TNFα antagonist in combination with PD-1 blocker to prevent or retard malignant transformation of B[a]P-induced chronic lung inflammation.

Benzo[a]pyrene (B[a]P) is a typical complete carcinogen in tobacco, but its mechanism of inducing the development of chronic pneumonia and consequent lung cancer is unclear. Here we elucidated the role of myeloid-derived suppressor cells (MDSCs) in developing B[a]P-induced chronic lung inflammation and efficacy of immunotherapy in preventing subsequent malignant transformation. Our study showed that as B[a]P could induce the accumulation of MDSCs in lung tissues and enhance the immunosuppressive effect regulated by cytokines and metabolites, thereby promoting the formation of immunosuppressive microenvironment, where effector T cells were exhausted, NK cells were dysfunctional, regulatory T (Treg) cells were expanded, polarized alveolar macrophages were transformed from M1 to M2. Subsequently, we performed the immunotherapy to block TNFɑ only or both TNFɑ and PD-1 at the early- or middle-stage of B[a]P-induced chronic lung inflammation to ameliorate the immunosuppressive microenvironment. We found that TNFɑ antagonist alone or with PD-1 blocker was shown to exert therapeutic effects on malignant transformation at the early stage of B[a]P-induced chronic lung inflammation. Taken together, our findings demonstrated that B[a]P-induced chronic lung inflammation resulted in the accumulation of MDSCs in lung tissues and exercise their immunosuppressive functions, thereby developing an immunosuppressive microenvironment, thus TNFɑ antagonist alone or with PD-1 blocker could prevent or retard the malignant transformation of B[a]P-induced chronic lung inflammation.

The association between cumulative C-reactive protein and brachial-ankle pulse wave velocity.

BACKGROUND AND AIMS: This study aimed to investigate the association between cumulative C-reactive protein (cumCPR) and arterial stiffness. METHODS: The cross-sectional study included 15,432 participants from the Kailuan Cohort. The participants were divided into four groups according to cumCRP quartiles. The average brachial-ankle pulse wave velocity (baPWV) and detective rate of increased arterial stiffness were compared between exposure groups. Statistical analysis was performed with multiple logistic regression analysis to estimate the association between cumCRP and arterial stiffness by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). The several sensitivity analyses were performed to test the robustness of our findings. RESULTS: The average baPWV increased from 1425.70 cm/s of Q1 group to 1626.48 cm/s of Q4 group. And the detective rate of arterial stiffness increased from 44.7 to 70.1% (P < 0.001). Multiple logistic regression analysis showed that after adjusting the confounding factors, compared to the Q1 group, the Q4 group had 42% (adjusted OR 1.42; 95% CI 1.24-1.63) higher arterial stiffness risk. In addition, 10% (adjusted OR 1.10; 95% CI 1.02-1.18) arterial stiffness risk was increased per 1 standard deviation (SD) of cumCRP after a fully adjusted regression model. CONCLUSION: Higher cumCRP exposure is associated with increased arterial stiffness.

Use of real-time cellular analysis and Plackett-Burman design to develop the serum-free media for PC-3 prostate cancer cells.

In this study, we developed a rapid strategy to screen a serum-free medium for culturing the anchorage-dependent PC-3 prostate cancer cells, which was going to be prepared in large scale to generate GM-CSF/TNFα-surface-modified whole cell prostate cancer vaccine. Automated real-time cellular analysis as a rapid and non-invasive technology was used to monitor the growth of PC-3 cells in 16-well plates. At the same time, Plackett-Burman design was employed to identify the most influential formulation by integrating relevant information statistically. The effects of the 16 selected factors were evaluated during exponential cell growth and three medium constituents (EGF, FGF and linoleic acid) were identified to have significant effects on the cell growth. Subsequently, the response surface methodology with central composite design was applied to determine the interactions among the three factors so that these factors were optimized to improve cell growth. Finally, the prediction of the best combination was made under the maximal response to optimize cell growth by Design-Expert software 7.0. A total of 20 experiments were conducted to construct a quadratic model and a second-order polynomial equation. With the optimized combination validated by the stability test of serial passaging PC-3 cells, the serum-free medium had similar cell density and cell viability to the original serum medium. In summary, this high-throughput scheme minimized the screening time and may thus provide a new platform to efficiently develop the serum-free media for adherent cells.

Correlation between the trajectory of systolic blood pressure and new renal damage in a nonhypertensive population.

OBJECTIVE: This study aims to investigate the correlation between the trajectory of systolic blood pressure (SBP) and new renal damage in a nonhypertensive population. PATIENTS AND METHODS: This prospective cohort study included a total of 14 382 nonhypertensive individuals, employees of Kailuan Group of Companies, who took part in five healthy examinations in 2006-2007, 2008-2009, 2010-2011, 2012-2013, and 2014-2015, and had complete data. These individuals were divided into four groups according to the different trajectories of SBP: low-low, low-stable, middle-high, and high-high groups. The correlation between the trajectory of SBP and new renal damage in a nonhypertensive population was analyzed using a multivariate Cox's proportional hazard regression model. RESULTS: (a) A total of 14 382 individuals had complete data and the average age of these individuals was 44.6±10.8 years. Among these, 10 888 (75.7%) individuals were men and 3494 (24.3%) individuals were women. (b) These individuals were divided into four groups according to different trajectories of blood pressure: low-low group, accounting for 13.15% (blood pressure was <106 mmHg); low-stable group, accounting for 53.91% (blood pressure was between 115 and 116 mmHg); middle-high group, accounting for 28.77% (blood pressure was between 125 and 131 mmHg); and high-high group, accounting for 4.6% (blood pressure was between 126 and 151 mmHg). (c) With the increase in the trajectory of SBP, the detection rate of renal damage increased gradually. From the low-low group to the high-high group, the detection rates of estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m were 2.3, 2.4, 3.6, and 4.3%, respectively; the positive rates of urinary protein were 1.7, 2.9, 3.8, and 5.5%, respectively; and the detection rates of eGFR less than 60 ml/min/1.73 m or positive urinary protein were 4, 5.2, 7.3, and 9.3%, respectively (P<0.05). (d) After adjustment for other confounding factors, multivariate Cox's proportional hazard regression analysis showed that compared with the low-low group, the risk of eGFR less than 60 ml/min/1.73 m increased by nearly 1.5 times in the high-high group and in the low-stable, middle-high, and high-high groups, the risks of positive urinary protein, eGFR less than 60 ml/min/1.73 m, or positive urinary protein increased by 1.48-2.34 and 1.20-1.70 times, respectively. CONCLUSION: In a nonhypertensive population, the high trajectory of SBP is a risk factor for kidney damage.