Tuberculosis in Kazakhstan: analysis of risk determinants in national surveillance data

Development of tuberculosis (TB) is determined by various risk factors and the interactions of temporal and spatial distributions. The aim of this study was to identify the most salient risk factors for TB disease as well as multidrug resistant TB (MDR-TB) at the oblast (provincial) level in Kazakhstan

Tuberculosis in Kazakhstan: analysis of risk determinants in national surveillance data

Background: Development of tuberculosis (TB) is determined by various risk factors and the interactions of temporal and spatial distributions. The aim of this study was to identify the most salient risk factors for TB disease as well as multidrug resistant TB (MDR-TB) at the oblast (provincial) level in Kazakhstan. Methods: Correlational and descriptive analyses were conducted at the oblast and national level using data provided by the country’s National Institute of Geography (NIG) and the National Tuberculosis Program (NTP). Reported incident case notification rates (CNRs) and prevalence vary by oblast, thus the study investigated which determinants contributed to this regional variation and compared burdens among oblasts. Results: The results showed that while tuberculosis CNRs decreased over the study period, MDR-TB conversely increased. Two oblasts -Atyrauskaya and Mangystauskaya - presented especially significant anomalies with large decreases in TB incident CNRs coupled with comparatively large increases in MDR-TB incident CNRs. Conclusion: Understanding the distribution of TB and MDR-TB cases and associated risk factors, especially the “unknown risk factor” categorization points to the need for future research

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

Tuberculosis in Kazakhstan: analysis of risk determinants in national surveillance data

Abstract Background Development of tuberculosis (TB) is determined by various risk factors and the interactions of temporal and spatial distributions. The aim of this study was to identify the most salient risk factors for TB disease as well as multidrug resistant TB (MDR-TB) at the oblast (provincial) level in Kazakhstan. Methods Correlational and descriptive analyses were conducted at the oblast and national level using data provided by the country’s National Institute of Geography (NIG) and the National Tuberculosis Program (NTP). Reported incident case notification rates (CNRs) and prevalence vary by oblast, thus the study investigated which determinants contributed to this regional variation and compared burdens among oblasts. Results The results showed that while tuberculosis CNRs decreased over the study period, MDR-TB conversely increased. Two oblasts -Atyrauskaya and Mangystauskaya - presented especially significant anomalies with large decreases in TB incident CNRs coupled with comparatively large increases in MDR-TB incident CNRs. Conclusion Understanding the distribution of TB and MDR-TB cases and associated risk factors, especially the “unknown risk factor” categorization points to the need for future research.</p

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency ofCTCs and lack of appropriate models. Here, we describe the characterization of a novelCTC-derived breast cancer cell line, designatedCTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER+) breast cancer, resistant to endocrine therapy.CTC-ITB-01 remainedER(+)in culture, and copy number alteration (CNA) profiling showed high concordance betweenCTC-ITB-01 andCTCs originally present in the patient with cancer at the time point of blood draw.RNA-sequencing data indicate thatCTC-ITB-01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductalPDXmouse model mirrored the clinical progression ofER(+)breast cancer. DownstreamERsignaling was constitutively active inCTC-ITB-01 independent of ligand availability, and theCDK4/6 inhibitor Palbociclib strongly inhibitedCTC-ITB-01 growth. Thus, we established a functional model that opens a new avenue to studyCTCbiology

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency ofCTCs and lack of appropriate models. Here, we describe the characterization of a novelCTC-derived breast cancer cell line, designatedCTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER+) breast cancer, resistant to endocrine therapy.CTC-ITB-01 remainedER(+)in culture, and copy number alteration (CNA) profiling showed high concordance betweenCTC-ITB-01 andCTCs originally present in the patient with cancer at the time point of blood draw.RNA-sequencing data indicate thatCTC-ITB-01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductalPDXmouse model mirrored the clinical progression ofER(+)breast cancer. DownstreamERsignaling was constitutively active inCTC-ITB-01 independent of ligand availability, and theCDK4/6 inhibitor Palbociclib strongly inhibitedCTC-ITB-01 growth. Thus, we established a functional model that opens a new avenue to studyCTCbiology