Perioperative fluid management for adult cardiac surgery: network meta-analysis pooling on twenty randomised controlled trials.

BACKGROUND: The aim of this study was to evaluate colloids and crystalloids used in perioperative fluid therapy for cardiac surgery patients to further investigate the optimal management strategies of different solutions. METHOD: RCTs about adult surgical patients allocated to receive perioperative fluid therapy for electronic databases, including Ovid MEDLINE, EMBase, and Cochrane Central Register of Controlled Trials, were searched up to February 15, 2023. RESULTS: None of the results based on network comparisons, including mortality, transfuse PLA, postoperative chest tube output over the first 24 h following surgery, and length of hospital stay, were statistically significant. Due to the small number of included studies, the results, including acute kidney injury, serum creatinine, serum microglobulin, and blood urea nitrogen, are from the direct comparison. For transfusion of RBCs, significant differences were observed in the comparisons of 3% gelatine vs. 6% HES 200/0.5, 4% albumin vs. 5% albumin, 4% gelatine vs. 5% albumin, 5% albumin vs. 6% HES 200/0.5, and 6% HES 130/0.4 vs. 6% HES 200/0.5. In transfusion of FFP, significant differences were observed in comparisons of 3% gelatine vs. 4% gelatine, 3% gelatine vs. 6% HES 200/0.5, 5% albumin vs. 6% HES 200/0.5, 4% gelatine vs. 5% albumin, 4% gelatine vs. 6% HES 200/0.4, and 6% HES 130/0.4 vs. 6% HES 200/0.5. For urinary output at 24 h after surgery, the results are deposited in the main text. CONCLUSION: This study showed that 3% gelatin and 5% albumin can reduce the transfuse RBC and FFP. In addition, the use of hypertonic saline solution can increase urine output, and 5% albumin and 6% HES can shorten the length of ICU stay. However, none of the perioperative fluids showed an objective advantage in various outcomes, including mortality, transfuse PLA, postoperative chest tube output over the first 24 h following surgery, and length of hospital stay. The reliable and sufficient evidences on the injury of the kidney, including acute kidney injury, serum creatinine, serum microglobulin, and blood urea nitrogen, was still lacking. In general, perioperative fluids had advantages and disadvantages, and there were no evidences to support the recommendation of the optimal perioperative fluid for cardiac surgery.

Pulmonary delivery of icariin-phospholipid complex prolongs lung retention and improves therapeutic efficacy in mice with acute lung injury/ARDS.

Icariin has been shown the promising therapeutic potential to treat inflammatory airway diseases, yet its poor lung distribution and retention restrict the clinical applications. To this end, this work aimed to prepare an icariin-phospholipid complex (IPC) formulation for sustained nebulization delivery that enabled excellent inhalability, improved lung exposure and prolonged duration of action. Icariin was found to react with soybean phospholipid to form supramolecular IPC, which was able to self-assemble into nanoparticle suspension. The suspension was stable during steam sterilization and nebulization processes, and its aerosols generated by a commercial nebulizer exhibited excellent aerodynamic properties and delivery efficiency. In vitro studies showed that the formation of complex sustained drug release, enhanced lung affinity and slowed lung clearance. The drug distribution in lung epithelial lining fluid (ELF) also demonstrated in vivo sustained release after intratracheal administration to mice. In addition, compared to free icariin, IPC improved the drug exposure to lung tissues and immune cells in the ELF by 4.61-fold and 39.5-fold, respectively. This resulted in improved and prolonged local anti-inflammatory effects up to 24 h in mice with lipopolysaccharide (LPS)-induced acute lung injury. Moreover, IPC improved survival rate of mice with acute respiratory distress syndrome (ARDS). Overall, the present phospholipid complex represented a promising formulation of icariin for the treatment of acute lung injury/ARDS by nebulization delivery.

Inhalable spray-dried porous microparticles containing dehydroandrographolide succinate phospholipid complex capable of improving and prolonging pulmonary anti-inflammatory efficacy in mice.

Due to the unique physiological barriers within the lungs, there are considerable challenges in developing drug delivery systems enabling prolonged drug exposure to respiratory epithelial cells. Here, we report a PulmoSphere-based dry powder technology that incorporates a drug-phospholipid complex to promote intracellular retention of dehydroandrographolide succinate (DAS) in respiratory epithelial cells following pulmonary delivery. The DAS-phospholipid complex has the ability to self-assemble into nanoparticles. After spray-drying to produce PulmoSphere microparticles loaded with the drug-phospholipid complex, the rehydrated microparticles discharge the phospholipid complex without altering its physicochemical properties. The microparticles containing the DAS-phospholipid complex exhibit remarkable aerodynamic properties with a fine particle fraction of ∼ 60% and a mass median aerodynamic diameter of ∼ 2.3 µm. These properties facilitate deposition in the alveolar region. In vitro cell culture and lung tissue explants experiments reveal that the drug-phospholipid complex prolongs intracellular residence time and lung tissue retention due to the slow intracellular disassociation of drug from the complex. Once deposited in the lungs, the DAS-phospholipid complex loaded microparticles increase and extend drug exposure to the lung tissues and the immune cells compared to the free DAS counterpart. The improved drug exposure to airway epithelial cells, but not immune cells, is related to a prolonged duration of pulmonary anti-inflammation at decreased doses in a mouse model of acute lung injury induced by lipopolysaccharide. Overall, the phospholipid complex loaded microparticles present a promising approach for improved treatment of respiratory diseases, e.g. pneumonia and acute respiratory distress syndrome.

Cancer burden and risk in the Chinese population aged 55 years and above: A systematic analysis and comparison with the USA and Western Europe.

Background: We analysed the cancer burden among elderly Chinese people over the age of 55 years and compared them to USA and Western Europe to explore the cancer model in China. Methods: We retrieved data on 29 cancers with 34 risk factors from the 2019 Global Burden of Disease database to evaluate the cancer burden in Chinese elderly individuals aged 55 years and older. We then used the age-standardised incidence rate (ASIR), age-standardised death rate (ASDR), age-standardised disability-adjusted life year (DALY) rate, and average annual percentage change (AAPC) to compare the characteristics and change trend of cancers among China, USA, and Western Europe. Results: In 2019, the number of incident cases of 29 cancers among people aged 55 years and above in China increased more than 3-fold compared to 1990, while the number of deaths and DALYs approximately doubled. We also found that the cancer population in China was ageing; meanwhile, the cancer burden became significantly higher for men than for women, and the gap between men and women had widened. Cancers with the highest cancer DALYs were lung cancer (13 444 500; 95% uncertainty interval (UI) = 11 307 100, 15 853 700), stomach cancer (7 303 900; 95% UI = 6 094 600, 8 586 500), oesophageal cancer (4 633 500; 95% UI = 3 642 500, 5 601 200), colon and rectum cancer (4 386 500; 95% UI = 3 769 500, 5 067 200), liver cancer (2 915 100, 95% UI = 2 456 300, 3 463 900), and pancreatic cancer (2 028 400; 95% UI = 1 725 000, 2 354 900). Compared with 1990, the DALY rate and incidence rate of stomach cancer, oesophageal cancer, and liver cancer had markedly decreased. The DALY rate and incidence rate of lung, colon, rectum, and pancreatic cancer had increased significantly, as did the incidence rate of breast cancer in women. Smoking and diet were the top two cancer risk factors, and the impact of ambient particulate matter pollution on cancer increased each year. The overall 29 cancers age-standardised DALY rate and ASDR in China, USA, and Western Europe were similar, and all showed downward trend in the past 30 years. Compared with the USA and Western Europe, the age-standardised DALY rate of liver, nasopharyngeal, oesophageal, stomach, and cervical cancers in China was more prominent. The age-standardised DALY rate of lung cancer and colon and rectum cancer decreased annually in Western Europe and the USA, but increased in China. Conclusions: Over the past 30 years, China had made progress in controlling stomach, oesophageal, and liver cancer. However, lung, colon, rectum, pancreatic, and breast cancers had become more prevalent, having risen alongside economic development. The risks of smoking and dietary were major issues that need to be addressed urgently. The cancer situation in China remains serious; future cancer prevention efforts need to balance economic development with people's physical health, identify key groups, improve the health environment of residents and guide them to live a healthy life, and expand the scope of cancer screening.

Management of priming fluids in cardiopulmonary bypass for adult cardiac surgery: network meta-analysis.

BACKGROUND: Cardiopulmonary bypass (CPB) is frequently employed for cardiac surgery, and selecting a suitable priming fluid is a prerequisite for CPB. Currently, the commonly used priming fluids in clinics are classified as crystalloids and colloids, including balanced crystalloids, albumin, dextran, gelatin and hydroxyethyl starch (HES). This network meta-analysis compared the effects of eight fluids used during CPB in adults to determine optimal priming fluid during CPB surgery. METHODS: Randomised controlled trials assessing priming fluids for CPB in adult cardiac surgery published before 13 April 2023 were searched across Ovid MEDLINE(R) ALL, OVID EMbase, and Cochrane Central Register of Controlled Trials. Various priming fluids were classified into eight categories, including balanced crystalloids, 0.9% NaCl, iso-oncotic human albumin, hyperoncotic human albumin, HES with molecular weight 130k, HES with molecular weight 200k, gelatin and dextran. RESULTS: The NMA of platelet counts revealed no significant differences in any result. In direct comparison results, only the comparison of HES with molecular weight 130k vs. gelatin (standard mean difference = -0.40, 95% confidence interval [95%CI: -0.63, -0.16) revealed a significant difference. According to the SUCRA, balanced crystalloids had the highest platelet count, followed by gelatin, and HES with a molecular weight of 130k had the lowest platelet, followed by HES with a molecular weight of 200k. CONCLUSION: Patients using dextran have a low mortality rate and a short mean CPB time, the use of balanced crystalloids is beneficial in terms of platelet count, and HES with molecular weight 130k is beneficial for postoperative urine volume at 24h. However, all priming fluids have pros and cons quite, and the optimal choice of priming fluids remains unsupported by current evidences. When performing CPB surgery, the type of priming fluid should be selected according to the actual situation in CPB for adult cardiac surgery.

When dextran was used as the CPB priming fluid, patients had the lowest mortality and shortest mean CPB time.With iso-oncotic HA, patients had the shortest length of ICU stay, the least blood loss 24h after surgery, and the lowest chest tube output 24h after surgery.The use of balanced crystalloids was beneficial for platelet count, the use of L-HES was beneficial for urine output 24h after surgery, and the use of H-HES resulted in the shortest hospital stay.In summary, each of these fluids has pros and cons quite, and an optimal choice of priming fluids during CPB surgery remains unsupported by current evidence.When performing CPB surgery, the type of priming fluids should be selected according to the actual condition of the patient's body.

COVID-19 vaccination effectiveness and safety in vulnerable populations: a meta-analysis of 33 observational studies.

Background: Even 3 years into the COVID-19 pandemic, questions remain about how to safely and effectively vaccinate vulnerable populations. A systematic analysis of the safety and efficacy of the COVID-19 vaccine in at-risk groups has not been conducted to date. Methods: This study involved a comprehensive search of PubMed, EMBASE, and Cochrane Central Controlled Trial Registry data through 12 July 2022. Post-vaccination outcomes included the number of humoral and cellular immune responders in vulnerable and healthy populations, antibody levels in humoral immune responders, and adverse events. Results: A total of 23 articles assessing 32 studies, were included. The levels of IgG (SMD = -1.82, 95% CI [-2.28, -1.35]), IgA (SMD = -0.37, 95% CI [-0.70, -0.03]), IgM (SMD = -0.94, 95% CI [-1.38, -0.51]), neutralizing antibodies (SMD = -1.37, 95% CI [-2.62, -0.11]), and T cells (SMD = -1.98, 95% CI [-3.44, -0.53]) were significantly lower in vulnerable than in healthy populations. The positive detection rates of IgG (OR = 0.05, 95% CI [0.02, 0.14]) and IgA (OR = 0.03, 95% CI [0.01, 0.11]) antibodies and the cellular immune response rates (OR = 0.20, 95% CI [0.09, 0.45]) were also lower in the vulnerable populations. There were no statistically significant differences in fever (OR = 2.53, 95% CI [0.11, 60.86]), chills (OR = 2.03, 95% CI [0.08, 53.85]), myalgia (OR = 10.31, 95% CI [0.56, 191.08]), local pain at the injection site (OR = 17.83, 95% CI [0.32, 989.06]), headache (OR = 53.57, 95% CI [3.21, 892.79]), tenderness (OR = 2.68, 95% CI [0.49, 14.73]), and fatigue (OR = 22.89, 95% CI [0.45, 1164.22]) between the vulnerable and healthy populations. Conclusion: Seroconversion rates after COVID-19 vaccination were generally worse in the vulnerable than healthy populations, but there was no difference in adverse events. Patients with hematological cancers had the lowest IgG antibody levels of all the vulnerable populations, so closer attention to these patients is recommended. Subjects who received the combined vaccine had higher antibody levels than those who received the single vaccine.

Global, regional, and national trends of syphilis from 1990 to 2019: the 2019 global burden of disease study.

BACKGROUND: Syphilis is a sexually transmitted disease caused by Treponema pallidum, and the infection source is syphilis patients. This study aimed to estimate the incidence, mortality rate, and disability-adjusted life years (DALYs) of syphilis to improve the understanding of the current global situation of syphilis. METHODS: This study collected data on syphilis incidence, mortality, and DALYs from the 2019 Global Burden of Disease database. RESULTS: The global number of incident cases and age-standardized incidence rate (ASIR) increased from 8,845,220 (95% UI: 6,562,510-11,588,860) in 1990 to 14,114,110 (95% UI: 10,648,490-18,415,970) in 2019 and 160.03/100,000 persons (95% UI: 120.66-208.1) to 178.48/100,000 persons (95% UI: 134.94-232.34), respectively. The estimated annual percentage change (EAPC) in the ASIR was 0.16 (95% CI: 0.07-0.26). The EAPC in the ASIR associated with high and high-middle sociodemographic indices increased. The ASIR increased among males but decreased among females, and the incidence peaked among males and females between the ages of 20 and 30 years. The EAPCs in the age-standardized death rate and age-standardized DALY rate decreased. CONCLUSIONS: The incidence and ASIR of syphilis increased worldwide from 1990 to 2019. Only the regions with high and high-middle sociodemographic indices showed an increase in the ASIR. Moreover, the ASIR increased among males but decreased among females. The age-standardized death rate and DALY rate both declined worldwide. The increase in the global ASIR of syphilis is a challenge.

Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer.

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

Clinical outcomes of recommended active pharmacotherapy agents from NICE guideline for post-traumatic stress disorder: Network meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship violence, combat exposure, witnessing death, or serious injury. This study aimed to identify the most suitable drugs for the management of PTSD based on a network meta-analysis (NMA). METHODS: Six databases (Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and Web of Science) were searched from inception to September 6, 2022. RESULTS: Thirty articles with a total of 5170 participants were included. Compared with placebo, active drugs including olanzapine (SMD = -0.66, 95% CI: -1.19 to -0.13), risperidone (SMD = -0.23, 95% CI: -0.42 to -0.03), quetiapine (SMD = -0.49, 95% CI: -0.93 to -0.04), venlafaxine (SMD = -0.29, 95% CI: -0.42 to -0.16), sertraline (SMD = -0.23, 95% CI: -0.34 to -0.11), paroxetine (SMD = -0.48, 95% CI: -0.60 to -0.36) and fluoxetine (SMD = -0.27, 95% CI: -0.42 to -0.12), significantly reduced the total clinician-administered PTSD scale score. CONCLUSION: The results of this study support the use of paroxetine, venlafaxine, and quetiapine as first-line treatment for PTSD. In addition, quetiapine is recommended for patients with PTSD affected by symptoms of hyperarousal and re-experience disorder. Clinicians should prescribe medications based on the severity of PTSD symptoms and other conditions to develop the best treatment strategy for this patient population.

Global, regional and national burden of chronic obstructive pulmonary disease over a 30-year period: Estimates from the 1990 to 2019 Global Burden of Disease Study.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic respiratory disease. This study investigated the global, regional and country burden of COPD based on gender, age and socio-demographic indices (SDIs) in the last 30-year period from 1990 to 2019. METHODS: The COPD data, including incidence, mortality and disability-adjusted life years (DALYs), were obtained from the 2019 Global Burden of Disease Study. If age-standardized incidence rate (ASIR) or death rate (ASDR) remains almost constant or decreases, the number of cases will still increase as the global population increases substantially. Estimated annual percentage change (EAPC) was calculated to assess incidence, mortality and DALY trends. RESULTS: The incidence of COPD increased by 85.89% from 8,722,966 cases in 1990 to 16,214,828 cases in 2019, and the ASIR decreased from 216.48/100,000 persons in 1990 (95%UI, 204.56-227.33) to 200.49 per 100,000 persons (95%UI, 188.63-212.57) in 2019. The ASIR increased (EAPC = 0.05, 95%CI, 0.01-0.10) in the low SDI region, was stable in the high SDI region, and fell in the other three SDI regions. Men had a higher ASIR than women over the past 30 years, and there were differences in the incidence rates for different age groups. Male mortality and DALYs were higher than female mortality. ASDR decreased by 2.13% (95%CI, -2.23% to -2.02%) per year and the annual age-standardized DALY rate decreased by 1.97% (95%CI, -2.05% to -1.89%). CONCLUSIONS: The ASIR, ASDR and age-standardized DALY rate of COPD declined overall in the last 30 years, and were highest in the low-middle SDI region.

Cognitive behavioral therapy for children and adolescents with post-traumatic stress disorder: meta-analysis.

BACKGROUND: Children and adolescents who experience traumatic events may develop post-traumatic stress disorder (PTSD), which is often associated with other psychiatric disorders, including depression and anxiety. Cognitive behavioral therapy (CBT) is widely used in psychotherapy to treat PTSD in children and adolescents. This meta-analysis evaluated previous studies on the effectiveness of CBT in the treatment of PTSD in children and adolescents. METHODS: Randomized controlled trials (RCTs) published before July 25, 2021, were retrieved from seven databases. All RCTs of CBT compared to control, including conventional treatment or other treatments, in children or adolescents with PTSD. Random effect models were employed for all outcomes. Risk of bias was performed by Cochrane Collaboration's tool. The publication bias was evaluated using the Egger's regression analysis. RESULTS: Nineteen RCTs were included in the meta-analysis. Compared with control, CBT was effective in reducing the symptoms of PTSD in children and adolescents, with a variety of scales used to measure the overall PTSD symptoms: CAPS (SMD = -0.41, 95%CI [-0.71, -0.12]), CPSS (SMD = -0.88, 95%CI [-1.42, -0.34]) and UCLA-PTSD RI (SMD = -1.70, 95%CI [-2.98, -0.42]). Furthermore, CBT also improved the comorbidities of depression (SMD = -0.43, 95%CI [-0.70, -0.17]) and anxiety (SMD = -0.29, 95%CI [-0.56, -0.03]) associated with PTSD. However, CBT was not effective in reducing avoidance symptoms (SMD = 0.38, 95%CI [-0.55, 1.31]). CONCLUSION: CBT can reduce the severity of PTSD in children and adolescents and improve the symptoms of depression and anxiety, as evident in the treatment of PTSD victims of sexual abuse and war and in patients aged more than 7 years.

Pharmaceutical administration for severe hypertension during pregnancy: Network meta-analysis.

Aims: To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy. Methods: Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the Cochrane Library for randomized clinical trials from the establishment of the database to 15 July 2021 that were eligible for inclusion and analyzed the pharmaceuticals used for severe hypertension in pregnancy. Results: 29 relevant trials with 2,521 participants were involved. Compared with diazoxide in rate of achieving target blood pressure, other pharmaceuticals, including epoprostenol (RR:1.58, 95%CI:1.01-2.47), hydralazine\dihydralazine (RR:1.57, 95%CI:1.07-2.31), ketanserin (RR:1.67, 95%CI:1.09-2.55), labetalol (RR:1.54, 95%CI:1.04-2.28), nifedipine (RR:1.54, 95%CI:1.04-2.29), and urapidil (RR:1.57, 95%CI:1.00-2.47), were statistically significant in the rate of achieving target blood pressure. According to the SUCRA, diazoxide showed the best therapeutic effect, followed by nicardipine, nifedipine, labetalol, and nitroglycerine. The three pharmaceuticals with the worst therapeutic effect were ketanserin, hydralazine, and urapidil. It is worth noting that the high ranking of the top two pharmaceuticals, including diazoxide and nicardipine, comes from extremely low sample sizes. Other outcomes were reported in the main text. Conclusion: This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that the instability of hydralazine reducing blood pressure and the high benefit of labetalol with high dosages intakes should also be of concern to clinicians.

ZFP90 drives the initiation of colitis-associated colorectal cancer via a microbiota-dependent strategy.

Chronic inflammation and gut microbiota dysbiosis are risk factors for colorectal cancer. In clinical practice, patients with inflammatory bowel disease (IBD) have a greatly increased risk of developing colitis-associated colorectal cancer (CAC). However, the underlying mechanism of the initiation of CAC remains unknown. Systematic analyses using an existing genome-wide association study (GWAS) and conditional deletion of Zfp90 (encoding zinc finger protein 90 homolog) in a CAC mouse model indicated that Zfp90 is a putative oncogene in CAC development.Strikingly, depletion of the gut microbiota eliminated the tumorigenic effect of Zfp90 in the CAC mouse model. Moreover, fecal microbiota transplantation demonstrated that Zfp90 promoted CAC dependent on the gut microbiota. Analysis of 16s rDNA sequences in fecal specimens from the CAC mouse model allowed us to speculate that a Prevotella copri-defined microbiota might mediate the oncogenic role of Zfp90 in the development of CAC. Mechanistic studies revealed Zfp90 accelerated CAC development through the TLR4-PI3K-AKT-NF-κB pathway. Our findings revealed the crucial role of the Zfp90-microbiota-NF-κB axis in creating a tumor-promoting environment and suggested therapeutic targets for CAC prevention and treatment.

RNA N6-Methyladenosine Modifications and the Immune Response.

N6-methyladenosine (m6A) is the most important modification of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in higher eukaryotes. Modulation of m6A modifications relies on methyltransferases and demethylases. The discovery of binding proteins confirms that the m6A modification has a wide range of biological effects and significance at the molecular, cellular, and physiological levels. In recent years, techniques for investigating m6A modifications of RNA have developed rapidly. This article reviews the biological significance of RNA m6A modifications in the innate immune response, adaptive immune response, and viral infection.

A 16q22.1 variant confers susceptibility to colorectal cancer as a distal regulator of ZFP90.

Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.

TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1.

TEAD4 (TEA domain family member 4) was recently revealed as an oncogenic character in tumorigenesis. However, its role remains unclear in colorectal tumorigenesis. Here, we firstly found that the expression level of TEAD4 was significantly elevated in clinical samples of colorectal adenomas (CRA) and correlated with the size and histological type of CRA. Moreover, patients with higher TEAD4 expression in normal colon mucosa are more prone to be recurrent after polypectomy. TEAD4 knockdown significantly inhibited colorectal cell proliferation in vitro and suppressed tumor growth in vivo. RNA-seq and GSEA analysis reveals TEAD4 can probably regulate Hippo pathway and further experiment confirm the downstream target gene YAP1. The subsequent ChIP-qPCR and luciferase report assay indicated that TEAD4 regulated YAP1 by direct binding and transcriptional activation. In summary, our study reveals that TEAD4 plays an important tumor-promoting role in colorectal cancer by directly targeting the YAP1, thus we suggests TEAD4 may be used as a novel biomarker in colorectal tumorigenesis and provides TEAD4/YAP1 axis as a potential therapeutic option for colorectal cancer.

Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer.

Members of the inositol phosphate metabolism pathway regulate cell proliferation, migration and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and are frequently dysregulated in cancer. Whether germline genetic variants in inositol phosphate metabolism pathway are associated with cancer risk remains to be clarified. We examined the association between inositol phosphate metabolism pathway genes and risk of eight types of cancer using data from genome-wide association studies. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-based associations were tested using the permutation-based adaptive rank-truncated product method. The overall inositol phosphate metabolism pathway was significantly associated with risk of lung cancer (P = 2.00 × 10(-4)), esophageal squamous cell carcinoma (P = 5.70 × 10(-3)), gastric cancer (P = 3.03 × 10(-2)) and renal cell carcinoma (P = 1.26 × 10(-2)), but not with pancreatic cancer (P = 1.40 × 10(-1)), breast cancer (P = 3.03 × 10(-1)), prostate cancer (P = 4.51 × 10(-1)), and bladder cancer (P = 6.30 × 10(-1)). Our results provide a link between inherited variation in the overall inositol phosphate metabolism pathway and several individual genes and cancer. Further studies will be needed to validate these positive findings, and to explore its mechanisms.

A long non-coding RNA signature to improve prognosis prediction of colorectal cancer.

Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC.

MicroRNA sequence polymorphisms and the risk of different types of cancer.

MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. Single nucleotide polymorphisms (SNPs) in miRNAs (MirSNPs) might promote carcinogenesis by affecting miRNA function and/or maturation; however, the association between MirSNPs reported and cancer risk remain inconsistent. Here, we investigated the association between nine common MirSNPs and cancer risk using data from large scale case-control studies. Eight precursor-miRNA (pre-miRNA) SNPs (rs2043556/miR-605, rs3746444/miR-499a/b, rs4919510/miR-608, rs2910164/miR-146a, rs11614913/miR-196a2, rs895819/miR-27a, rs2292832/miR-149, rs6505162/miR-423) and one primary-miRNA (pri-miRNA) SNP (rs1834306/miR-100) were analyzed in 16399 cases and 21779 controls from seven published studies in eight common cancers. With a novel statistic, Cross phenotype meta-analysis (CPMA) of the association of MirSNPs with multiple phenotypes indicated rs2910164 C (P = 1.11E-03), rs2043556 C (P = 0.0165), rs6505162 C (P = 2.05E-03) and rs895819 (P = 0.0284) were associated with a significant overall risk of cancer. In conclusion, MirSNPs might affect an individual's susceptibility to various types of cancer.