Multi-scaled self-attention for drug-target interaction prediction based on multi-granularity representation.

BACKGROUND: Drug-target interaction (DTI) prediction plays a crucial role in drug discovery. Although the advanced deep learning has shown promising results in predicting DTIs, it still needs improvements in two aspects: (1) encoding method, in which the existing encoding method, character encoding, overlooks chemical textual information of atoms with multiple characters and chemical functional groups; as well as (2) the architecture of deep model, which should focus on multiple chemical patterns in drug and target representations. RESULTS: In this paper, we propose a multi-granularity multi-scaled self-attention (SAN) model by alleviating the above problems. Specifically, in process of encoding, we investigate a segmentation method for drug and protein sequences and then label the segmented groups as the multi-granularity representations. Moreover, in order to enhance the various local patterns in these multi-granularity representations, a multi-scaled SAN is built and exploited to generate deep representations of drugs and targets. Finally, our proposed model predicts DTIs based on the fusion of these deep representations. Our proposed model is evaluated on two benchmark datasets, KIBA and Davis. The experimental results reveal that our proposed model yields better prediction accuracy than strong baseline models. CONCLUSION: Our proposed multi-granularity encoding method and multi-scaled SAN model improve DTI prediction by encoding the chemical textual information of drugs and targets and extracting their various local patterns, respectively.

Intraperitoneal chromophore injections delay early-onset and rapid retinal cone degeneration in a mouse model of Leber congenital amaurosis.

Highly expressed in the retinal pigment epithelium (RPE), the RPE-specific 65-kDa (RPE65) enzyme is indispensable to generate 11-cis-retinal (11cRAL), a chromophore for rhodopsin and cone photopigments. RPE65 deficiency can lead to Leber congenital amaurosis type 2 (LCA2), in which the isomerization of photobleached all-trans-retinal into photosensitive 11cRAL is blocked, ultimately causing severe retinal dysfunction and degeneration. The related mouse models, which are constructed through gene knockout or caused by spontaneous mutations, morphologically present with early-onset and rapid retinal cone cells degeneration, including loss of short-wavelength-sensitive cone opsins (S-opsins) and mislocalization of medium-wavelength-sensitive cone opsins (M-opsins). Studies have shown that routine Rpe65 gene replacement therapy, mediated by an adeno-associated virus (AAV) vector, can restore RPE65 protein. However, AAV transfection and Rpe65 transgene expression require at least one to two weeks, and the treatment cannot fully block the early-onset cone degeneration. To determine the feasibility of delaying cone degeneration before gene therapy, we investigated the impact of 11cRAL treatment in an early-age LCA2 retinal degeneration 12 (rd12) mouse model. Similar to human patients, the mouse model carries a spontaneous mutation in the Rpe65 gene, which results in disrupted endogenous 11cRAL regeneration. We found that RPE65 deficiency did not notably affect rodent retinal vessels. Under red light illumination, the rd12 mice were intraperitoneally injected with exogenous 11cRAL from postnatal day (P) 14 to P21. Three days after the last injection, a notable recovery of retinal function was observed using scotopic and photopic electroretinograms. Using optical coherence tomography and histological analyses of the deficient retinas, we found changes in the thickness of the photoreceptor outer segment (OS); this change could be rescued by early 11cRAL treatment. In addition, the treatment notably preserved M- and S-opsins, both of which maintained appropriate localization inside cone cells, as shown by the wild-type mice. In contrast, the age-matched untreated rd12 mice were characterized by retinal S-opsin loss and M-opsin mislocalization from the photoreceptor OS to the inner segment, outer nuclear layer, or outer plexiform layer. Notably, 11cRAL treatment could not maintain retinal function for a long time. Ten days after the last injection, the rod and M-cone electroretinograms significantly decreased, and S-cone responses almost extinguished. Our findings suggest that early 11cRAL treatment is useful for restoring retinal function and rescuing morphology in the rd12 mouse model, and the early-onset and rapid cone degeneration can be delayed before gene therapy.

Rodent retinal microcirculation and visual electrophysiology following simulated microgravity.

How the absence of gravity affects the physiology of human beings is generating global research interest as space exploration, including missions aboard the International Space Station, continues to push boundaries. Here, we examined changes in retinal microcirculation and visual electrophysiology in mice suspended by their tails to simulate the cephalad movement of blood that occurs under microgravity conditions. Tail suspension was performed with a head-down tilt with a recommended angle of 30°. Mice in the control groups were similarly attached to a tether but could maintain a normal position. Morphologically, the 15-day tail-suspended mice showed retinal microvascular dilation, tortuosity, and a relatively long fluorescence retention; however, the average diameter of the major retinal vessels was not notably changed. In addition, optical coherence tomography showed their optic nerve head had an increased diameter. However, the mice could adapt to the change, with microcirculation and the optic nerve head recovering following 30-day tail suspension. Expression of rhodopsin and cone-opsins was not notably changed, and no retinal apoptotic-positive cells were detected between 15- and 30-day tail suspensions. Moreover, the three experimental groups of suspended mice showed normal retinal layers and thickness. Functionally, following 15-day tail suspension, scotopic electroretinograms showed a decline in the oscillatory potentials (OPs), but not in the b wave; simultaneously, the peak time of flash visual evoked potential component N1 was delayed compared to its baseline and the time-matched control. Following 30-day tail suspension, the OPs (O2) amplitude recovered to approximately 97% of its baseline or 86% of the time-matched control level. By simulating cephalad shifting of blood, short-term tail suspension can affect rodent retinal microcirculation, the optic nerve head, and disturb visual electrophysiology. However, the change is reversible with no permanent injury observed in the retina. The mice could adapt to the short-term change of retinal microcirculation, indicating new conditions that could be combined with, or could enhance, simulated microgravity for further studying the impact of short- or long-term outer space conditions on the retina.

Derivation and Evaluation of a Risk-Scoring Tool to Predict Participant Attrition in a Lifestyle Intervention Project.

Participant attrition in clinical trials and community-based interventions is a serious, common, and costly problem. In order to develop a simple predictive scoring system that can quantify the risk of participant attrition in a lifestyle intervention project, we analyzed data from the Special Diabetes Program for Indians Diabetes Prevention Program (SDPI-DP), an evidence-based lifestyle intervention to prevent diabetes in 36 American Indian and Alaska Native communities. SDPI-DP participants were randomly divided into a derivation cohort (n = 1600) and a validation cohort (n = 801). Logistic regressions were used to develop a scoring system from the derivation cohort. The discriminatory power and calibration properties of the system were assessed using the validation cohort. Seven independent factors predicted program attrition: gender, age, household income, comorbidity, chronic pain, site's user population size, and average age of site staff. Six factors predicted long-term attrition: gender, age, marital status, chronic pain, site's user population size, and average age of site staff. Each model exhibited moderate to fair discriminatory power (C statistic in the validation set: 0.70 for program attrition, and 0.66 for long-term attrition) and excellent calibration. The resulting scoring system offers a low-technology approach to identify participants at elevated risk for attrition in future similar behavioral modification intervention projects, which may inform appropriate allocation of retention resources. This approach also serves as a model for other efforts to prevent participant attrition.

Cysteine-Mediated Intracellular Building of Luciferin to Enhance Probe Retention and Fluorescence Turn-On.

The development of sensitive and selective small molecular probes that enable real-time detection of endogenous cysteine (Cys) has become an attractive topic because of the essential roles played by Cys in controlling the cellular nitrogen balance and in maintaining biological redox homeostasis. Herein, we report a Cys-specific probe, 2-cyanobenzothiazol-6-yl acrylate (CBTOA), that shows not only fluorescence turn-on for sensitive detection of endogenous Cys but also enhanced probe retention inside cells for real-time monitoring of Cys levels upon external stimulation. Cys-mediated intracellular formation of luciferin from CBTOA was the key strategy leading to this new type of fluorogenic probe. CBTOA showed fast response to Cys in living cells and liver tissue slices with high sensitivity and selectivity. By using CBTOA as a real-time probe, we were able to monitor the change in Cys levels in living HeLa cells under ROS-induced oxidative stress as well as in human mesenchymal stem cells during adipogenic differentiation.

Participant and site characteristics related to participant retention in a diabetes prevention translational project.

Using multilevel analysis, this study investigated participant and site characteristics associated with participant retention in a multisite diabetes prevention translational project among American Indian and Alaska Native (AI/AN) people. We analyzed data from the Special Diabetes Program for Indians Diabetes Prevention Program (SDPI-DP), a lifestyle intervention to prevent diabetes implemented in 36 AI/AN grantee sites. A total of 2,553 participants were recruited and started the intervention between January 1, 2006 and July 31, 2008. They were offered the 16-session Lifestyle Balance Curriculum from the Diabetes Prevention Program (DPP) in the first 16-24 weeks of intervention. Generalized estimating equation models and proportional hazards models with robust standard error estimates were used to evaluate the relationships of participant and site characteristics with retention. As of July 31, 2009, about 50 % of SDPI-DP participants were lost to follow-up. Those who were younger, male, with lower household income, no family support person, and more baseline chronic pain were at higher risk for both short-term and long-term retention failure (i.e., not completing all 16 DPP sessions and loss to follow-up, respectively). Sites with large user populations and younger staff had lower likelihood of retaining participants successfully. Other site characteristics related to higher risk for retention failure included staff rating of participant disinterest in SDPI-DP and barriers to participant transportation and child/elder care. Future translational initiatives need to pay attention to both participant- and site-level factors in order to maximize participant retention.

Copper-induced injectable hydrogel with nitric oxide for enhanced immunotherapy by amplifying immunogenic cell death and regulating cancer associated fibroblasts.

BACKGROUND: Immunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT). METHODS: In this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism. RESULTS: Due to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo. CONCLUSIONS: The ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy.

Polydopamine-coated thalidomide nanocrystals promote DSS-induced murine colitis recovery through Macrophage M2 polarization together with the synergistic anti-inflammatory and anti-angiogenic effects.

High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs (Thali@PDA). Thali@PDA possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of Thali@PDA on IBD. Upon repeated dosing of Thali@PDA for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that Thali@PDA is a safe formulation.

The Long-Term Effect of Blue-Light Blocking Spectacle Lenses on Adults' Contrast Perception.

Purpose: To evaluate the long-term effect of two different degrees of blue-light blocking (BB) spectacle lenses on adults' contrast perception under various lighting conditions. Methods: In total, 144 healthy adults aged 24.70 (±4.32 years) were recruited to this randomized controlled trial. The participants were randomly divided into three groups and used three different spectacle lenses (15% BB: 15% blue-blocking spectacle lenses; 30% BB: 30% blue-blocking spectacle lenses; RC: regular clear lenses serving as control). Contrast sensitivity under four light conditions (scotopic and photopic, both with/without glare) was measured using standard clinical tests at baseline, 1 month, 3 months and 6 months of use. The area under the log contrast sensitivity function (AULCSF) was also computed as an index for their overall contrast sensitivity across spatial frequencies. Results: There was no significant difference in AULCSFs among the three types of spectacle lenses under any light condition (all P > 0.81). No statistical difference was found in the AULSCF among the four time points (all P > 0.39), with no interaction between the effects of group and time (all P > 0.42). Conclusion: Wearing blue-light blocking lens had no clinically significant effect on adults' long-term contrast perception under scotopic or photopic conditions, or with glare.

Tumor immunotherapy boosted by R837 nanocrystals through combining chemotherapy and mild hyperthermia.

Melanoma is a malignant skin cancer that is prone to metastasis in the early stage and has a poor prognosis. Immunomodulatory therapy for melanoma has been a hot research topic in recent years. However, low immune cell infiltration and loss of tumor immunogenicity may occur in tumors, resulting in low response rates to immunotherapy. Thus, immunomodulatory therapy is usually used in combination with chemotherapy and radiotherapy. Development of combined therapeutic strategies with low systemic toxicity, high immune responsiveness and long-term inhibition of metastasis and recurrence of melanoma is the goal of current research. In this study, the insoluble immune adjuvant imiquimod (R837) was prepared as nanocrystals and coated with polydopamine (PDA) to form R837@PDA, which was then loaded into chitosan hydrogel (CGP) to form the drug-loaded gel system, R837@PDA@CGP (RPC), to combine immunomodulation effects, induction of immunogenic cell death (ICD) effects and immune-enhancement effects. After treatment with RPC, ICD in melanoma was induced, and the infiltration rate of cytotoxic T cells (CTLs) in melanoma was also significantly enhanced, which turned the tumor itself into an in situ vaccine and boosted the cancer-immunity cycle at the tumor site. Therefore, melanoma growth, metastasis and recurrence were notably inhibited.

Advanced oxidation protein products trigger apoptosis and block epithelial-to-mesenchymal transition in crypt epithelial cells.

Advanced oxidation protein products (AOPPs) are uremic toxins. The present study aimed to investigate the effects of AOPPs on the epithelial mesenchymal transition (EMT) and apoptosis of rat crypt epithelial cells, and to assess the signaling pathways involved. The oxidized rat serum albumin was obtained by sodium hypochlorite modification as AOPPs, and the rat serum albumin (RSA) without sodium hypochlorite modification was set as the control. Different concentrations of AOPPs or RSA were incubated with rat crypt epithelial cells (IEC-6 cells). After culturing for 48 and 72 h, apoptosis was detected by flow cytometry. IEC-6 cells were divided into three groups: A normal group, an AOPPs group and an RSA group. Three groups of cells were collected following treatment for 2 h, and the phosphorylation levels of Akt and p65 NF-κB were detected by western blotting. After 72 h of treatment, the cells were collected and the apoptotic rate was detected by flow cytometry. The expression of EMT-related proteins was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. The apoptotic rate of IEC-6 cells increased with the concentration of AOPPs, and the apoptotic rate of the AOPPs group was higher than that of the RSA group. The expression of fibronectin, snail, slug and collagen I in the AOPPs group was lower than that in the RSA group, while the expression of E-cadherin was not significantly different between the two groups. In addition, the expression of fibronectin, snail, slug and collagen I genes in the AOPPs-treated group was equal to or lower than that in the normal group. Compared with the normal group, the Akt phosphorylation level was decreased and the p65 phosphorylation level was increased in the AOPPs- or RSA-treated groups. Compared with the AOPPs-treated group, Akt and p65 phosphorylation levels in RSA-treated group were slightly higher. In conclusion, AOPPs trigger apoptosis and inhibit the EMT of rat crypt epithelial cells, which may be associated with the inhibition of Akt phosphorylation and the promotion of p65 phosphorylation.

Sleep Duration and Diabetes Risk in American Indian and Alaska Native Participants of a Lifestyle Intervention Project.

STUDY OBJECTIVES: We examine the association between self-reported sleep duration and diabetes incidence in a national sample of American Indians/ Alaska Natives (AI/ANs) with prediabetes. METHODS: Data were derived from the Special Diabetes Program for Indians Diabetes Prevention demonstration project. This longitudinal analysis included 1,899 participants with prediabetes recruited between January 1, 2006 and July 31, 2009 who reported sleep duration and completed all 16 classes of the lifestyle intervention consisting of diet, exercise, and behavior modification sessions to promote weight loss. Three years of follow-up data were included to fit Cox regression models to compute hazard ratios (HRs) for diabetes incidence across sleep duration categories. RESULTS: The crude diabetes incidence rate was 4.6 per 100 person-years among short sleepers (≤ 6 h per night) compared to 3.2 among those sleeping 7 h and 3.3 among those sleeping 8 h or more. After adjustment for age and sex, short sleep (≤ 6 h vs. others) was associated with increased diabetes risk (HR 1.55 [95% confidence interval 1.11-2.17]); risk remained significantly elevated after controlling for socioeconomic characteristics, health behaviors, and health status. When adjusting for body mass index and percent weight loss, the short sleep-diabetes relationship was attenuated (HR 1.32 [95% confidence interval 0.92-1.89]). No significant long sleep-diabetes association was found. Further, short sleepers lost significantly less weight than others (3.7% vs. 4.3%, P = 0.003). CONCLUSIONS: Short sleep duration, but not long duration, was significantly associated with increased diabetes risk and less weight loss among AI/ANs in a lifestyle intervention. Further exploration of the complex factors underlying short sleep duration is warranted.

[Expression of transcriptional coactivator with PDZ-binding motif (TAZ) in colon cancer tissues and its clinical significance].

OBJECTIVE: To investigate the expression of transcriptional coactivator with PDZ-binding motif(TAZ) in colon cancer tissues and its association with clinicopathological parameters and prognosis of patients. METHODS: The expression of TAZ protein was detected in 56 resected colon cancer tissues and matched tumor-adjacent tissues using immunohistochemistry. The positive expression rate of TAZ was compared between patients with different clinicopathological features. The association between TAZ expression and prognosis was analyzed. RESULTS: Expression of TAZ protein located in the nucleolus. The positive expression rate of TAZ in colon cancer tissues was significantly higher than that in matched tumor-adjacent tissues(73.2% vs. 12.5%, P=0.000). Clinicopathological evaluation suggested that the expression of TAZ protein was associated with tumor size(P=0.009), depth of infiltration(P=0.026), lymph node metastasis (P=0.007) and TNM staging(P=0.004). Colon cancer patients with negative expression of TAZ showed a better 5-year survival as compared with those with positive expression of TAZ (66.7% vs. 22.9%, P=0.0017). Multivariate Cox regression analysis revealed that positive TAZ expression was an independent factor for predicting poor prognosis in colon cancer (HR:3.532, 95% CI: 1.3-9.9, P=0.016). CONCLUSION: The expression of TAZ protein is up-regulated in colon cancer tissues and its high expression is associated with poor prognosis of colon cancer patients.

Socioeconomic Disparities in Weight and Behavioral Outcomes Among American Indian and Alaska Native Participants of a Translational Lifestyle Intervention Project.

OBJECTIVE: To investigate possible socioeconomic disparities in weight and behavioral outcomes among American Indian and Alaska Native (AI/AN) participants in a translational diabetes prevention project. RESEARCH DESIGN AND METHODS: We analyzed data from the Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) Program, an evidence-based lifestyle intervention to prevent diabetes in 36 AI/AN grantee sites. A total of 2,553 participants started the 16-session Lifestyle Balance Curriculum between 1 January 2006 and 31 July 2008. Linear mixed models were used to evaluate the relationships of participant and staff socioeconomic characteristics with weight and behavioral outcomes at the end of the curriculum. RESULTS: A strong, graded association existed between lower household income and less BMI reduction, which remained significant after adjusting for other socioeconomic characteristics. Compared with others, participants with annual income <$15,000 also had less improvement in physical activity and unhealthy food consumption in bivariate models, but the relationships were only marginally significant in multivariate regressions. Furthermore, grantee sites with fewer professionally prepared staff were less successful at improving participant BMI and healthy food consumption than the other sites. The strong association between income and BMI reduction was reduced by 20-30% in the models with changes in diet variables but was unrelated to changes in physical activity. CONCLUSIONS: Significant socioeconomic disparities exist in weight outcomes of lifestyle intervention at both participant and site staff levels. Helping low-income participants choose more affordable healthy foods and increasing the proportion of professionally trained staff might be practical ways to maximize the effectiveness of lifestyle interventions implemented in "real-world" settings.

Effects of recombinant human interleukin 11 on thrombocytopenia and neutropenia in irradiated rhesus monkeys.

The effects of recombinant human interleukin 11 (rhIL11) on thrombocytopenia and neutropenia in irradiated rhesus monkeys were evaluated after administration different doses at different times. Twenty-three rhesus monkeys were exposed to a total-body irradiation (TBI) with a single dose of 3 Gy 60Co gamma rays. Either placebo, rhIL11 at a dose of 30, 60 or 120 microg/kg day(-1) on days 0-13, or rhIL11 at a dose of 60 microg/kg day(-1) on days 13-26 after TBI was administered to the animals. The results showed that the immediate treatment with rhIL11 but not treatment on days 13-26 resulted in much higher platelet nadirs than in the placebo-treated group. The accelerated recovery of platelets to normal levels after TBI was demonstrated in all groups treated with rhIL11, but the effects of rhIL11 were independent of dose. However, rhIL11 treatment could also accelerate the recovery of leukocytes to normal levels. The numbers of colony-forming bone marrow cells (CFU-E, CFU-Mix, CFU-MK and CFU-GM) in all groups treated with rhIL11 were increased 4- to 14-fold relative to those of the placebo group on day 30. We conclude that rhIL11 may directly promote megakaryocyte development and ameliorate myelosuppression in irradiated monkeys.

Protective effect of polydatin against lipopolysaccharide-induced myocardial injury.

OBJECTIVE: To observe the effect of lipopolysaccharide (LPS) on actin cytoskeleton of rat cardiac myocytes and the intervention effect of polydatin against this effect. METHODS: Rat cardiac myocytes were isolated from newborn SD rats (3 days old) and cultured in vitro, which were then divided into control group (treated with D-Hank's solution for 30 min), polydatin group (with 0.2 mmol/L polydatin treatment for 10 min), LPS group (with 100 ng/ml LPS stimulation for 30 min), and LPS/polydatin group (with 100 ng/ml LPS stimulation for 30 min followed by incubation with 0.2 mmol/L polydatin for 10 min). When the treatments were completed, the cells were analyzed for myocardial F-actin by immunofluorescent staining. RESULTS: In the control group, F-actin was localized in the cortex of cardiac myocytes and the cells were filled with F-actin organized into reticular structures. After LPS stimulation, the staining for F-actin was faint or even invisible in the cortex, with the formation of stress fibers observed in the cells, which disappeared upon the 10-min polydatin treatment and the F-actin resumed normal arrangement. No obvious difference was found between the control and polydatin groups. CONCLUSION: LPS may directly induce stress fiber formation, therefore cause damages to rat cardiac myocytes, which can be reverted by polydatin through the mechanism of participating in the F-actin organization.

[Effect of polydatin on lipopolysaccharide-induced leucocyte chemotaxis].

OBJECTIVE: To understand the action mechanisms of polydatin (PD) in the treatment of septic shock in view of its effect on lipopolysaccharide (LPS)-induced chemotaxis of the leucocytes. METHOD: Chemotactic chamber assay was used to investigate the regulative role of PD in chemotaxis of the neutrophils in response to LPS stimulation. RESULTS: The chemotactic index of normal neutrophils was 4.96+/-0.69, which was significantly increased by LPS stimulation. LPS stimulation at the doses of 10, 100, and 1000 ng/ml resulted in the elevation of the chemotactic index of the neutrophils to 8.94+/-1.73, 10.31+/-1.180 and 7.12+/-1.46 respectively (P<0.05), an effect potently reversed by the application of PD at the concentrations ranging from 0.008 to 0.8 mg/ml, of which 0.08 mg/ml was the most effective concentration that produced a decrease of the chemotactic index to 1.95+/-0.17. In addition, PD exhibited obvious anti-LPS effect after treatment for 5 to 60 min (P<0.05), while showing no influence on the chemotaxis of normal neutrophils (P>0.05). CONCLUSION: PD can regulate neutrophil chemotaxis in inflammatory reactions and may play a crucial role in the treatment of infections and inflammation.

[Comparison of short- and long-term efficacy of three procedures in postoperative digestive tract reconstruction for upper gastric cancer].

OBJECTIVE: To compare the short- and long-term efficacy of three different procedures used for digestive tract reconstruction after radical gastrectomy for upper gastric cancer. METHODS: Clinical data of 191 patients with upper gastric cancer undergoing radical gastrectomy in the Fujian Provincial Hospital between January 2000 and December 2012 were analyzed retrospectively. Surgical procedures were classified as total gastrectomy followed by Roux-en-Y esophagojejunostomy (TG-RY, n=123), proximal gastrectomy followed by esophagogastrostomy (PG-EG, n=40), and proximal gastrectomy followed by jejunal interposition (PG-JI, n=28). Clinicopathological characteristics, perioperative and long-term outcomes were compared among the three groups. RESULTS: The operative time was shorter (178 vs. 248 and 224 min, P<0.05), and the intraoperative blood loss was less (194 vs. 323 and 265 ml, P<0.05) in PG-EG group than those in TG-RY and PG-JI groups. Early postoperative complications and hospital stay were comparable (both P>0.05). With respect to gastrectomy-associated symptoms, reflux and heartburn were more frequent in PG-EG patients, while dumpling syndrome was more frequent after TG-RY. Postoperative weight loss was not significantly different among three procedures (P>0.05), however, hemoglobin and serum albumin levels were lower in TG-RY patients (both P<0.05). The 5-year survival rate was similar (P>0.05). CONCLUSIONS: Surgeons need to choose the proper procedure according to tumor features and patient condition. PG-JI should be the first choice in terms of fewer complaints and better nutrition. TG-RY tends to be used for larger and more advanced tumors. PG-EG is the most minimally invasive procedure and thus may be suitable for older and high-risk patients.

[Expression of miR-146a in colon cancer and its significance].

OBJECTIVE: To investigate miR-146a expression in colonic cancer and its clinical implications. METHODS: Quantitative real-time PCR was employed to detect the levels of miR-146a expression in colonic cancer tissues, pair-matched adjacent normal tissues and different colonic cancer cell lines. MTT essay was used to evaluate the proliferation of colonic cancer SW260 cells transfected with miR-146a mimics, and the cell cycle and apoptosis of the cells were analyzed with flow cytometry. RESULTS: Compared with the normal tissues, 38 of the 43 colonic cancer samples showed down-regulated miR-146a expression, which was associated with poor tumor differentiation. The expression of miR-146a in the tumor tissues was significantly correlated with tumor size and clinical stages. The patients with high miR-146a expression levels had significantly longer total survival time than those with low expression of miR-146a. In SW260 cell cultures, transfection with miR-146a mimics significantly inhibited cell growth (P<0.05) and increased the cell apoptosis rate (11.9% vs 5.9%) but produced no obvious effect on cell cycle. CONCLUSIONS: miR-146a may serve as a potential therapeutic target for colonic cancer for its role in inhibiting colonic cancer cell proliferation.

Translating the Diabetes Prevention Program into American Indian and Alaska Native communities: results from the Special Diabetes Program for Indians Diabetes Prevention demonstration project.

OBJECTIVE: The landmark Diabetes Prevention Program (DPP) showed that lifestyle intervention can prevent or delay the onset of diabetes for those at risk. We evaluated a translational implementation of this intervention in a diverse set of American Indian and Alaska Native (AI/AN) communities. RESEARCH DESIGN AND METHODS: The Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) demonstration project implemented the DPP lifestyle intervention among 36 health care programs serving 80 tribes. A total of 2,553 participants with prediabetes were recruited and started intervention by 31 July 2008. They were offered the 16-session Lifestyle Balance Curriculum and underwent a thorough clinical assessment for evaluation of their diabetes status and risk at baseline, soon after completing the curriculum (postcurriculum), and annually for up to 3 years. Diabetes incidence was estimated. Weight loss, changes in blood pressure and lipid levels, and lifestyle changes after intervention were also evaluated. RESULTS: The completion rates of SDPI-DP were 74, 59, 42, and 33% for the postcurriculum and year 1, 2, and 3 assessments, respectively. The crude incidence of diabetes among SDPI-DP participants was 4.0% per year. Significant improvements in weight, blood pressure, and lipid levels were observed immediately after the intervention and annually thereafter for 3 years. Class attendance strongly correlated with diabetes incidence rate, weight loss, and change in systolic blood pressure. CONCLUSIONS: Our findings demonstrate the feasibility and potential of translating the lifestyle intervention in diverse AI/AN communities. They have important implications for future dissemination and institutionalization of the intervention throughout the Native American health system.