and total gain than group 4 wk, but no difference of total gain with that of groups 8 wk, 10 wk, and control group. And weaning calves at 6-week age brought higher feed efficiency and average daily gain from wk 14 to wk 22, and higher dry matter and organic matter digestibility at 21 wk. Conclusion It is concluded that the weaning of calves at 6 weeks of age gave positive results

Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

Fenofibrate (FEN) is a dyslipidemia treatment agent which is poorly soluble in water. FEN has tendency to form polymorphs and its crystallisation behaviour is difficult to predict. The nucleation process can be initiated by mechanical disruption such as ball milling or surface scratching which may result in different crystallisation behaviour to that observed in the unperturbed system. This study has obtained insights into the controllability of FEN crystallisation by means of regulating the exposed surface and growth temperatures during its crystallisation. The availability of an open top surface (OTS) during the crystallisation of the FEN melt resulted in a mixture containing FEN form I and IIa (I ≫ IIa) at room temperature, and in the range 40 to 70 °C. Covering the surface led to significant increases in the yield of form IIa at room temperature and at 40 and 50 °C. These temperatures also yielded the highest amount of form IIa in the OTS samples whilst crystallisation at 70 °C led to only FEN form I crystals regardless of the availability of the free surface. The metastable FEN form IIa transforms to the stable form I under the influence of a mechanical stress. Additionally, the introduction of OTS before the completion of crystallisation of form IIa led to a ‘switch’ of from IIa growth to form I. This study demonstrates that the polymorph selection of FEN can be obtained by the manipulation of the crystallisation conditions

Clinical-radiomics-based treatment decision support for KIT Exon 11 deletion in gastrointestinal stromal tumors: a multi-institutional retrospective study

Objectivegastrointestinal stromal tumors (GISTs) with KIT exon 11 deletions have more malignant clinical outcomes. A radiomics model was constructed for the preoperative prediction of KIT exon 11 deletion in GISTs.MethodsOverall, 126 patients with GISTs who underwent preoperative enhanced CT were included. GISTs were manually segmented using ITK-SNAP in the arterial phase (AP) and portal venous phase (PVP) images of enhanced CT. Features were extracted using Anaconda (version 4.2.0) with PyRadiomics. Radiomics models were constructed by LASSO. The clinical-radiomics model (combined model) was constructed by combining the clinical model with the best diagnostic effective radiomics model. ROC curves were used to compare the diagnostic effectiveness of radiomics model, clinical model, and combined model. Diagnostic effectiveness among radiomics model, clinical model and combine model were analyzed in external cohort (n=57). Statistics were carried out using R 3.6.1.ResultsThe Radscore showed favorable diagnostic efficacy. Among all radiomics models, the AP-PVP radiomics model exhibited excellent performance in the training cohort, with an AUC of 0.787 (95% CI: 0.687-0.866), which was verified in the test cohort (AUC=0.775, 95% CI: 0.608-0.895). Clinical features were also analyzed. Among the radiomics, clinical and combined models, the combined model showed favorable diagnostic efficacy in the training (AUC=0.863) and test cohorts (AUC=0.851). The combined model yielded the largest AUC of 0.829 (95% CI, 0.621–0.950) for the external validation of the combined model. GIST patients could be divided into high or low risk subgroups of recurrence and mortality by the Radscore.ConclusionThe radiomics models based on enhanced CT for predicting KIT exon 11 deletion mutations have good diagnostic performance

Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk.</p> <p>Methods</p> <p>A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for <it>CYP2E1 </it>G1259C, <it>hOGG1 </it>C326G, <it>MTHFR </it>C677T, <it>MPO </it>G463A, and <it>ALDH2 </it>allele genes were identified in blood samples collected from all participants.</p> <p>Results</p> <p>The alleles <it>ALDH2 </it>and <it>MTHFR </it>C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the <it>ALDH </it>1*1 genotype, the <it>ALDH </it>2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of <it>MTHFR </it>C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of <it>ALDH </it>2 and TT/TC of <it>MTHFR </it>C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (OR_G) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus.</p> <p>Conclusions</p> <p>The study demonstrated that the genotypes <it>ALDH2*2 </it>and <it>MTHFR </it>677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.</p

Prevalence and trend of hepatitis C virus infection among blood donors in Chinese mainland: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Blood transfusion is one of the most common transmission pathways of hepatitis C virus (HCV). This paper aims to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for HCV infection among blood donors in Chinese mainland, so as to help make prevention strategies and guide further research.</p> <p>Methods</p> <p>A systematic review was constructed based on the computerized literature database. Infection rates and 95% confidence intervals (95% CI) were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Data manipulation and statistical analyses were performed using STATA 10.0 and ArcGIS 9.3 was used for map construction.</p> <p>Results</p> <p>Two hundred and sixty-five studies met our inclusion criteria. The pooled prevalence of HCV infection among blood donors in Chinese mainland was 8.68% (95% CI: 8.01%-9.39%), and the epidemic was severer in North and Central China, especially in Henan and Hebei. While a significant lower rate was found in Yunnan. Notably, before 1998 the pooled prevalence of HCV infection was 12.87% (95%CI: 11.25%-14.56%) among blood donors, but decreased to 1.71% (95%CI: 1.43%-1.99%) after 1998. No significant difference was found in HCV infection rates between male and female blood donors, or among different blood type donors. The prevalence of HCV infection was found to increase with age. During 1994-1995, the prevalence rate reached the highest with a percentage of 15.78% (95%CI: 12.21%-19.75%), and showed a decreasing trend in the following years. A significant difference was found among groups with different blood donation types, Plasma donors had a relatively higher prevalence than whole blood donors of HCV infection (33.95% <it>vs </it>7.9%).</p> <p>Conclusions</p> <p>The prevalence of HCV infection has rapidly decreased since 1998 and kept a low level in recent years, but some provinces showed relatively higher prevalence than the general population. It is urgent to make efficient measures to prevent HCV secondary transmission and control chronic progress, and the key to reduce the HCV incidence among blood donors is to encourage true voluntary blood donors, strictly implement blood donation law, and avoid cross-infection.</p