Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide-induced production of IL-1 beta and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects.Web of Science849849018488

High CXCR3 on leukemic cells distinguishes IgHV(mut) from IgHV(unmut) in chronic lymphocytic leukemia: Evidence from CD5(high) and CD5(low) clones

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5(high) and CD5(low) neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5(high)and CD5(low) subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n=60) subgrouped according to the IgHV mutational status (IgHV(mut),n=24;IgHV(unmut),n=36). CD5(high) subpopulation showed a high percentage of CXCR3 (P<0.001), CCR10 (P=0.001), and CD62L (P=0.031) and high levels of CXCR5 (P=0.005), CCR7 (P=0.013) compared to CD5(low) cells expressing high CXCR4 (P<0.001). Comparing IgHV(mut) and IgHV(unmut)patients, high levels of CXCR3 on CD5(high) and CD5(low) subpopulations were detected in theIgHV(mut) patients, with better discrimination in CD5(low) subpopulation. Levels of CXCR3 on CD5(low) subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5(high) and CD5(low) neoplastic cells inIgHV(mut) with a better prognosis compared to IgHV(unmut) patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.Web of Science2020art. no. 708426

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukaemia using patient similarity networks

The tissue microenvironment in chronic lymphocytic leukaemia (CLL) plays a key role in the pathogenesis of CLL, but the complex blood microenvironment in CLL has not yet been fully characterised. Therefore, immunophenotyping of circulating immune cells in 244 CLL patients and 52 healthy controls was performed using flow cytometry and analysed by multivariate Patient Similarity Networks (PSNs). Our study revealed high inter-individual heterogeneity in the distribution and activation of bystander immune cells in CLL, depending on the bulk of the CLL cells. High CLL counts were associated with low activation on circulating monocytes and T cells and vice versa. The highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. PSNs revealed a low activation of immune cells in CLL progression, irrespective of IgHV status, Binet stage and TP53 disruption. Patients with high intermediate monocytes (>5.4%) with low activation were 2.5 times more likely (95% confidence interval 1.421-4.403, P=0.002) to had shorter time-to-treatment than those with low monocyte counts. Our study demonstrated the association between the activation of circulating immune cells and the bulk of CLL cells. The highest activation of bystander immune cells was detected in patients with slow disease course and in those treated with novel agents. The subset of intermediate monocytes showed predictive value for time-to-treatment in CLL.Web of Science111art. no. 32

Assessment of two different methods of calculating a heating demand

Phenomenon of today′s era is lowering overall energy performance and greenhouse gas emissions. European Union and its members came from an “uncontrollable” fossil fuel usage to an era of dependence reduction from fossil fuel usage. EU industry is now in era of utilizing renewable energy sources. Construction industry is responsible for 40% of total energy performance of EU; hence the great emphasis on energy effective design on new buildings as well as importance on energy effective renovation of already constructed buildings. Effort on lowering total energy performance in construction industry has signed on research on new project solutions, new insulation materials and new building services technologies which are maximizing energy gain from renewable energy sources. Simulation software and different engines are more than helpful tool when predicting building thermal behaviour. That is why simulation software is used more often in the process of designing energy efficient buildings or in the process of energy performance optimization of existing buildings. simulation and analytics itself, is dealing with simulation of chosen buildings (family houses) on heating demand based on the newest knowledge of constructions and materials. Results of heating demands of different family houses were confronted against heating demands calculated according national standards – using non-variable conditions. Next, the differences between two calculation approaches were characterized in percentages

Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers

Germline pathogenic ATM (ataxia-telangiectasia mutated) variants are associated with the risk of multiple cancers; however, genetic testing reveals a large number of ATM variants of uncertain significance (VUS). Here, we studied germline ATM variants occurring in a real-world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two-thirds of rare germline ATM variants are pathogenic (18%-50%) or VUS-predicted pathogenic (50%-82%), depending on cancer type and reaching a prevalence of up to 8%, and one-third are VUS-predicted benign. Patients with both pathogenic and VUS-predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic ATM inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic ATM variants. A functional assay of ATM activity in primary CLL cells proved that VUS-predicted pathogenic ATM variants partially reduce ATM activity and concurrent del(11q) leads to complete loss of ATM activity. The rare germline variants were associated with reduced progression-free survival in CLL on novel agents, comparable to somatic ATM or TP53 disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as ATM.Web of Science199338137

Towards a better characterisation of leukemic cells in chronic lymphocytic leukaemia: Cell-size heterogeneity reflects their activation status and migratory abilities

Chronic lymphocytic leukaemia (CLL) is a genetically, morphologically and phenotypically heterogeneous chronic disease with clinical variability between patients. Whether the significant heterogeneity of cell size within the CLL population contributes to the heterogeneous features of this disease has not been investigated. The present study aimed to characterise the phenotypic and functional properties of two subpopulations of typical CLL cells that differ in cell size: small (s-CLL) and large (l-CLL) CLL cells delineated by forward scatter cytometry. The s-CLL cells were characterised by the CD5lowCXCR4hi phenotype, while the l-CLL cells were characterised by the CD5hiCXCR4dim phenotype and indicated a higher expression of CXCR3, CD20, CD38 and HLA-DR. The l-CLL cells displayed higher migration activity towards CXCL12, a tendency towards a higher proliferation rate and an increased capacity to produce IgM in the presence of CpG compared with s-CLL cells. When stimulated with CpG and CXCL12, l-CLL cells were characterised by a higher polarisation phenotype and motility than s-CLL cells. Our study revealed that the differences in CLL cell size reflected their activation status, polarisation and migratory abilities. Our data provide evidence of the importance of cell-size heterogeneity within a CLL pool and the dynamics of cell-size changes for disease pathogenesis, thus deserving further investigation.Web of Science1319art. no. 492

Chinese views of the world at the time of the Russia-Ukraine war

This report is a result of a large-scale online survey of public opinion in Mainland China, conducted between 9-23 March 2022,3 with a research sample (N=3039) representative of the Chinese population with respect to gender, age (18-65 years), and country region. This survey is part of a broader research project ‘Sinophone Borderlands – Interaction at the Edges’, funded by the European Regional Development Fund. As part of this project, a series of public opinion surveys have been conducted in various parts of the world. We sum up some of the findings from the Mainland China survey here, especially in relation to Chinese views of Russia, the US, and international affairs. More outcomes from this research project will follow in future, focusing on a number of more concrete issues. Overall, Chinese respondents expressed very positive views of Russia and very negative views of the US. In fact, of the 25 countries respondents were asked about, Russia was the most positively perceived country, while the US was the most negatively perceived. As our survey was collected at the height of the Chinese public and media attention towards the Russia-Ukraine war (and before the escalation of the Covid-19 in China in late March), these results suggest that the Chinese public was not disturbed by the Russian aggression, and even appeared to support Russia. This is consistent with available qualitative studies of Chinese official and social media, which show how Russia’s invasion of Ukraine has been portrayed not as an act of unprovoked aggression against a sovereign nation, but as a rightful response to US and NATO’s “bullying” of Russia. Russia appears to be strongly supported in resisting what is redefined as American aggression