RESUMO
Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56+/16+ NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL.
RESUMO
BACKGROUND: Type 2 diabetes mellitus (DM) rates are increasing rapidly in South Asians. Cardiovascular complications are more frequent and occur earlier in our patients than patients in many other ethnic groups. Reasons for this are not fully understood. AIMS: The aim of this study is to evaluate the body total and central fat percentage in type 2 Diabetes Mellitus patients and to check correlation with BMI, waist circumference and metabolic profile. SETTINGS AND DESIGN: A cross-sectional study conducted at endocrine clinic, Aga Khan University Hospital Karachi, Pakistan, from May to December 2012. MATERIALS AND METHODS: Patients of either gender with type 2 diabetes mellitus were randomly selected. A separate proforma for each patient was recorded for demographics, risk factors, bioelectrical impedance measurement for body fat and investigations. STATISTICAL ANALYSIS: Correlation between body fat and other covariate were compared by Pearson correlation coefficient test. A P < 0.05 was considered significant. SPSS19.0 was used to analyze the data. RESULTS: One hundred and seventy five patients (95 male and 80 female) with mean age of 54.1 ± 12 years were evaluated. Mean duration of diabetes was 8.1 years, mean HbA1c was 8.1% and 53.7% were on oral agents and rest were on insulin with or without oral agents. Hypertension was present in 65.7%, 13.7% had known coronary artery disease and 2.3% had cerebrovascular disease. Mean BMI in males was 29.1 ± 4.74 kg/m(2) and females 31.7 ± 5.3 kg/m(2). Mean waist circumference in males was 107.3 ± 16.6 cm and 103 ± 12 cm in females. Total body fat percentage (%BF) in males was 30.9 ± 7.1% and females 40 ± 8.2% with 89% of the total cohort having total body fat percentage above the normal, less than 25% central fat percentage was 13.3 ± 5.2% in males and 14.6 ± 5.5% in females with 79.4% of cohort having increased central fat (normal <9%). Total and central body fat correlated with BMI (r = 0.68, P < 0.001) and waist circumference (r = 0.66, P < 0.001) but not with HbA1c, triglyceride level or with fasting or random blood glucose levels. Women had significantly higher total body fat percentage compared to men (P < 0.001) although central fat percentage was similar in both sexes. CONCLUSIONS: High body fat percentage, waist circumference are seen especially in woman and central body fat percentage in both sexes among patients with type 2 diabetes mellitus in Pakistan. Body fat percentage should be measured and followed as this may be an important contributing factor to the high macrovascular complication rate in this part of world.
