R2-DDI: relation-aware feature refinement for drug-drug interaction prediction.

Precisely predicting the drug-drug interaction (DDI) is an important application and host research topic in drug discovery, especially for avoiding the adverse effect when using drug combination treatment for patients. Nowadays, machine learning and deep learning methods have achieved great success in DDI prediction. However, we notice that most of the works ignore the importance of the relation type when building the DDI prediction models. In this work, we propose a novel R$^2$-DDI framework, which introduces a relation-aware feature refinement module for drug representation learning. The relation feature is integrated into drug representation and refined in the framework. With the refinement features, we also incorporate the consistency training method to regularize the multi-branch predictions for better generalization. Through extensive experiments and studies, we demonstrate our R$^2$-DDI approach can significantly improve the DDI prediction performance over multiple real-world datasets and settings, and our method shows better generalization ability with the help of the feature refinement design.

Characterization of a novel detergent-resistant type I pullulanase from Bacillus megaterium Y103 and its application in laundry detergent.

This study aims to find a moderate pullulanase for detergent industry. The pulY103B gene (2217 bp) from Bacillus megaterium Y103 was cloned and expressed in Escherichia coli. PulY103B contained four conserved regions of glycoside hydrolase family (GH) 13 and the typical sequence of type I pullulanase. The optimal reaction conditions of PulY103B were pH 6.5 and 40 °C. In addition, it remained stable below 40 °C and over 80% of activity was retained at pH ranging from 6.0 to 8.5. The best substrate for the enzyme was pullulan. Furthermore, it exhibited activity toward wheat starch (36.5%) and soluble starch (33.4%) but had no activity toward amylose and glycogen. Maltotriose and maltohexaose were major pullulan hydrolysis products. Soluble starch and amylopectin were mainly hydrolyzed into maltotetraose. These results indicated that PulY103B is a novel type I pullulanase with transglycosylation activity via formation of α-1,4-glucosidic linkages. Moreover, PulY103B was strongly stimulated by nonionic detergents [viz, Tween 20 (10%), Tween 80 (1%), Triton X-100 (20%)] and commercial liquid detergents (3.0 g/L). Wash performance tests demonstrated that the mixture of PulY103B and detergent removed starch-based stains better than using detergent alone (p < 0.05). Therefore, this pullulanase has big potential as a detergent additive.

Marinobacter mangrovi sp. nov., isolated from mangrove sediment.

A novel marine bacterium, designated strain CHFG3-1-5T, was isolated from mangrove sediment sampled at Jiulong River estuary, Fujian, PR China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CHFG3-1-5T belonged to the genus Marinobacter, with the highest sequence similarity to Marinobacter segnicrescens SS011B1-4T (97.6%), followed by Marinobacter nanhaiticus D15-8WT (97.5%), Marinobacter bohaiensis T17T (97.1%) and Marinobacter hydrocarbonoclasticus SP.17T (90.6%). The bacterium was Gram-stain-negative, facultative anaerobic, oxidase- and catalase-positive, rod-shaped and motile with a polar flagellum. Strain CHFG3-1-5T grew optimally at 32-37 °C, pH 6.0-8.0 and in the presence of 2.0-3.0% (w/v) NaCl. The G+C content of the chromosomal DNA was 61.1 mol%. The major respiratory quinone was determined to be Q-9. The principal fatty acids were C16 : 0, summed feature 3 (C16 : 1 ω7c/ω6c), C12 : 0, summed feature 9 (C17 : 1 iso ω9c and/or C16 : 0 10-methyl), C12 : 0 3-OH and summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, three phospholipids, one glycolipid and two aminolipids. The average nucleotide identity and digital DNA-DNA hybridization values among the genomes of strain CHFG3-1-5T and the reference strains were 73.4-79.4 and 19.6-22.4%, respectively. Like many other species reported in the genus Marinobacter, strain CHFG3-1-5T was able to oxidise iron. The combined genotypic and phenotypic data showed that strain CHFG3-1-5T represents a novel species within the genus Marinobacter, for which the name Marinobacter mangrovi sp. nov. is proposed, with the type strain CHFG3-1-5T (=MCCC 1A18306T=KCTC 82398T).

Cloning and characterization of a novel amylopullulanase from Bacillus megaterium Y103 with transglycosylation activity.

OBJECTIVE: To obtain a novel pullulanase with synthetic ability from a microorganism and characterize its substrates specificity. RESULTS: A novel pullulanase, PulY103A, from Bacillus megaterium Y103 was purified, characterized and expressed in Escherichia coli. PulY103A contained the signature sequences of type I pullulanases and showed 94.7% identity with a type I pullulanase (BmPul) from B. megaterium WW1210, showing similar molecular weight (110.8 kDa) and optimal pH (6.5). However, PulY103A had an optimal temperature of of 45 °C and exhibited relatively higher activity toward amylose (48.3%) compared with pullulan (100%), soluble starch (67.5%), and amylopectin (23.1%). The thin-layer chromatography results showed that the major pullulan hydrolysis products were maltotriose and maltohexaose, which differed from those reported in other pullulanases. On the basis of enzyme specificity, PulY103A was an amylopullulanase, which presented transglycosylation activity by forming α-1,4-glucosidic linkages. CONCLUSIONS: A novel amylopullulanase with transglycosylation activity was characterized. The features of this enzyme suggested its potential to produce maltohexaose.

Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible. Cigarette smoking is one of the most commonly and important risk factors for COPD, which contributes to airway remodeling, the outstanding pathological changes in COPD. One potential mechanism which might be important for airway remodeling is the process called epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms of EMT in CS-induced COPD are still poorly understood. METHODS: Two Gene Expression Omnibus (GEO) datasets (GSE108134 and GSE5058) were combined to identify the key genes involved in COPD. Then, single-gene analysis of Lyn was performed. Lyn expression was confirmed in patients with COPD. 16HBE cells were treated with cigarette smoking extracts (CSE). Wild type (WT) C57BL/6 J mice and Lyn+/+ transgenic mice were exposed to CSE to establish CS-exposed model. Pathological changes were observed by hematoxylin-eosin staining. The expression levels of EMT markers were examined by using western blot and immunofluorescence. The expression and phosphorylation levels of Lyn and Smad2/3 were detected as well. RESULTS: The gain of mesenchymal markers vimentin and α-SMA with a concomitant loss of E-cadherin was observed in both in vivo and in vitro studies. Meanwhile, cigarette smoking extracts (CSE) induced EMT in 16HBE cells in a time- and dose- dependent manner. Furthermore, by analyzing GEO datasets and using molecular methods, we explored a kinase, Lyn, its expression correlated with the expression of E-cadherin, vimentin and α-SMA in CS-exposed model. Moreover, we found that EMT induced by CSE was regulated by activated Lyn through phosphorylation of Smad2/3. CONCLUSIONS: In summary, we found that Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling. As a kinase, Lyn is "druggable", and might provide a therapeutic opportunity for targeting EMT. Therefore, our research might provide a new method to treat COPD by targeting Lyn kinase specifically.

Method of distortion and pointing correction of a ground-based telescope.

Detection accuracy is an important performance indicator of ground-based telescopes and is affected mainly by pointing error, geometric distortion of the optical system, and parameter errors caused by machining error and installation error. To improve detection accuracy, a modified algorithm based on a simulated annealing algorithm is proposed in this paper; this algorithm is able to correct pointing, derive a geometric distortion solution, and re-estimate some parameters of telescopes simultaneously. The efficiency of the proposed method is verified by using the observation data of the telescope, whose aperture is 600 mm under two distortion models (the physical model and polynomial fitting model). The results show that the method presented in this paper can effectively solve the problem of nonconvergence of the distortion solution with a pointing error. The final angle error under the polynomial fitting model is 1.07″, and the pixel error is 0.06 pixels; the errors under the physical model are 1.08″ and 0.07 pixels. The correction effect under the two distortion models is basically the same, but the averaged operation speed based on the physical model is 19.45% faster.

Retinoid-X-receptors (α/ß) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.

Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRß, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/ß. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/ß. Loss of RXRs α/ß specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.

Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor.

In order to further promote the standardization of diagnosis and treatment of gastrointestinal stromal tumor (GIST) in China, the members of Chinese Society of Clinical Oncology (CSCO) Expert Committee on GIST thoroughly discussed the key contents of the consensus guidelines, and voted on the controversial issue. In final, the Chinese consensus guidelines for the diagnosis and management of GIST (2017 edition) was formed on the basis of 2013 edition consensus guidelines, which is hereby announced. The consensus included the pathological diagnosis, recurrence risk classification evaluation, targeted agent therapy, surgery and principles of surveillance of GIST.

Randomness Regularization With Simple Consistency Training for Neural Networks.

Randomness is widely introduced in neural network training to simplify model optimization or avoid the over-fitting problem. Among them, dropout and its variations in different aspects (e.g., data, model structure) are prevalent in regularizing the training of deep neural networks. Though effective and performing well, the randomness introduced by these dropout-based methods causes nonnegligible inconsistency between training and inference. In this paper, we introduce a simple consistency training strategy to regularize such randomness, namely R-Drop, which forces two output distributions sampled by each type of randomness to be consistent. Specifically, R-Drop minimizes the bidirectional KL-divergence between two output distributions produced by dropout-based randomness for each training sample. Theoretical analysis reveals that R-Drop can reduce the above inconsistency by reducing the inconsistency among the sampled sub structures and bridging the gap between the loss calculated by the full model and sub structures. Experiments on 7 widely-used deep learning tasks ( 23 datasets in total) demonstrate that R-Drop is universally effective for different types of neural networks (i.e., feed-forward, recurrent, and graph neural networks) and different learning paradigms (supervised, parameter-efficient, and semi-supervised). In particular, it achieves state-of-the-art performances with the vanilla Transformer model on WMT14 English → German translation ( 30.91 BLEU) and WMT14 English → French translation ( 43.95 BLEU), even surpassing models trained with extra large-scale data and expert-designed advanced variants of Transformer models.

[Epidemiology survey of gastrointestinal stromal tumor in Shanxi Province in 2011].

OBJECTIVE: To explore the incidence and distribution of gastrointestinal stromal tumor (GIST) in Shanxi Province. METHODS: Newly diagnosed and suspected GIST cases of Shanxi Province on January 1, 2011 to December 31, 2011 were collected from medical insurance records and hospital surveys. All specimens were sent to the Department of Pathology at Shanxi Provincial Tumor Hospital for examinations. And the data were analyzed by SPSS statistical analysis software. RESULTS: There were 153 newly discovered cases of GIST in Shanxi Province in 2011. And its distribution was scattered in different regions. The incidence was 4.3 per million (153/35 932 786) . The high-risk areas were Taiyuan (n = 25) and Changzhi (n = 25). There were 83 (54.2%) males and 70 (45.8%) females. And the incidence of males was not different from that of females ( (4.5 vs 4.0 )per million, P > 0.05). The median onset age was 59 (24-79) years. A high incidence of GIST occurred at an age range of 50-59 years (n = 33). Among the 139 patients, the tumor locations were stomach (n = 88, 63.3%), small intestine (n = 21, 15.1%), colon (n = 7, 5.0%), duodenum (n = 6, 4.3%), esophagus (n = 3, 2.2%) and extra-gastrointestinal (n = 14, 10.1%). And 113 cases had a record of tumor size. The median diameter was 5.78 (0.3-25.0) cm. The largest diameter was ≤ 2 cm (n = 30, 26.5%), > 2-5 cm (n = 33, 29.2%), > 5-10 cm (n = 36, 31.9%) and >10 cm (n = 14, 12.4%). The cell types of 141 cases were spindle cell (n = 112, 79.4%), epithelial (n = 11, 7.8%) and mixed (n = 18, 12.8%). CONCLUSIONS: Shanxi Province has a low incidence of GIST. And no statistically significant difference exists in the incidence between males and females. Taiyuan and Changzhi are relatively more prevalent.

[Accuracy of endorectal ultrasonography in preoperative staging of rectal cancer].

OBJECTIVE: To evaluate the accuracy of endorectal ultrasonography in preoperative staging of rectal carcinoma. METHODS: The 319 patients with rectal adenocarcinoma underwent endorectal ultrasonography evaluation from January 2007 to March 2010. There were 175 males and 144 females, and the age of patients were 22-82 year old (median 59 years). According their visiting time, 319 patients were divided into 3 groups (period A: January to December 2007; period B: January to December 2008; and period C: January 2009 to March 2010). All patients underwent endorectal ultrasonography, and the 3 doctors had finished evaluations with 272 cases (Doctor 1, 2, 3 had finished evaluations with 162, 64 and 46 cases respectively). The endorectal ultrasonography staging was compared with the pathology findings based on the surgical specimens in 319 patients who had surgery. RESULTS: Overall accuracy in assessing the level of rectal wall invasion was 67%. The accuracy of uT2 and uT3 were 43% and 81% respectively, and the difference was statistically significant (χ(2) = 30.54, P < 0.01), and the accuracy of uT4a was 59%, which was lower than uT3 (81%,χ(2) = 13.77, P < 0.01). Overall accuracy in assessing nodal involvement in the 311 patients treated with radical surgery was 66%. Staging accuracy tends to improve with experience, the accuracy with Doctor 1 in period C(staging accuracy of T and N were 84% and 81% respectively) were higher than period A(staging accuracy of T and N were 55% and 41% respectively) (χ(2) = 6.65 and 13.27, P < 0.01). CONCLUSIONS: Transrectal ultrasound for preoperative staging of rectal has higher accuracy with mastered ultrasound doctor.

Manipulation of crystallization nucleation and thermal degradation of PLA films by multi-morphologies CNC-ZnO nanoparticles.

Currently, the quest for more renewable and biodegradable materials is a scientific priority to address the problems of petroleum-based plastics are difficult to degrade. In this work, cellulose nanocrystals (CNC) have been used as a template and four morphologies of CNC-ZnO nanocomposites were prepared via a hydrothermal method, and CNC-ZnO/polylactic acid (PLA) composite films were obtained by solution casting. We find that CNC-ZnO nanocomposites as heterogeneous nucleating agents improved the crystallinity and the film with flower-like CNC-ZnO was improved by 2.4 %. Ea required for thermal degradation of the PLA films decreased to 66-81 % of that of neat PLA, calculated by the Kissinger method, the Friedman method, and the Flynn-Wall-Ozawa (FWO) method. The R2 model was the solid degradation mechanism of the PLA films, analyzed through the Coats-Redfern method and the Criado method. The H-bond content of the composite films was significantly reduced after thermal aging at 150 °C. We found that three-dimensional CNC-ZnO (ZnO-3) made more prominent contributions to the crystallization, thermal degradation, and thermal aging of PLA films than other dimensional. The thermal properties can be regulated by the dimension, size, and apparent morphology of CNC-ZnO nanoparticles.

Structural and functional analysis of a new subfamily of glycosyltransferases required for glycosylation of serine-rich streptococcal adhesins.

Serine-rich repeat glycoproteins (SRRPs) are a growing family of bacterial adhesins found in many streptococci and staphylococci; they play important roles in bacterial biofilm formation and pathogenesis. Glycosylation of this family of adhesins is essential for their biogenesis. A glucosyltransferase (Gtf3) catalyzes the second step of glycosylation of a SRRP (Fap1) from an oral streptococcus, Streptococcus parasanguinis. Although Gtf3 homologs are highly conserved in SRRP-containing streptococci, they share minimal homology with functionally known glycosyltransferases. We report here the 2.3 Å crystal structure of Gtf3. The structural analysis indicates that Gtf3 forms a tetramer and shares significant structural homology with glycosyltransferases from GT4, GT5, and GT20 subfamilies. Combining crystal structural analysis with site-directed mutagenesis and in vitro glycosyltransferase assays, we identified residues that are required for UDP- or UDP-glucose binding and for oligomerization of Gtf3 and determined their contribution to the enzymatic activity of Gtf3. Further in vivo studies revealed that the critical amino acid residues identified by the structural analysis are crucial for Fap1 glycosylation in S. parasanguinis in vivo. Moreover, Gtf3 homologs from other streptococci were able to rescue the gtf3 knock-out mutant of S. parasanguinis in vivo and catalyze the sugar transfer to the modified SRRP substrate in vitro, demonstrating the importance and conservation of the Gtf3 homologs in glycosylation of SRRPs. As the Gtf3 homologs only exist in SRRP-containing streptococci, we conclude that the Gtf3 homologs represent a unique subfamily of glycosyltransferases.

Effect of alginate coatings incorporated with chitinase from 'Baozhu' pear on the preservation of cherry tomato during refrigerated storage.

The effects of edible coatings based on sodium alginate with 'Baozhu' pear chitinase on the quality of cherry tomatoes during refrigerated storage were evaluated. Cherry tomatoes inoculated with Fusarium oxysporum were coated and stored up to 21 days. All coatings with the chitinase significantly reduced F. oxysporum proliferation on cherry tomatoes during storage and extended the shelf life of cherry tomatoes effectively (p < .05). Results showed that alginate coatings with the chitinase could prevent weight loss, maintain firmness, and slow down the changes of titratable acidity and vitamin C (p < .05) in a dose-dependent manner. However, no significant differences were observed between T3 (1% alginate/0.15% 'Baozhu' pear chitinase/1% glycerin) and T4 (1% sodium alginate/0.3% 'Baozhu' pear chitinase/1% glycerin) (p > .05). Overall, alginate coating with 0.15% 'Baozhu' pear chitinase could be a promising method to maintain the quality of cherry tomatoes.

Material properties of phase-separated TFEB condensates regulate the autophagy-lysosome pathway.

Very little is known about how the material properties of protein condensates assembled via liquid-liquid phase separation (LLPS) are maintained and affect physiological functions. Here we show that liquid-like condensates of the transcription factor TFEB exhibit low fusion propensity in vitro and in living cells. We directly measured the attraction force between droplets, and we characterized the interfacial tension, viscosity, and elasticity of TFEB condensates. TFEB condensates contain rigid interfacial boundaries that govern their interaction behaviors. Several small molecules, including Ro-3306, modify the material properties of TFEB condensates, increasing their size and fusion propensity. These compounds promote lysosomal biogenesis and function in a TFEB-dependent manner without changing its cytoplasmic-nuclear translocation. Ro-3306 promotes autophagy activity, facilitating degradation of toxic protein aggregates. Our study helps explain how protein condensates are maintained as physically separate entities and reveals that the material properties of TFEB condensates can be harnessed to modulate TFEB activity.

MicroRNA Content of Ewing Sarcoma Derived Extracellular Vesicles Leads to Biomarker Potential and Identification of a Previously Undocumented EWS-FLI1 Translocation.

Objective: Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic EWS-ETS chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing. Importantly, small extracellular vesicles (sEVs), including those frequently referred to as exosomes have been shown to be highly enriched with tumor-derived small RNAs such as miRNAs. We hypothesized that ESFT-specific sEVs are enriched with certain miRNAs which could be utilized toward an exo-miRNA biomarker signature specific to this disease. Methods: We performed miRNAseq to compare both the exo-derived and cell-derived miRNA content from 8 ESFT, 2 osteosarcoma, 2 non-cancerous cell lines, and pediatric plasma samples. Results: We found that sEVs derived from ESFT cells contained nearly 2-fold more number of unique individual miRNAs as compared to non-ESFT samples. Quantitative analysis of the differential enrichment of sEV miRNAs resulted in the identification of 62 sEV-miRNAs (exo-miRNAs) with significant (P < .05) enrichment variation between ESFT and non-ESFT sEV samples. To determine if we could utilize this miRNA signature to diagnose ESFT patients via a liquid biopsy, we analyzed the RNA content of total circulating sEVs isolated from 500 µL plasma from 5 pediatric ESFT patients, 2 pediatric osteosarcoma patients, 2 pediatric rhabdomyosarcoma patients, and 4 non-cancer pediatric controls. Pearson's clustering of 60 of the 62 candidate exo-miRNAs correctly identified 80% (4 of 5) of pathology confirmed ESFT patients. Importantly, RNAseq analysis of tumor tissue from the 1 outlier, revealed a previously uncharacterized EWS-FLI1 translocation.Conclusions: Taken together, these findings support the development and validation of an exo-miRNA-based liquid biopsy to aid in the diagnosis and monitoring of ESFT.

New cell surface protein involved in biofilm formation by Streptococcus parasanguinis.

Dental biofilm formation is critical for maintaining the healthy microbial ecology of the oral cavity. Streptococci are predominant bacterial species in the oral cavity and play important roles in the initiation of plaque formation. In this study, we identified a new cell surface protein, BapA1, from Streptococcus parasanguinis FW213 and determined that BapA1 is critical for biofilm formation. Sequence analysis revealed that BapA1 possesses a typical cell wall-sorting signal for cell surface-anchored proteins from Gram-positive bacteria. No functional orthologue was reported in other streptococci. BapA1 possesses nine putative pilin isopeptide linker domains which are crucial for pilus assembly in a number of Gram-positive bacteria. Deletion of the 3' portion of bapA1 generated a mutant that lacks surface-anchored BapA1 and abolishes formation of short fibrils on the cell surface. The mutant failed to form biofilms and exhibited reduced adherence to an in vitro tooth model. The BapA1 deficiency also inhibited bacterial autoaggregation. The N-terminal muramidase-released-protein-like domain mediated BapA1-BapA1 interactions, suggesting that BapA1-mediated cell-cell interactions are important for bacterial autoaggregation and biofilm formation. Furthermore, the BapA1-mediated bacterial adhesion and biofilm formation are independent of a fimbria-associated serine-rich repeat adhesin, Fap1, demonstrating that BapA1 is a new streptococcal adhesin.

[Analysis of predictors of axillary node metastases in 787 breast cancer patients].

OBJECTIVE: To explore the predictors of axillary nodal metastass in patients with breast cancer. METHODS: A retrospective study was performed using the clinicopathological data of breast cancer cases diagnosed and treated in our Hospital between Dec 2006 and Nov 2008. Logistic regression analysis was used to determine the predictors of axillary node positivity. RESULTS: The total number of patients was 1133. 69.5% of them (787) had complete clinical and pathological data. The median age was 49 years old (range 20-85). The average number of lymph nodes removed was 14.6 per person. The average number of involved nodes was 3.5 per person. Increasing tumor size was associated with increased risk of lymph node metastases. Assessed by multivariate analysis, the tumor size, age, ER status, and pathological type were significantly associated with node metastasis. CONCLUSIONS: Axillary nodal metastases are significantly affected by the tumor size, ER status, age, and pathological type in breast cancer patients.

[Pathological changes of rectal cancer after irinotecan, 5-fluorouracil or combined short-term radiotherapy].

OBJECTIVE: To observe and evaluate the pathologic changes and curative effects of irinotecan (CPT-11), 5-fluorouracil (5-FU) and combined short-term radiotherapy before low-set rectal cancer operation so as to provide a theoretic basis for formulating a new effective adjuvant therapeutic regimen. METHODS: A total of 41 patients of low rectal cancer were treated with CPT-11, 5-FU therapy or CPT-11 plus 5-FU combined short-term radiotherapy from April 2002 to April 2009. They were divided into 2 groups according to different treatment schemes, including irinotecan group (n = 18) and irinotecan combined short-term radiotherapy group (n = 23). The pathologic changes before and after treatment were observed and the differences of two treatment approaches compared. RESULTS: Tumor cells had different degrees of degeneration and necrosis under microscope in two groups. Compared with computed tomographic findings before therapy, tumor sizes of two groups were reduced by an average of 33.1% (13.5 mm vs 20.2 mm) and 34.4% (12.8 mm vs 19.5 mm) respectively. Two groups were graded according to the RCRG (rectal cancer regression grade) score: RCRG1: 7 cases vs 18 cases, RCRG2: 4 cases vs 3 cases and RCRG3: 7 cases vs 2 cases. According to the pathologic evaluation standard, 3-degree necrosis, cell interstitial fibrosis and intimal thickening in vessels were observed in two groups: 7 cases vs 17 cases, 6 cases vs 17 cases and 3 cases vs 14 cases respectively (all P < 0.05). Five patients achieved complete pathological remission in the irinotecan combined short-term radiotherapy group. CONCLUSION: Based on the pathological changes and mitigation results after treatment, CPT-11 and 5-FU may be used as neoadjuvant drugs for rectal cancer. If the above two drugs can be used in combination with short-term radiation, the curative effect will be better.

LPS-induced vein endothelial cell injury and acute lung injury have Btk and Orai 1 to regulate SOC-mediated calcium influx.

Patients with sepsis and sepsis-related complications have a high mortality. Endothelial cell dysfunction plays a central role in sepsis pathophysiological process. In sepsis patients, endothelial cell apoptosis is associated with intracellular calcium overload. Multiple functions in the apoptotic process have been found to be regulated by calcium signaling. Our previous work had proved that LPS-induced cell injury was associated with store-operated calcium (SOC) entry mediated by stromal interaction molecule-1 (STIM 1) in Human umbilical vein endothelial cells (HUVEC), but the underlying molecular mechanism has not been adequately defined. Here we report that the LPS-induced cell injury is related to the calcium overload in HUVEC. SOC entry mediated by calcium release-activated calcium modulator (Orai) 1 and transient receptor potential canonical (TRPC) 1 was associated with LPS-induced calcium overload and cell apoptosis. Bruton's tyrosine kinase (Btk)/Phospholipase C(PLC) γ/inositol 1,4,5-triphosphate receptor (IP3R) played a major role in regulating calcium overload in LPS-induced HUVEC. Knockdown of Btk markedly inhibited the expressions of Orai 1 and its downstream molecule IP3R but not that of TRPC1 in LPS-induced HUVEC. In mice, knockdown of Btk and Orai 1 inhibited LPS-induced calcium overload, pulmonary vascular endothelial cell (VEC) injury and acute lung injury. These findings demonstrated that Btk acts as a regulator of calcium-dependent signaling, especially in the Orai 1-mediated SOC entry of the LPS-induced VEC.