PCSK9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Randomized, Double- Blind, Placebo-Controlled, Multicenter SHAWN Study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at one-year follow-up between two groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Comparison of intravascular ultrasound-guided with angiography-guided double kissing crush stenting for patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DKCRUSH VIII trial.

BACKGROUND: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion. TRIAL DESIGN: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure. CONCLUSIONS: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.

Different growth behaviors and metabolomic profiles in yogurts induced by multistrain probiotics of Lactobacillus casei Zhang and Bifidobacterium lactis V9 under different fermentation temperatures.

The growth behaviors and metabolomic profiles in yogurts induced by multistrain probiotics of Lactobacillus casei Zhang (LCZ) and Bifidobacterium lactis V9 (V9) at the fermentation termination and 10 d of storage at 4°C under different fermentation temperatures (37°C and 42°C) were compared using metabolomics based on liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. The growths of LCZ and V9 were affected by fermentation temperatures; the viable cell density of LCZ was higher at 37°C than that at 42°C; however, V9 was higher at 42°C. Multistrain probiotics had higher contribution to the changes in volatile and nonvolatile metabolomic profiles at 42°C than those at 37°C. At fermentation termination, there were 2 common enriched pathways increased by multistrain probiotics at 37°C and 42°C, which were biosynthesis of peptides and amino- and nucleotide-sugar metabolism. At 10 d of storage, 4 common increased enriched pathways were alanine, aspartate and glutamate metabolism; tyrosine metabolism; valine, leucine, and isoleucine degradation; and valine, leucine, and isoleucine biosynthesis. This work provided a detailed insight into different effects of different multistrain probiotics of LCZ and V9 fermentation temperatures on the growth behaviors and volatile and nonvolatile metabolomic profiles of yogurts.

Knockout of AKAP150 improves impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3ß signalling contributed to decreased BK-ß1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-ß1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-ß1 expression, and treatment with AKAP150 siRNA suppressed GSK3ß expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

A prospective cohort study of MTHFR C677T gene polymorphism and its influence on the therapeutic effect of homocysteine in stroke patients with hyperhomocysteinemia.

BACKGROUND: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular and cerebrovascular diseases. The C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR polymorphism and the therapeutic effect of lowering HCY in stroke patients with HHCY. METHODS: Baseline data were collected from stroke patients with HHCY for this prospective cohort study. The C677T MTHFR genotype was detected by polymerase chain reaction-restriction fragment length polymorphism and the therapeutic effect to reduce HCY was compared. RESULTS: Of 200 stroke patients 162 (81.0%) completed follow-up and were evaluated. Most of them responded well to treatment (103 cases, 63.5%), but 59 (36.4%) patients were in the poor efficacy group. There was a significant difference in terms of age (P < 0.001), hypertension (P = 0.041), hyperuricemia (P = 0.042), HCY after treatment (P < 0.001), and MTHFR genotype (P < 0.001) between the poor efficacy and effective groups, with increased frequency of the TT genotype in the poor efficacy group. Logistic regression showed that the T allele was associated with poor efficacy (OR = 0.733, 95%CI: 0.693, 0.862, P < 0.001). In the codominant model the TT genotype was associated with poor outcome (OR = 0.862, 95%CI: 0.767, 0.970, P = 0.017) and this was also the case in the recessive model (OR = 0.585, 95%CI: 0.462, 0.741, P < 0.001) but there was no association between CT and TT in the dominant model. CONCLUSIONS: The T allele and TT genotype of the MTHFR C677T polymorphism was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY. TRIAL REGISTRATION: The registration number of the clinical trial is ChiCTR1800020048. Registration date: December 12, 2018.

Dynamic profile and clinical implications of hematological parameters in hospitalized patients with coronavirus disease 2019.

Objectives As people across the world suffer from coronavirus disease 2019 (COVID-19), further studies are needed to facilitate evaluating the severity and prognosis of COVID-19 patients. In the study, we aimed to dissect the dynamic profile and clinical implications of hematological findings in hospitalized patients with COVID-19. Methods We retrospectively analyzed the hematological findings of 72 patients with COVID-19 admitted from January 21 to February 17, 2020. The final date of follow-up was March 20, 2020. Dynamic profile of vital hematological parameters in severe and non-severe patients was presented at different time points (day 1, 5, 7, 9, 11, 13, 15 after admission), and the correlation of hematological parameters with hospitalization time was indicated. Results Of 72 patients with COVID-19, lymphopenia and leukopenia occurred in 39 (54.2%) and 20 (27.8%) patients with COVID-19, respectively. Fifteen (20.8%) patients were defined as severe cases and 57 (79.2%) were non-severe cases. Compared to non-severe patients, leukocyte count, neutrophil count and neutrophil-to-lymphocyte ratio (NLR) were significantly higher, whereas lymphocyte count was declined in severe patients at each time point. A growing trend in platelet count was found in non-severe patients over the follow-up period. In addition, a positive correlation of NLR with hospitalization time was detected from day 5 after admission. Conclusions Dynamic changes in vital hematological parameters from severe and non-severe patients had been characterized in the course of hospitalization. During hospitalization, NLR was found to have certain relevance to the hospitalization days and a role in forecasting disease prognosis for patients with COVID-19.

Platelet Surface CD62p and Serum Vitamin D Levels are Associated with Clopidogrel Resistance in Chinese Patients with Ischemic Stroke.

BACKGROUND: To explore the association of platelet activation markers, vitamin D, and antiplatelet drugs resistance in ischemic stroke patients. METHODS: A total of 230 patients with ischemic stroke were enrolled in this study. Platelet aggregation, platelet activation marker (CD62p), and vitamin D were measured after 7-14 days of dual antiplatelet treatment (aspirin + clopidogrel). All individuals were divided into a drug resistance group and a drug sensitive group according to the platelet maximum aggregation rate induced by antagonist adenosine diphosphate or arachidonic acid. RESULTS: In this study, the prevalence of aspirin resistance was low (1.2%), while the prevalence of clopidogrel resistance (CR) was 24.8%, so we focused on CR. The percentage of CD62p on activated platelet [(25.74 ± 4.61) versus (12.41 ± 3.93), P < .001] and the prevalence of hypertension [93.0% (53) versus 79.8% (138), P = .021] in CR group were significantly higher than those in clopidogrel sensitive (CS) group, while the vitamin D concentration [(8.96 ± 4.41) versus (13.9 ± 4.84) ng/mL, P = .003] in CR group was significantly lower compared with the CS group. No significant difference was found in soluble P-selectin between these 2 groups [(56.2 ± 16.13) versus (54.2 ± 14.87) ng/mL, P = .258], neither in calcium [(2.29 ± .12) versus (2.33 ± .13) mmol/L, P = .821]. Logistic regression analysis showed that hypertension (odds ratio [OR] = 5.348, 95% confidence intervals [CI] 1.184-23.350, P = .026), expression of platelet CD62p (OR = 1.095, 95% CI 1.052-1.201, P = .018) and vitamin D level (OR = .832, 95% CI .763-.934, P = .005) were associated with CR in ischemic stroke patients. CONCLUSIONS: CR in ischemic stroke patients is associated with several independent predictors, including increased platelet activation marker CD62p, decreased vitamin D level, and hypertension.

Gut microbiota dysbiosis in male patients with chronic traumatic complete spinal cord injury.

BACKGROUND: Neurogenic bowel dysfunction (NBD) is a major physical and psychological problem in patients with spinal cord injury (SCI), and gut dysbiosis is commonly occurs in SCI. Here, we document neurogenic bowel management of male patients with chronic traumatic complete SCI in our centre and perform comparative analysis of the gut microbiota between our patients and healthy males. METHODS: A total of 43 male patients with chronic traumatic complete SCI (20 with quadriplegia and 23 with paraplegia) and 23 healthy male adults were enrolled. Clinical data and fresh stool specimens were collected from all participants. Face-to-face interviews were conducted to survey the neurogenic bowel management of 43 patients with SCI. Gut microbiomes were analysed by sequencing of the V3-V4 region of the 16S rRNA gene. RESULTS: NBD was common in adult male patients with chronic traumatic complete SCI. Patients with quadriplegia exhibited a longer time to defecate than did those with paraplegia and had higher NBD scores and heavier neurogenic bowel symptoms. The diversity of the gut microbiota in the SCI group was reduced, and the structural composition was different from that of the healthy adult male group. The abundance of Veillonellaceae and Prevotellaceae increased, while Bacteroidaceae and Bacteroides decreased in the SCI group. The abundance of Bacteroidaceae and Bacteroides in the quadriplegia group and Acidaminococcaceae, Blautia, Porphyromonadaceae, and Lachnoclostridium in the paraplegia group were significantly higher than those in the healthy male group. Serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time and COURSE had significant correlations with microbial community structure. Microbial community structure was significantly associated with serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time, and COURSE. CONCLUSIONS: This study presents a comprehensive landscape of the gut microbiota in adult male patients with chronic traumatic complete SCI and documents their neurogenic bowel management. Gut microbiota dysbiosis in SCI patients was correlated with serum biomarkers and NBD symptoms.

Fas signaling induces stemness properties in colorectal cancer by regulation of Bmi1.

Fas signaling promotes colorectal cancer (CRC) metastasis by inducing epithelial-mesenchymal transition (EMT). The acquisition of EMT properties in turn induces stemness but the mechanism by which Fas signaling contributes to it still remains unclear. Hence, the aim of this study was to investigate how Fas signaling regulates CRC stemness. For this purpose, soft agar assay, sphere formation assay, cell survival analysis, immunoblot, qRT-PCR, chromatin immunoprecipitation, and luciferase reporter assay were performed. Expression of FasL, Bmi1, and the miR-200c in CRC specimens was examined through immunohistochemistry, qRT-PCR, and immunoblot. In our study, Fas signaling induced stem cell properties in CRC specimens, relying on ERK1/2 MAPK pathway, with Bmi1 being mainly responsible for FasL-induced stemness. FasL treatment promoted Bmi1 expression by inhibiting miR-200c, which targets Bmi1 3'UTR region. Furthermore, FasL-induced Zeb1 binded with miR-200c promoter and inhibited its expression. Moreover, FasL-induced ß-catenin nuclear expression promoted Zeb1 expression by binding with Zeb1 promoter. GSK-3ß, which regulates ß-catenin, was inhibited by FasL-induced ERK1/2 MAPK signaling. Finally, FasL and Bmi1 expression in clinical samples increased during CRC progression, and a positive correlation between them was observed. Patients with high FasL and Bmi1 expression had a worse prognosis than patients with low expression. In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK-3ß/ß-catenin/Zeb1/miR-200c axis, suggesting that Fas signaling-based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.

Association between the MTHFR A1298C polymorphism and risk of cancer: evidence from 265 case-control studies.

Many molecular, epidemiological studies have been performed to explore the association between MTHFR A1298C polymorphism and cancer risk. However, the results were inconsistent or even contradictory. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR A1298C (81,040 cases and 114,975 controls from 265 studies) polymorphism. Overall, significant association was observed between MTHFR A1298C polymorphism and cancer risk when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly increased cervical cancer (dominant model: OR 1.46, 95 % CI 1.13-1.90; AC vs. AA: OR 1.48, 95 % CI 1.13-1.92) and lymphoma (dominant model: OR 1.22, 95 % CI 1.04-1.44; recessive model: OR 1.66, 95 % CI 1.15-2.39; CC vs. AA: OR 1.75, 95 % CI 1.21-2.53) risk were observed in Asians, and significantly decreased colorectal cancer risk was found in Asians (recessive model: OR 0.75, 95 % CI 0.59-0.96; CC vs. AA: OR 0.77, 95 % CI 0.60-1.00). In summary, this meta-analysis suggests that MTHFR A1298C polymorphism is associated with increased cervical cancer and lymphoma risk in Asians, and MTHFR A1298C polymorphism is associated with decreased colorectal cancer risk in Asians. Moreover, this meta-analysis also points out the importance of new studies, such as oral cancer and chronic myeloid leukemia, because they had high heterogeneity in this meta-analysis (I (2) > 75 %).

High platelet reactivity affects the clinical outcomes of patients undergoing percutaneous coronary intervention.

BACKGROUND: The association of platelet reactivity and clinical outcomes, especially stent thrombosis, was not so clear. We sought to investigate whether high platelet reactivity affects clinical outcomes of patients with drug eluting stents (DESs) implantation. METHODS: All enrolled individuals treated with DESs implantation were evaluated by PL-11, using sequentially platelet counting method. The primary end point was the occurrence of definite and probable stent thrombosis at 2 years. The secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all cause death, spontaneous myocardial infarction (MI), target vessel revascularization (TVR), and ischemic stroke. RESULTS: A total of 1331consecutive patients were enrolled at our center. There were 91 patients (6.8 %) identified with high platelet reactivity (HPR) on aspirin, and 437 patients (32.9 %) with HPR on clopidogrel. At 2-year follow-up, the incidence of stent thrombosis was significantly higher in patients with HPR on aspirin (9.9 % vs. 0.4 %, p < 0.001), and HPR on clopidogrel (3.0 % vs. 0.1 %, p < 0.001). There were increased MACCE in the HPR on aspirin group (16.5 % vs. 8.5 %, p = 0.021), mainly driven by the higher all cause death (7.7 % vs. 1.6 %, p = 0.002) and MI (9.9 % vs. 1.9 %, p < 0.001) in the HPR on aspirin group. Similarly, the rate of MACCE was higher in the HPR on clopidogrel group (12.4 % vs. 7.4 %, p = 0.004). No differences in all bleeding and hemorrhagic stroke were observed. CONCLUSIONS: The present study demonstrated that high platelet reactivity on both aspirin and clopidogrel were associated with incremental stent thrombosis following DESs implantation.

Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis.

The previous, published data on the association between CYP1B1 polymorphisms and cancer risk remained controversial. To derive a more precise estimation of the association between the CYP1B1 polymorphisms and cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP1B1 Leu432Val, Asn453Ser, Arg48Gly, and Ala119Ser polymorphisms. For Asn453Ser and Arg48Gly polymorphisms, significantly decreased endometrial cancer was observed among Caucasians. For Ala119Ser polymorphism, we found that individuals with the minor variant genotypes had a high risk of prostate cancer. For Leu432Val polymorphism, we found that individuals with the minor variant genotypes had a higher risk of endometrial cancer and lung cancer and had a lower risk of ovarian cancer. In summary, this meta-analysis suggests that Leu432Val polymorphism is associated with ovarian cancer, lung cancer, and endometrial cancer risk; Asn453Ser and Arg48Gly polymorphisms are associated with endometrial cancer risk among Caucasians, Ala119Ser polymorphism is associated with prostate cancer risk, and Ala119Ser polymorphism is associated with breast cancer risk in Caucasians. In addition, our work also points out the importance of new studies for Ala119Ser polymorphism in endometrial cancer, because high heterogeneity was observed (I (2) > 75 %).

Association between the STK15 polymorphisms and risk of cancer: a meta-analysis.

The previous published data on the association between STK15 F31I and V57I polymorphisms and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and STK15 F31I (42,315 cases and 50,542 controls from 62 studies) and V57I polymorphisms (12,891 cases and 17,391 controls from 18 studies) in different inheritance models. Overall, significant association was observed between F31I and cancer risk when all the eligible studies were pooled into the meta-analysis (recessive model: OR = 1.14, 95 % CI = 1.06-1.24; AA vs. TT: OR = 1.12, 95 % CI = 1.02-1.24; A vs. T: OR = 1.05, 95 % CI = 1.01-1.09). In the further stratified and sensitivity analyses, for STK15 F31I, significantly increased breast cancer (recessive model: OR = 1.16, 95 % CI = 1.02-1.33; AA vs. TT: OR = 1.16, 95 % CI = 1.01-1.33) and ovarian cancer (dominant model: OR = 1.20, 95 % CI = 1.07-1.34; TA vs. TT: OR = 1.19, 95 % CI = 1.06-1.34; A vs. T: OR = 1.15, 95 % CI = 1.05-1.26) risk was found among Caucasians, and significantly decreased lung cancer risk was found among Caucasians (recessive model: OR = 0.65, 95 % CI = 0.49-0.87; AA vs. TT: OR = 0.65, 95 % CI = 0.49-0.88). For V57I polymorphism, significant decreased breast cancer risk was found among Caucasians (recessive model: OR = 0.76, 95 % CI = 0.61-0.95; AA vs. GG: OR = 0.75, 95 % CI = 0.60-0.94; A vs. G: OR = 0.92, 95 % CI = 0.86-0.98). In summary, this meta-analysis suggests that STK15 F31I polymorphism is associated with increased breast cancer and ovarian cancer risk among Caucasians, F31I polymorphism is associated with decreased lung cancer risk among Caucasians, and V57I polymorphism is associated with decreased breast cancer risk among Caucasians.

Association between the CYP1A2 polymorphisms and risk of cancer: a meta-analysis.

The previously published data on the association between CYP1A2*1C (rs2069514) and CYP1A2*1F (rs762551) polymorphisms and cancer risk have remained controversial. Hence, we performed a meta-analysis to investigate the association between CYP1A2*1F and CYP1A2*1C polymorphisms and cancer risk under different inheritance models. Overall, significant association was observed between CYP1A2*1F and cancer risk when all the eligible studies were pooled into the meta-analysis (dominant model: OR 1.08, 95 % CI 1.02-1.15; heterozygous model: OR 1.06, 95 % CI 1.01-1.12; additive model: OR 1.07, 95 % CI 1.02-1.13). In the further stratified and sensitivity analyses, for CYP1A2*1F polymorphism, significantly increased lung cancer risk and significantly decreased bladder cancer risk were observed in Caucasians. For CYP1A2*1C polymorphism, no significant association was found in overall and all subgroup analyses. In summary, this meta-analysis suggests that CYP1A2*1F polymorphism is associated with lung cancer and bladder cancer risk in Caucasians.

Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies.

Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I(2) > 75%).

Human serum inhibits adhesion and biofilm formation in Candida albicans.

BACKGROUND: Candida albicans can form biofilms on intravenous catheters; this process plays a key role in the pathogenesis of catheter infections. This study evaluated the effect of human serum (HS) on C. albicans biofilm formation and the expression of adhesion-related genes in vitro. A C. albicans laboratory strain (ATCC90028) and three clinical strains were grown for 24 h in RPMI 1640 supplemented with HS or RPMI 1640 alone (as a control). The growth of biofilm cells of four strains was monitored by a Live Cell Movie Analyzer, and by XTT reduction assay. The expression of the adhesion-related genes BCR1, ALS1, ALS3, HWP1 and ECE1 was analyzed by RT-PCR at three time points (60 min, 90 min, and 24 h). RESULTS: In the adhesion phase, C. albicans cells kept a Brownian movement in RPMI medium containing HS until a large number of germ tubes were formed. In the control group, C. albicans cells quickly adhered to the bottom of the reaction plate. Compared with RPMI 1640, medium supplemented with 3-50% HS caused a significant decrease in biofilm development (all p < 0.001). However, the presence of HS had no significant inhibitory effect on the pre-adhered biofilms (all p > 0.05). Biofilm formation was also inhibited by heat-inactivated and proteinase K pre-treated HS. The presence of 50% HS did not significantly affect the planktonic growth of C. albicans (p > 0.05). At three time points, HS inhibited expression of the ALS1 and ALS3 genes and promoted expression of the HWP1 and ECE1 genes. Significant up-regulation of BCR1 was observed only at the 90-min point. CONCLUSIONS: Human serum reduces biofilm formation by inhibiting the adhesion of C. albicans cells. This response may be associated with the down-regulation of adhesion-related genes ALS1, ALS3 and BCR1. The inhibitory serum component is protease-resistant and heat stable.

Human papillomavirus type-specific prevalence in women referred for colposcopic examination in Beijing.

Human papillomavirus (HPV) is associated with several disorders of the genital tract, skin, and oropharynx. This study investigated the prevalence of infection by 37 HPV genotypes among women of the Beijing area in China. Cervical specimens from 1,082 patients and 165 healthy controls were tested for HPV genotypes using a chip hybridization assay. Based on the local pathology, patients were divided into cervicitis and cervical lesion groups. Overall HPV infection rates were 30.5% for the cervicitis group and 78.4% for the cervical lesion group; whereas infection rates for high-risk HPV types (i.e., those associated with cervical cancers) were 24.0% and 73.4%, respectively. The most common HPV genotypes were HPV 52, 16, 81, 58, and 18 in healthy controls, HPV 52, 61, 55, 16, and 53 in those with cervicitis, HPV 52, 16, 33, 39, and 58 in cervical intraepithelial neoplasia grade 1, HPV 16, 58, 31, 52, and 33 in cervical intraepithelial neoplasia grade 2 or grade 3, and HPV 16, 33, 18, 52, and 58 in cervical cancer. Established high-risk HPV showed two peaks, in patients aged 30-34 and 55-79 years. In Beijing, HPV 16, 52, 58, and 33 are the most prevalent HPV types in women with cervical lesions, which should affect development of a cervical cancer vaccination for local use.

Association between the CYP3A4 and CYP3A5 polymorphisms and cancer risk: a meta-analysis and meta-regression.

Previously published data on the association between CYP3A4 A392G and CYP3A5 Met235Thr polymorphisms and the risk of cancer remained controversial. Thus, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP3A4 A392G (18,629 cases and 22,323 controls from 49 studies) and CYP3A5 Met235Thr polymorphisms (14,334 cases and 18,183 from 39 studies) in different inheritance models. We used odds ratios with 95 % confidence intervals to assess the strength of the association. Overall, significant association was found between CYP3A4 A392G polymorphism and cancer susceptibility (dominant model, odds ratio (OR) = 1.19; 95 % confidence interval (CI) = 1.03-1.38). In the further stratified and sensitivity analyses, significant increased prostate cancer risk was found among Caucasians (dominant model, OR = 1.88; 95 % CI = 1.20-2.95; recessive model, OR = 2.10; 95 % CI = 1.23-3.60; additive model, OR = 1.80, 95 % CI = 1.24-2.63; homozygous model, OR = 2.34, 95 % CI = 1.36-4.03; heterozygote model, OR = 1.79, 95 % CI = 1.11-2.89) for CYP3A4 A392G. For CYP3A5 Met235Thr polymorphism, no significant association was found among overall analysis and any subgroup analysis. In summary, this meta-analysis suggests that CYP3A4 A392G polymorphism is associated with increased prostate cancer risk among Caucasians and CYP3A5 Met235Thr polymorphism is not associated with the risk of cancer.

ATM-R: An Adaptive Tradeoff Model With Reference Points for Constrained Multiobjective Evolutionary Optimization.

The goal of constrained multiobjective evolutionary optimization is to obtain a set of well-converged and well-distributed feasible solutions. To achieve this goal, a delicate tradeoff must be struck among feasibility, diversity, and convergence. However, balancing these three elements simultaneously through a single tradeoff model is nontrivial, mainly because the significance of each element varies in different evolutionary phases. As an alternative approach, we adapt distinct tradeoff models in various phases and introduce a novel algorithm named adaptive tradeoff model with reference points (ATM-R). In the infeasible phase, ATM-R takes the tradeoff between diversity and feasibility into account, aiming to move the population toward feasible regions from diverse search directions. In the semi-feasible phase, ATM-R promotes the transition from "the tradeoff between feasibility and diversity" to "the tradeoff between diversity and convergence." This transition is instrumental in discovering an adequate number of feasible regions and accelerating the search for feasible Pareto optima in succession. In the feasible phase, ATM-R places an emphasis on balancing diversity and convergence to obtain a set of feasible solutions that are both well-converged and well-distributed. It is worth noting that the merits of reference points are leveraged in ATM-R to accomplish these tradeoff models. Also, in ATM-R, a multiphase mating selection strategy is developed to generate promising solutions beneficial to different evolutionary phases. Systemic experiments on a diverse set of benchmark test functions and real-world problems demonstrate that ATM-R is effective. When compared to eight state-of-the-art constrained multiobjective optimization evolutionary algorithms, ATM-R consistently demonstrates its competitive performance.