Effects of joint screening for prostate, lung, colorectal, and ovarian cancer - results from a controlled trial.

Background: Although screening is widely used to reduce cancer burden, untargeted cancers are frequently missed after single cancer screening. Joint cancer screening is presumed as a more effective strategy to reduce overall cancer burden. Methods: Gender-specific screening effects on PLCO cancer incidence, PLCO cancer mortality, all-neoplasms mortality and all-cause mortality were evaluated, and meta-analyses based on gender-specific screening effects were conducted to achieve the pooled effects. The cut-off value of time-dependent receiver-operating-characteristic curve of 10-year combined PLCO cancer risk was used to reclassify participants into low- and high-risk subgroups. Further analyses were conducted to investigate screening effects stratified by risk groups and screening compliance. Results: After a median follow-up of 10.48 years for incidence and 16.85 years for mortality, a total of 5,506 PLCO cancer cases, 1,845 PLCO cancer deaths, 3,970 all-neoplasms deaths, and 14,221 all-cause deaths were documented in the screening arm, while 6,261, 2,417, 5,091, and 18,516 outcome-specific events in the control arm. Joint cancer screening did not significantly reduce PLCO cancer incidence, but significantly reduced male-specific PLCO cancer mortality (hazard ratio and 95% confidence intervals [HR(95%CIs)]: 0.88(0.82, 0.95)) and pooled mortality [0.89(0.84, 0.95)]. More importantly, joint cancer screening significantly reduced both gender-specific all-neoplasm mortality [0.91(0.86, 0.96) for males, 0.91(0.85, 0.98) for females, and 0.91(0.87, 0.95) for meta-analyses] and all-cause mortality [0.90(0.88, 0.93) for male, 0.88(0.85, 0.92) for female, and 0.89(0.87, 0.91) for meta-analyses]. Further analyses showed decreased risks of all-neoplasm mortality was observed with good compliance [0.72(0.67, 0.77) for male and 0.72(0.65, 0.80) for female] and increased risks with poor compliance [1.61(1.40, 1.85) for male and 1.30(1.13, 1.40) for female]. Conclusion: Joint cancer screening could be recommended as a potentially strategy to reduce the overall cancer burden. More compliance, more benefits. However, organizing a joint cancer screening not only requires more ingenious design, but also needs more attentions to the potential harms. Trial registration: NCT00002540 (Prostate), NCT01696968 (Lung), NCT01696981 (Colorectal), NCT01696994 (Ovarian).

Associations of chest X-ray trajectories, smoking, and the risk of lung cancer in two population-based cohort studies.

Objectives: Despite the increasing use of computed tomography (CT), chest X-ray (CXR) remains the first-line investigation for suspected lung cancer (LC) in primary care. However, the associations of CXR trajectories, smoking and LC risk remain unknown. Methods: A total of 52,486 participants from the PLCO and 22,194 participants from the NLST were included. The associations of CXR trajectories with LC risk were evaluated with multivariable COX regression models and pooled with meta-analyses. Further analyses were conducted to explore the stratified associations by smoking status and the factors associated with progression and regression in CXR. Results: Compared to stable negative CXR (CXRSN), HRs (95%CIs) of LC incidence were 2.88(1.50-5.52), 3.86(2.03-7.35), and 1.08(0.80-1.46) for gain of positive CXR (CXRGP), stable positive CXR (CXRSP), and loss of positive CXR (CXRLP), while the risk of LC mortality were 1.58(1.33-1.87), 2.56(1.53-4.29), and 1.05(0.89-1.25). Similar trends were observed across different smoking status. However, LC risk with CXRGP overweighed that with CXRSP among ever smokers [2.95(2.25-3.88) vs. 2.59(1.33-5.02)] and current smokers [2.33(1.70-3.18) vs. 2.26(1.06-4.83)]. Moreover, compared to CXRSN among never smokers, even no progression in CXR, the HRs(95%CIs) of LC incidence were 7.39(5.60-9.75) and 31.45(23.58-41.95) for ever and current smokers, while risks of LC mortality were 6.30(5.07-7.81) and 27.17(21.65-34.11). If participants gained positive CXR, LC incidence risk significantly climbed to 22.04(15.37-31.60) and 71.97(48.82-106.09) for ever and current smokers, while LC mortality risk climbed to 11.90(8.58-16.50) and 38.92(27.04-56.02). CXRLP was associated with decreased LC risk. However, even smokers lost their positive CXR, and the increased risks of LC incidence and mortality did not decrease to non-significant level. Additionally, smoking was significantly associated with increased risk of CXRGP but not CXRLP. Conclusion: LC risk differed across CXR trajectories and would be modified by smoking status. Comprehensive intervention incorporating CXR trajectories and smoking status should be recommended to reduce LC risk.

Risk-stratified multi-round PSA screening for prostate cancer integrating the screening reference level and subgroup-specific progression indicators.

BACKGROUND: Although prostate-specific antigen (PSA) is widely used in prostate cancer (PCa) screening, nearly half of PCa cases are missed and less than one-third of cases are non-lethal. Adopting diagnostic criteria in population-based screening and ignoring PSA progression are presumed leading causes. METHODS: A total of 31,942 participants with multi-round PSA tests from the PLCO trial were included. Time-dependent receiver-operating-characteristic curves and area under curves (tdAUCs) were performed to determine the screening reference level and the optimal subgroup-specific progression indicator. Effects of risk-stratified multi-round PSA screening were evaluated with multivariable Cox regression and measured with hazard ratio [HR (95%CIs)]. RESULTS: After a median follow-up of 11.6 years, a total of 3484 PCa cases and 216 PCa deaths were documented. The tdAUC of 10-year incidence PCa with PSA was 0.816, and the cut-off value was 1.61 ng/ml. Compared to subgroup with stable negative PSA in both first-round (FR) and last-round (LR) tests [FR(-)/LR(-)], HRs (95%CI) of PCa incidence were 1.66 (1.20-2.29), 8.29 (7.25-9.48), and 14.52 (12.95-16.28) for subgroups with loss of positive PSA[FR(+)/LR(-)], gain of positive PSA[FR(-)/LR(+)], and stable positive PSA[FR(+)/LR(+)]; while HRs(95%CI) of PCa mortality were 1.47 (0.52-4.15), 5.71 (3.68-8.86), and 5.01 (3.41-7.37). After excluding regressive PSA [(namely FR(+)/LR(-)], absolute velocity was the shared optimal progression indicator for subgroups with FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), with tdAUCs of 0.665, 0.681 and 0.741, and cut-off values of 0.07, 0.21, and 0.33 ng/ml/year. After reclassifying participants into groups with positive and negative progression based on subgroup-specific progression indicators, incidence HR (95%CI) were 2.41 (1.87-3.10), 2.91 (2.43-3.48), and 3.16 (2.88-3.46) for positive progression compared to negative progression within subgroups of FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), while mortality HR (95%CI) were 2.22 (0.91-5.38), 2.37 (1.28-4.38), and 2.98 (1.94-4.59). To improve screening performances by excluding regressive PSA and low-risk positive progression in FR(-)/LR(-), optimized screening strategy not only significantly reduce 32.4% of missed PCa (54.0% [1881/3484] vs. 21.6% [754/3484], P < 0.001), but also detected additional 8.0% of high-grade PCa (Gleason score 7-10: 36.0% [665/1849] vs. 28.0% [206/736], P < 0.001) than traditional screening strategy. CONCLUSIONS: Risk-stratified multi-round PSA screening strategy integrating the screening reference level and the optimal subgroup-specific progression indicator of PSA could be recommended as a fundamental strategy to reduce missed diagnosis and improve the detection of high-grade PCa cases.

[Study on the ability of mammalian reovirus BYD1 to induce apoptosis and analysis of the structure of viral major membrane penetration protein involved in proapoptosis induction].

OBJECTIVE: To study a newly isolated domestic mammalian reovirus, BYD1, its ability to induce apoptosis analyze the three-dimensional structure of its major membrane penetration protein to predict its function in inducing apoptosis. METHODS: HeLa cells infected with BYD1 reovirus were metered with flow cytometer (FCM) to quantify the ratio of apoptotic cells. The data were analyzed with Student's t-test to judge the ability of BYD1 strain to induce apoptosis. The primary sequence ranged from 582 to 675 per microliter protein of BYD1, T1L, T2J and T3D were aligned and compared. The three-dimensional comparative protein structure model of microliter protein was generated by homology-modeling pipeline SWISS MODEL was applied to annotate its secondary and tertiary structure. RESULTS: BYD1 strain was verified with the ability to induce the apoptosis of HeLa cells. The 643-675 segment composing an alpha-helix showed major difference compared with prototype T2J. CONCLUSION: The newly isolated reovirus BYD1 is an apoptosis inducing strain. The alpha-helix (residues 643 to 675) of microliter protein of BYD1 may play a key role to induce the proapoptotic activity of infected cells.

Immunogenicity and protective efficacy in monkeys of purified inactivated Vero-cell SARS vaccine.

BACKGROUND: In 2003, severe acute respiratory syndrome (SARS) resulted in hundreds of infections and deaths globally. We aim to assess immunogenicity and protective efficacy of purified inactivated Vero-cell SARS vaccine in monkeys. METHODS: The cultures of SARS coronavirus (SARS-CoV) BJ-01 strain infected Vero cells were inactivated with beta-propiolactone. Sequential procedures, including ultrafiltration, gel filtration and ion exchange chromatography, were performed to obtain purified inactivated SARS vaccine. The purified SARS vaccine was analyzed with electron microscope, HPLC and Western blotting. We immunized three groups of cynomolgus macaques fascicularis with adjuvant-containing purified vaccine, purified vaccine and unpurified vaccine, respectively, and a fourth group served as a control. Antibody titers were measured by plaque reduction neutralization test. The vaccinated monkeys were challenged with SARS-CoV BJ-01 strain to observe protective efficacy. Additionally, three groups of rhesus monkeys were immunized with different doses of the purified inactivated SARS vaccine (0.5, 1 and 2mug/time/monkey) on days 0 and 7, and the monkeys were challenged with SARS-CoV GZ-01 strain. We assessed the safety of the SARS vaccine and observed whether the antibody dependent enhancement (ADE) occurred under low levels of neutralizing antibody in rhesus. FINDINGS: The purity of SARS vaccine was 97.6% by HPLC identification and reacted with convalescent sera of SARS patients. The purified SARS vaccine induced high levels of neutralizing antibodies and prevented the replication of SARS-CoV in monkeys. Under low levels of neutralizing antibody, no exacerbation of clinical symptoms was observed when the immunized monkeys were challenged with SARS-CoV. In this preliminary animal trial, no side effects were detected when monkeys were immunized with purified SARS vaccine either at normal or large doses. INTERPRETATION: The purified inactivated SARS vaccine could induce high levels of neutralizing antibody, and protect the monkeys from the challenge of SARS-CoV. The SARS vaccine prepared in the study appeared to be safe in monkeys.

[Expression and nuclease activity analysis of staphylococcus nuclease in E.coli].

AIM: To express staphylococcus nuclease (SN) in E.coli and prepare rabbit antisera against SN. METHODS: The SN gene was amplified by high-fidelity PCR from plasmid pPLC-SN and then subcloned into expression vector pLEX to obtain the recombinant plasmid pLEX-SN. The expression of recombinant protein was induced by tryptophan. The expressed SN was used to immunize a rabbit to prepare specific antibody. RESULTS: SDS-PAGE analysis showed that the relative molecular mass (M(r)) of the expressed SN was about 17,000 and the expressed SN accounted for about 37% of total bacterial proteins. The prepared antisera were specific to react with recombinant SN. CONCLUSION: Expression vector of SN has been successfully constructed and rabbit antibody against SN was prepared. These results lay the foundation for developing SN as antiviral protein.