Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.

Extracellular vesicles from Zika virus-infected cells display viral E protein that binds ZIKV-neutralizing antibodies to prevent infection enhancement.

Mosquito-borne flaviviruses including Zika virus (ZIKV) represent a public health problem in some parts of the world. Although ZIKV infection is predominantly asymptomatic or associated with mild symptoms, it can lead to neurological complications. ZIKV infection can also cause antibody-dependent enhancement (ADE) of infection with similar viruses, warranting further studies of virion assembly and the function of envelope (E) protein-specific antibodies. Although extracellular vesicles (EVs) from flavivirus-infected cells have been reported to transmit infection, this interpretation is challenged by difficulties in separating EVs from flavivirions due to their similar biochemical composition and biophysical properties. In the present study, a rigorous EV-virion separation method combining sequential ultracentrifugation and affinity capture was developed to study EVs from ZIKV-infected cells. We find that these EVs do not transmit infection, but EVs display abundant E proteins which have an antigenic landscape similar to that of virions carrying E. ZIKV E-coated EVs attenuate antibody-dependent enhancement mediated by ZIKV E-specific and DENV-cross-reactive antibodies in both cell culture and mouse models. We thus report an alternative route for Flavivirus E protein secretion. These results suggest that modulation of E protein release via virions and EVs may present a new approach to regulating flavivirus-host interactions.

Tolerability, safety and efficacy of a novel phosphate binder VS-505 (AP301): a Phase 2 dose-escalation and dose-ranging study in patients undergoing maintenance hemodialysis.

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part Phase 2 study evaluated the tolerability, safety and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50 and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50 or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during Weeks 1-2 of treatment). Most gastrointestinal disorders resolved without intervention, and none was serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day [mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2) and -1.4 (-2.2, -0.5) mg/dL, respectively]. In both parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. CLINICAL TRIAL REGISTRATION NUMBER: NCT04551300 .

Sub-pm linewidth, high pulse energy, high beam quality microsecond-pulse Ti:sapphire laser at 766.699†nm.

In this letter, a sub-pm linewidth, high pulse energy and high beam quality microsecond-pulse 766.699 nm Ti:sapphire laser pumped by a frequency-doubled Nd:YAG laser is demonstrated. At an incident pump energy of 824 mJ, the maximum output energy of 132.5 mJ at 766.699 nm with linewidth of 0.66 pm and a pulse width of 100 µs is achieved at a repetition rate of 5 Hz. To the best of our knowledge, this is the highest pulse energy at 766.699 nm with pulse width of hundred micro-seconds for a Ti:sapphire laser. The beam quality factor M2 is measured to be 1.21. It could be precisely tuned from 766.623 to 766.755 nm with a tuning resolution of 0.8 pm. The wavelength stability is measured to be less than ±0.7 pm over 30 min. The sub-pm linewidth, high pulse energy and high beam quality Ti:sapphire laser at 766.699 nm can be used to create a polychromatic laser guide star together with a home-made 589 nm laser in the mesospheric sodium and potassium layer for the tip-tilt correction resulting in the near-diffraction limited imagery on a large telescope.

Metabolites in the TCA Cycle Promote Resistance to Chloramphenicol of Edwardsiella tarda.

Antibiotic-resistant bacteria are a serious threat to human and animal health. Metabolite-enabled eradication of drug-resistant pathogens is an attractive strategy, and metabolite adjuvants, such as fumarate, are used for restoring the bactericidal ability of antibiotics. However, we show that metabolites in the TCA cycle increase the viability of Edwardsiella tarda against chloramphenicol (CAP), based on the survival assay of differential metabolites identified by LC-MS/MS. Furthermore, NADPH promotes CAP resistance in the CAP-resistant strain, while oxidants restore the bactericidal ability. Finally, we show that the intracellular redox state determines the sensitivity to CAP, and the total antioxidative capacity is decreased significantly in the antibiotic-resistant strain. Considering that the metabolites promote CAP resistance, metabolite adjuvants should be applied very cautiously. Overall, our research expands on the knowledge that the redox state is related to the bactericidal ability of CAP.

Search for the Elusive Jet-Induced Diffusion Wake in Z/γ-Jets with 2D Jet Tomography in High-Energy Heavy-Ion Collisions.

Diffusion wake is an unambiguous part of the jet-induced medium response in high-energy heavy-ion collisions that leads to a depletion of soft hadrons in the opposite direction of the jet propagation. New experimental data on Z-hadron correlation in Pb+Pb collisions at the Large Hadron Collider show, however, an enhancement of soft hadrons in the direction of both the Z and the jet. Using a coupled linear Boltzmann transport and hydro model, we demonstrate that medium modification of partons from the initial multiple parton interaction (MPI) gives rise to a soft hadron enhancement that is uniform in azimuthal angle while jet-induced medium response and soft gluon radiation dominate the enhancement in the jet direction. After subtraction of the contributions from MPI with a mixed-event procedure, the diffusion wake becomes visible in the near-side Z-hadron correlation. We further employ the longitudinal and transverse gradient jet tomography for the first time to localize the initial jet production positions in Z/γ-jet events in which the effect of the diffusion wake is apparent in Z/γ-hadron correlation even without the subtraction of the MPI contribution.

Binding of cellular nucleolin with the viral core RNA G-quadruplex structure suppresses HCV replication.

Hepatitis C virus (HCV) infection is a major cause of human chronic liver disease and hepatocellular carcinoma. G-quadruplex (G4) is an important four-stranded secondary structure of nucleic acids. Recently, we discovered that the core gene of HCV contains a G4 RNA structure; however, the interaction between the HCV core RNA G4 and host cellular proteins, and the roles of the HCV core RNA G4 in HCV infection and pathogenesis remain elusive. Here, we identified a cellular protein, nucleolin (NCL), which bound and stabilized the HCV core RNA G4 structure. We demonstrated the direct interaction and colocalization between NCL and wild-type core RNA G4 at both in vitro and in cell physiological conditions of the alive virus; however no significant interaction was found between NCL and G4-modified core RNA. NCL is also associated with HCV particles. HCV infection induced NCL mRNA and protein expression, while NCL suppressed wild-type viral replication and expression, but not G4-modified virus. Silencing of NCL greatly enhanced viral RNA replication. Our findings provide new insights that NCL may act as a host factor for anti-viral innate immunity, and binding of cellular NCL with the viral core RNA G4 structure is involved in suppressing HCV replication.

Application of trauma time axis management in the treatment of severe trauma patients.

PURPOSE: This study aimed at exploring the application of trauma time axis management in the treatment of severe trauma patients by using the Medicalsystem trauma system. METHODS: We performed a retrospective cohort study involving patients with severe trauma. Patients who were admitted before the application of the Medicalsystem trauma system were divided into before system group; patients who were admitted after the application of the system were divided into after system group. Comparison was made between the two groups. For normally distributed data, means were reported along with standard deviation, and comparisons were made using the independent samples t test. Categorical data were compared using the Chi-square test. The Mann-Whitney U test was used to compare nonparametric variables. RESULTS: There were 528 patients admitted to the study during the study period. There was no significant statistical difference in the time from the start of trauma team to arrive at the resuscitation room between the two groups. The time from arrival at hospital to endotracheal intubation, to ventilator therapy, to blood transfusion, to completion of CT scan, to completion of closed thoracic drainage, to the start of operation, as well as the length of stay in resuscitation room and hospital were significantly lower after the application of the Medicalsystem trauma system. The mortality was decreased by 8.6% in the after system group compared with that in the before system group, but there was no statistical difference. CONCLUSION: The Medicalsystem trauma system can optimize diagnosis and treatment process for trauma patients, and accordingly improve the treatment efficiency and shorten the treatment time. Therefore, the Medicalsystem trauma system deserves further popularization and promotion.

Double-stranded RNA deaminase ADAR1 promotes the Zika virus replication by inhibiting the activation of protein kinase PKR.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a threat to global health. The family of adenosine deaminases acting on dsRNA (ADARs) are human host factors important for the genetic diversity and evolution of ZIKV. Here, we further investigated the role of ADAR1 in ZIKV replication by utilizing CRISPR/Cas9-based gene editing and RNAi-based gene knockdown techniques. Both ADAR1 knockout and knockdown significantly reduced ZIKV RNA synthesis, protein levels, and viral titers in several human cell lines. Trans-complementation with the full-length ADAR1 form p150 or the shorter form p110 lacking the Zα domain restored viral replication levels suppressed by the ADAR1 knockout. Moreover, we observed that the nuclear p110 form was redistributed to the cytoplasm in response to ZIKV infection. ADAR1 was not involved in viral entry but promoted viral protein translation by impairing ZIKV-induced activation of protein kinase regulated by dsRNA (PKR). Of note, the RNA-editing activity of ADAR1 was not required to promote ZIKV replication. We also found that the proviral role of ADAR1 was partially mediated through its ability to suppress IFN production and PKR activation. Our work identifies ADAR1 as a proviral factor involved in ZIKV replication, suggesting that ADAR1 could be a potential antiviral target.

Gradient Tomography of Jet Quenching in Heavy-Ion Collisions.

Transverse momentum broadening and energy loss of a propagating parton are dictated by the space-time profile of the jet transport coefficient q[over ^] in a dense QCD medium. The spatial gradient of q[over ^] perpendicular to the propagation direction can lead to a drift and asymmetry in parton transverse momentum distribution. Such an asymmetry depends on both the spatial position along the transverse gradient and path length of a propagating parton as shown by numerical solutions of the Boltzmann transport in the simplified form of a drift-diffusion equation. In high-energy heavy-ion collisions, this asymmetry with respect to a plane defined by the beam and trigger particle (photon, hadron, or jet) with a given orientation relative to the event plane is shown to be closely related to the transverse position of the initial jet production in full event-by-event simulations within the linear Boltzmann transport model. Such a gradient tomography can be used to localize the initial jet production position for more detailed study of jet quenching and properties of the quark-gluon plasma along a given propagation path in heavy-ion collisions.

Coffee drinking and cancer risk: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Epidemiological studies on the association between coffee intake and cancer risk have yielded inconsistent results. To summarize and appraise the quality of the current evidence, we conducted an umbrella review of existing findings from meta-analyses of observational studies. METHODS: We searched PubMed, Embase, Web of Science and the Cochrane database to obtain systematic reviews and meta-analyses of associations between coffee intake and cancer incidence. For each association, we estimated the summary effect size using the fixed- and random-effects model, the 95% confidence interval, and the 95% prediction interval. We also assessed heterogeneity, evidence of small-study effects, and excess significance bias. RESULTS: Twenty-eight individual meta-analyses including 36 summary associations for 26 cancer sites were retrieved for this umbrella review. A total of 17 meta-analyses were significant at P ≤ 0.05 in the random-effects model. For the highest versus lowest categories, 4 of 26 associations had a more stringent P value (P ≤ 10- 6). Associations for five cancers were significant in dose-response analyses. Most studies (69%) showed low heterogeneity (I2 ≤ 50%). Three and six associations had evidence of excessive significance bias and publication bias, respectively. Coffee intake was inversely related to the risk of liver cancer and endometrial cancer and was characterized by dose-response relationships. There were no substantial changes when we restricted analyses to meta-analysis of cohort studies. CONCLUSIONS: There is highly suggestive evidence for an inverse association between coffee intake and risk of liver and endometrial cancer. Further research is needed to provide more robust evidence for cancer at other sites.

Personal Characteristics Effects on Validation of Self-reported Type 2 Diabetes From a Cross-sectional Survey Among Chinese Adults.

BACKGROUND: The objective was to evaluate the effects of personal characteristics on the validation of self-reported type 2 diabetes among Chinese adults in urban Shanghai. METHODS: During 2015 through 2016, 4,322 participants were recruited in this validation study. We considered the criteria of diabetes verification to use the laboratory assays of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), or self-reported use of diabetic medication. RESULTS: When taking diabetic medication or FPG ≥7.0 mmol/L was as identified diabetes, the measurements of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Kappa value of self-reported diabetes were 72.0%, 99.2%, 95.1%, 93.9%, and 0.78, respectively. If an additional HbA1c test was used for 708 subjects (aged <65 years), slightly lower values of sensitivity, NPV, and Kappa were observed. More potential diabetes cases were found compared to only using FPG. Subjects who were female, older, or had a family history of diabetes had sensitivity over 75% and excellent Kappa over 0.8, while the sensitivity and Kappa of opposite groups had poorer values. Specificity, PPV, and NPV were similar among groups with different demographic or disease characteristics. The prevalence of type 2 diabetes was 19.3% in the study (14.1% diagnosed diabetes, 5.2% undiagnosed diabetes). About 26.2% of subjects were pre-diabetic. Additional HbA1c test indicated an increased prevalence of undiagnosed diabetes and pre-diabetes. CONCLUSIONS: Findings support self-reported diabetes is sufficiently valid to be used in large-scale, population-based epidemiologic studies. Participants with different characteristics may have different indicators in terms of validation, such as age, gender, and family history of diabetes in first-degree relatives.

Syntenin regulates hepatitis C virus sensitivity to neutralizing antibody by promoting E2 secretion through exosomes.

BACKGROUND & AIMS: Assembly of infectious hepatitis C virus (HCV) particles is known to involve host lipoproteins, giving rise to unique lipo-viro-particles (LVPs), but proteome studies now suggest that additional cellular proteins are associated with HCV virions or other particles containing the viral envelope glycoprotein E2. Many of these host cell proteins are common markers of exosomes, most notably the intracellular adaptor protein syntenin, which is required for exosome biogenesis. We aimed to elucidate the role of syntenin/E2 in HCV infection. METHODS: Using cell culture-derived HCV, we studied the biogenesis and function of E2-coated exosomes in both hepatoma cells and primary human hepatocytes (PHHs). RESULTS: Knockout of syntenin had a negligible impact on HCV replication and virus production, whereas ectopic expression of syntenin at physiological levels reduced intracellular E2 abundance, while concomitantly increasing the secretion of E2-coated exosomes. Importantly, cells expressing syntenin and HCV structural proteins efficiently released exosomes containing E2 but lacking the core protein. Furthermore, infectivity of HCV released from syntenin-expressing hepatoma cells and PHHs was more resistant to neutralization by E2-specific antibodies and chronic-phase patient serum. We also found that high E2/syntenin levels in sera correlate with lower serum neutralization capability. CONCLUSIONS: E2- and syntenin-containing exosomes are a major type of particle released from cells expressing high levels of syntenin. Efficient production of E2-coated exosomes renders HCV infectivity less susceptible to antibody neutralization in hepatoma cells and PHHs. LAY SUMMARY: This study identifies a key role for syntenin in the regulation of E2 secretion via exosomes. Efficient production of E2-coated exosomes was shown to make hepatitis C virus less sensitive to antibody neutralization. These results may have implications for the development of a hepatitis C virus vaccine.

Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet-induced insulin-resistant mice.

Insulin is critical for the regulation of de novo fatty acid synthesis, which converts glucose to lipid in the liver. However, how insulin signals are transduced into the cell and then regulate lipogenesis remains to be fully understood. Here, we identified CREB/ATF bZIP transcription factor (CREBZF) of the activating transcription factor/cAMP response element-binding protein (ATF/CREB) gene family as a key regulator for lipogenesis through insulin-Akt signaling. Insulin-induced gene 2a (Insig-2a) decreases during refeeding, allowing sterol regulatory element binding protein 1c to be processed to promote lipogenesis; but the mechanism of reduction is unknown. We show that Insig-2a inhibition is mediated by insulin-induced CREBZF. CREBZF directly inhibits transcription of Insig-2a through association with activating transcription factor 4. Liver-specific knockout of CREBZF causes an induction of Insig-2a and Insig-1 and resulted in repressed lipogenic program in the liver of mice during refeeding or upon treatment with streptozotocin and insulin. Moreover, hepatic CREBZF deficiency attenuates hepatic steatosis in high-fat, high-sucrose diet-fed mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced insulin resistance or genetically obese ob/ob mice and humans with hepatic steatosis, which may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions. CONCLUSION: These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (Hepatology 2018).

Bayesian Extraction of Jet Energy Loss Distributions in Heavy-Ion Collisions.

Based on the factorization in perturbative QCD, a jet cross section in heavy-ion collisions can be expressed as a convolution of the jet cross section in p+p collisions and a jet energy loss distribution. Using this simple expression and the Markov Chain Monte Carlo method, we carry out Bayesian analyses of experimental data on jet spectra to extract energy loss distributions for both single inclusive and γ-triggered jets in Pb+Pb collisions with different centralities at two colliding energies at the Large Hadron Collider. The average jet energy loss has a dependence on the initial jet energy that is slightly stronger than a logarithmic form and decreases from central to peripheral collisions. The extracted jet energy loss distributions with a scaling behavior in x=Δp_{T}/⟨Δp_{T}⟩ have a large width. These are consistent with the linear Boltzmann transport model simulations, in which the observed jet quenching is caused on the average by only a few out-of-cone scatterings.

Dietary protein intake and risk of type 2 diabetes: a dose-response meta-analysis of prospective studies.

PURPOSE: The association between dietary protein intake and type 2 diabetes risk has been inconsistent in the previous epidemiological studies. We aimed to quantitatively assess whether dietary total, animal, and plant protein would be associated with type 2 diabetes risk. METHODS: A comprehensive literature review was conducted to identify related articles by searching PubMed, Embase, Web of Science, and Wiley Online Library through 20th March 2018. Generalized least squares for trend estimation and restricted cubic spline regression model were applied in the dose-response analysis. RESULTS: Eight publications with ten prospective cohorts of 34,221 type 2 diabetes cases were included. After adjustment of potential confounders, a 5% of energy increment from dietary total and animal protein intake was related to a 9% (1.04, 1.13; I2 = 42.0%) and 12% (95% CI 1.08, 1.17; I2 = 14.0%) higher risk of type 2 diabetes respectively. However, for plant protein, a significant U-shaped curve was observed with the most risk reduction at intake of about 6% of energy intake from plant protein intake (Pnonlinearity = 0.001). The results were robust in sensitivity analysis and no publication bias was detected. CONCLUSIONS: These findings indicate that the consumption of protein particularly animal protein may be associated with an increased risk of type 2 diabetes.

Correction to: Construction of Medical Equipment-Based Doctor Health Monitoring System.

The original version of this article unfortunately contained a mistake. Corrections in equations which were highlighted in a doc file were not carried out. The original version has been corrected.

Construction of medical equipment-based doctor health monitoring system.

The health status of doctors has been overlooked by the society and even the doctors themselves, especially those doctors who work long hours. Their attention is always on patients, so they are more likely to ignore their own health problems. Therefore, in this paper, we propose a medical equipment-based doctor health monitoring system (hereinafter referred to as Doc-care). Doc-care can be used as a private health manager for doctors, and doctors can monitor their health indicators in real time while using medical equipment to aid diagnosis and treatment. When the doctor's health status is neglected, Doc-care can protect the doctor's health; combining with the convolutional neural network method to detect and grade the doctor's health indicators, to assess the doctor's real-time health status. After referring to the doctor's past health data in the cloud server, giving appropriate advice and predictions about the doctor's health status.

Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model.

OBJECTIVE: HCV is characterised by its ability to establish chronic infection in hepatocytes and to replicate in the presence of an inflammation. We mimicked this situation in vivo in immune-competent mice by syngeneic transplantation of HCV replicon-containing mouse hepatoma cells. DESIGN: A total of 5 million H-2b positive Hep56.1D cells, carrying a subgenomic genotype (gt) 2a replicon (HCV replicon cells) or stably expressing comparable levels of the HCV NS3/4A protease/helicase complex (NS3/4A hepatoma cells), were injected subcutaneously into syngeneic H-2b-restricted mice. Kinetics of tumour growth, HCV RNA replication levels and HCV-specific immune responses were monitored. For immune monitoring, new H-2b-restricted cytotoxic T cell epitopes within the gt2a NS3/4A region were mapped. Immune mice were generated by DNA-based vaccination. RESULTS: HCV replicon and NS3/4A hepatoma cells generated solid tumours in vivo. Similar to what is seen in human HCV infection did HCV RNA replicate in the presence of inflammation. NS3/4A-specific CD8+ T cells seemed to transiently reduce HCV RNA levels. Both CD4+ and CD8+ T cells were required for protection against tumour growth. Vaccine-induced NS3/4A(gt2a)-specific T cells protected against HCV replicon tumours in wild-type, but not in HCV NS3/4A(gt1a)-transgenic mice with dysfunctional HCV-specific T cells. Importantly, as in human HCV infection, HCV replicon cells neither primed nor boosted a strong NS3/4A-specific T cell response. CONCLUSION: Syngeneic transplantation of mouse HCV replicon cells into immune-competent animals mirrors many in vivo events in humans. This system is versatile and can be applied to any genetically modified H-2b-restricted mouse strain.

The joint effects of major lifestyle factors on colorectal cancer risk among Chinese men: A prospective cohort study.

Previous studies have suggested individual healthy lifestyle factors are related to lower risk of colorectal cancer. Their joint effects, however, have rarely been investigated. We aimed to assess the combined lifestyle impact on colorectal cancer risk and to estimate the population attributable risks of these lifestyle factors. Using data from the Shanghai Men's Health Study (2002-2013), we constructed healthy lifestyle index composing the following lifestyle factors: smoking, alcohol consumption, diet, waist-hip ratio and exercise participation. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Over a median of 9.28 years' follow-up, 671 colorectal cancer cases occurred (400 colon cancer and 274 rectal cancer) among 59,503 men. Each increment of healthy lifestyle index was associated with a 17% lower risk of colorectal cancer (HR = 0.83, 95% CI: 0.78, 0.89), 10% of colon cancer (HR = 0.90, 95% CI: 0.83, 0.99) and 27% of rectal cancer (HR = 0.73, 95% CI: 0.66, 0.82). If all men in the cohort followed a lifestyle as defined by these five factors, 21% colorectal cancer cases would have been prevented (PAR = 21%, 95% CI: 4%, 36%). In conclusion, combined lifestyle factors are significantly related to lower risk of colorectal cancer and the effects are more pronounced on rectal cancer than on colon cancer.