31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Association of sleep duration and sleep quality with hypertension in oil workers in Xinjiang

Objective The aim of this study is to explore sleep status and hypertension among oil workers in Xinjiang, China. It may provide new ideas and basis for the precise prevention and treatment of hypertension in occupational population. Methods Sleep status and hypertension were investigated in 3,040 workers by a multi-stage cluster sampling method in six oil field bases in Karamay City, Xinjiang. The Pittsburgh Sleep Quality Index was used to evaluate the sleep status of workers. Logistic regression was used to analyze the relationship between sleep duration and sleep quality, and hypertension. Stratified analysis was also performed. Results Our results show: 1. Insufficient sleep duration (OR = 1.51, 95% CI [1.19–1.90]) and poor sleep quality (OR = 1.78, 95% CI [1.33–2.38] were positively associated with hypertension. 2. Stratified analysis indicated insufficient sleep duration was associated with increased risk of hypertension in females (OR = 1.54, 95% CI [1.16–2.04]) than males (OR = 1.49, 95% CI [1.00–2.23]), and the risk of hypertension in the group 45 years old, sleeping > 8 h was associated with increased risk of hypertension (OR = 3.36, 95% CI [1.42–7.91]). Oil workers doing shift work had a higher risk of hypertension (OR = 1.55, 95% CI [1.16–2.07]) to no shift work (OR = 1.48, 95% CI [1.02–2.15]). The risk of hypertension in the group with 20 years (OR = 1.64, 95% CI [1.18–2.27]). The risk of hypertension in the group 30–45 years old is higher than that in the group > 45 years old (OR 30–45 years old = 1.71, 95% CI [1.10–2.66]; OR > 45 years old = 1.60, 95% CI [1.09–2.34]). Conclusion Insufficient sleep duration and poor sleep quality are the potential factors affecting hypertension in Xinjiang oil workers

Effect of interaction between occupational stress and polymorphisms of MTHFR gene and SELE gene on hypertension

Background Gene-environment interaction is related to the prevalence of hypertension, but the impact of genetic polymorphisms on hypertension may vary due to different geography and population. Objective To explore the impact of the interaction among occupational stress and MTHFR gene and SELE gene polymorphism on the prevalence of hypertension in Xinjiang oil workers. Methods A case-control study was conducted on 310 oil workers. In an oilfield base in Karamay City, Xinjiang, 155 hypertensive patients aged 18~60 years old with more than one year of service were selected as the case group, and 155 oil workers without hypertension were selected as the control group according to the 1:1 matching principle (matching conditions: the gender and shift were the same. The age is around 2 years old). The Occupational Stress Scale was used to evaluate the degree of occupational stress, PCR technique was used to detect MTHFR and SELE gene polymorphism, Logistic regression analysis was used to analyze the effects of gene and occupational stress on hypertension, and gene-gene and gene-environment interactions were analyzed by generalized multi-factor dimension reduction method. Results The G98T polymorphism of SELE gene (χ2 = 6.776, P = 0.034), the C677T (χ2 = 7.130, P = 0.028) and A1298C (χ2 = 12.036, P = 0.002) loci of MTHFR gene and the degree of occupational stress (χ2 = 11.921, P = 0.003) were significantly different between the case group and the control group. The genotypes GT at the G98T polymorphism of the SELE gene (OR = 2.151, 95% CI [1.227–3.375]), and the dominant model (AC/CC vs AA, OR = 1.925, 95% CI [1.613–3.816]); AC and CC at the A1298C polymorphism of the MTHFR gene (ORAC = 1.917, 95% CI [1.064–3.453]; ORCC = 2.233, 95% CI [1.082–4.609]), the additive model (CC vs AA, OR = 2.497, 95% CI [1.277–4.883]) and the dominant model (AC/CC vs AA, OR = 2.012, 95% CI [1.200–3.373]); at the C677T polymorphism of the MTHFR gene CT and TT (ORCT = 1.913, 95% CI [1.085–3.375]; ORTT = 3.117, 95% CI [1.430–6.795]), the additive model (CC vs AA, OR = 1.913, 95% CI [1.085–3.375]) and the dominant model (AC/CC vs AA, OR = 2.012, 95% CI [1.200–3.373]), which could increase hypertension risk (P < 0.05). The gene-gene interaction showed that there was a positive interaction between the A1298C and C677T sites of the MTHFR gene, and the gene-occupational stress interaction showed that there was a positive interaction between the A1298C and C677T sites of the MTHFR gene and the occupational stress. Conclusion The interaction of gene mutation and occupational stress in Xinjiang oil workers maybe increase the risk of hypertension

Immunoproteomics based identification of thioredoxin reductase GliT and novel <it>Aspergillus fumigatus </it>antigens for serologic diagnosis of invasive aspergillosis

Abstract Background There has been a rising incidence of invasive aspergillosis (IA) in critically ill patients, even in the absence of an apparent predisposing immunodeficiency. The diagnosis of IA is difficult because clinical signs are not sensitive and specific, and serum galactomannan has relatively low sensitivity in this group of patients. Therefore, more prompt and accurate disease markers for early diagnosis are needed. To establish disease markers demands a thorough knowledge of fungal antigens which may be detected in the serum or other body fluids of patients. Herein we report novel immunodominant antigens identified from extracellular proteins of Aspergillus fumigatus. Results Extracellular proteins of A. fumigatus were separated by two-dimensional electrophoresis (2-DE) and probed with the sera from critically ill patients with proven IA. The immunoreactive protein spots were identified by MALDI-TOF mass spectrometry (MALDI-TOF -MS). Forty spots from 2DE gels were detected and 17 different proteins were identified as immunogenic in humans. Function annotation revealed that most of these proteins were metabolic enzymes involved in carbohydrate, fatty acid, amino acid, and energy metabolism. One of the proteins, thioredoxin reductase GliT (TR), which showed the best immunoactivity, was analyzed further for secretory signals, protein localization, and homology. The results indicated that TR is a secretory protein with a signal sequence exhibiting a high probability for secretion. Furthermore, TR did not match any human proteins, and had low homology with most other fungi. The recombinant TR was recognized by the sera of all proven IA patients with different underlying diseases in this study. Conclusions The immunoreactive proteins identified in this study may be helpful for the diagnosis of IA in critically ill patients. Our results indicate that TR and other immunodominant antigens have potential as biomarkers for the serologic diagnosis of invasive aspergillosis.</p

Associations of serotonin transporter gene promoter polymorphisms and monoamine oxidase A gene polymorphisms with oppositional defiant disorder in a Chinese Han population

Abstract Background Oppositional defiant disorder (ODD) is a behavioral disorder that mainly refers to a recurrent pattern of disobedient, defiant, negativistic and hostile behaviors toward authority figures. Previous studies have showed associations of serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) with behavioral and psychiatric disorders. The purposes of this study were to investigate the potential association of 5-HTT gene promoter polymorphism (5-HTTLPR) and MAOA gene polymorphism with susceptibility to ODD in a Han Chinese school population. Methods The 5-HTTLPR gene polymorphism and the MAOA gene polymorphism were genotyped in a case–control study of 257 Han Chinese children (123 ODD and 134 healthy controls). Results There was significant difference in the allele distribution of 5-HTTLPR (χ2 = 7.849, P = 0.005) between the ODD and control groups. Further, there were significant differences in genotype (χ2 = 5.168, P = 0.023) and allele distributions (χ2 = 10.336, P = 0.001) of the MAOA gene polymorphism that is variable-number tandem repeat (MAOA-uVNTR) between two groups. Moreover, there were significant differences in genotype (χ2 = 4.624, P = 0.032) and allele distributions (χ2 = 9.248, P = 0.002) of MAOA-uVNTR only in the male ODD and healthy groups. Conclusions Our results suggest that 5-HTTLPR and MAOA-uVNTR gene variants may contribute to susceptibility to ODD. Further, MAOA-uVNTR gene polymorphism may play a role in susceptibility to ODD only in male children