Elucidation of the Role of DNA-Damage Response Genes in the Tumor Microenvironment and Molecular Characterization of a “Tropical” Chronic Lymphocytic Leukemia Cohort

In most human cancers such as diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), major genes of the DNA damage response (DDR) complex such as TP53, suffers inactivating mutations and dysregulation that impairs DNA repair processes and apoptotic machinery relevant for treatment. Despite the successes with Chemoimmunotherapy (CIT), many B-cells malignancies remain a major clinical challenge as therapy resistance account for 90% of cancer related fatalities. The tumor microenvironment (TME) is particularly culpable. Protumorigenic TME promotes complex crosstalk of tumor and stroma cells to facilitate tumor survival, proliferation, immune escape and metastasis. This study elucidated the role of DDR in TME interactions and characterized molecular signature of Ghanaian CLL cohort. Using shRNA to downregulate DDR genes in an ABC-subtype of DLBCL cell line we demonstrate that, functional TP53 and ATX (SMG-1) genes are critical for ADCP of DLBCL cells and that loss of TP53 and ATX in DLBCL induce resistance towards CIT by inhibition of macrophage effector functions through changes in formation/secretion of cellular secretome. Additionally, phagocytosis is significantly enhanced in ABC-DLBCL expressing high levels of PD-L1 and CD47 antigens when treated in vitro with CIT/anti-CD47, anti-PD-L1 or anti-PD1 combination. Particularly, CD47/Sirp-α blockade circumvent impaired ADCP due to TP53, ATX, KD providing a rational for incorporation of checkpoint inhibitors into current R-CHOP regimen for the management of TP53, ATX mutated, resistant/refractory ABC-DLBCL. Characterization of tropical African CLL showed females predominant incidence (51.1% vs 48.9%), lower median age of incidence (59yrs with 42.2% < 55yrs) compared to Western CLL which shows predominant males incidence (2:1) with a higher median age (71yrs, with 5-11% < 55yrs). Measurement of informative molecular markers showed 80% good prognosis by ZAP-70 and CD38 but 88.4% presentation at late clinical stage of disease, higher monotypic sIgM than dual IgM+/IgD+ (54.5% vs 34.1%) compared to predominant dual IgM+/IgD+ expression among European patients. These differences in CLL biology and clinical outcome may reflect interplay of genetic and environmental factors among racial groups in different geographical settings

Evaluation of the measles surveillance system of the Ga West Municipality, Ghana, 2017

Introduction: Over 140,000 people globally died from measles in 2018; most of which occurred in developing countries. In Ghana, measles is one of the diseases earmarked for elimination in the Integrated Disease Surveillance and Response (IDSR) strategy. The measles surveillance system seeks to monitor trends, detect outbreaks and report in a timely manner. In order to improve upon the performance of the Ga West Municipal Measles surveillance system, it was evaluated with the aim of determining its effectiveness. Methods: We used CDC updated guidelines for surveillance system evaluation to assess system attributes. Measles surveillance data from 2012 – 2016 were abstracted from the DHIMS. Case investigation forms, weekly and monthly IDSR reporting forms were reviewed to validate abstracted data. Key surveillance officers were interviewed on system operations. Data was analyzed descriptively to generate frequencies and relative frequencies. Results: The system operated with a reasonable number of disease variables and case definition was simple to apply. The system was found to be integrated with the national IDSR. Government facilities across all seven sub-districts, owned and contributed data to the system. Of the 48 suspected case-patients, 39 (81.0%) were investigated; none of which was positive giving a Predictive value positive (PVP) of 0%. Majority of facilities (though privately owned) did not contribute data to the system. All tested samples were received at the laboratory within the stipulated three (3) days. The system was stable with available case base forms. Over 56% (22/39) of the samples tested had no vaccination records. Data is used to guide routine and supplementary immunization activities. Conclusion: Ga west Municipal measles surveillance system is simple, flexible and generally acceptable. It is sensitive, timely, stable but with low representativeness. It is therefore effective. Municipal health officials have been sensitized on private sector participation and need for quality and timely data

Sports anaemia and anthropometric evaluation of footballers at Kwame Nkrumah University of Science and Technology (KNUST)

Introduction: Sports anaemia is a physiological activity that occurs amongst footballers and may be due to poor diet, over-training, as well as an increase in plasma volume in endurance training activities. High plasma volume leads to changes in haematological parameters that may impact on endurance of footballers. The objective of the study was to determine the correlation between haematological and an-thropometric indices and their role in sports anaemia in a tropical setting. Methods: Venous blood was taken into EDTA for 12 soccer players of KNUST soccer team before training and after training for the first (W1) and fifth (W5) weeks of training sessions. Complete blood count analysis was done for each blood sample and anthropometric parameters such as height, weight, body mass index, body fat percent and lean body mass were also measured. Cross-tabulations with mean and standard deviation or median and range were computed. Paired t-test &amp; and Mann-Whitney test for parametric and non-parametric data computations were carried out and a p-value ≤ 0.05 was taken to rep-resent significant difference between data groups. Results: There was significant reduction in haemoglobin (p =0.003), haematocrit (p =0.002), mean cell volume (MCV) (p =0.034) and red blood cell (RBC) count (p=0.011) as a result of a significant expansion of plasma volume (p= 0.006). Neutrophil, lymphocyte and eosinophil counts were reduced significantly (p= 0.043, 0.001 and 0.007, respectively) after the training at W5. Lean body mass (LBM) inversely correlated with haemoglobin (r= -0.787, p= 0.002) and haematocrit (r= -0.588, p= 0.044). Body fat percentage (BFP) also negatively correlated with lymphocyte count (r= -0.700, p= 0.011). Furthermore, there was a positive correlation between body mass index (BMI) and plasma volume change after the training programme (r=0.689, p= 0.013). Conclusion: The results suggest that sports anaemia was induced by an increase in plasma volume that resulted in changes in haematological parameters.Pan African Medical Journal 2016; 2

Interplay between foetal haemoglobin, micronutrients and oxidative stress biomarkers in sickle cell anaemia children

Foetal haemoglobin (HbF) has been speculated to have an impact on the quantity of micronutrients and the latter also have a role to play in oxidative stress (OS) in sickle cell anaemia (SCA). No previous study in Ghana has examined the interplay of these factors together among SCA children. This study compared the levels of OS biomarkers (8-hydroxy-deoxyguanosine [8-OHdG] total antioxidant capacity [TAC]) and micronutrients (zinc and copper), and their relationship with HbF in SCA and sickle cell negative, apparently healthy children. This case-control study recruited 58 SCA (out-patients [n = 42] and in-patients [n = 16]) children aged 1–14 years as cases and 62 sickle cell negative children as controls from the Sickle Cell Unit at the Eastern Regional Hospital, Ghana. The micronutrients were measured using the atomic absorption spectrophotometer (AAS) whereas OS biomarkers and HbF were assayed using enzyme-linked immunosorbent assay (ELISA). SCA out-patients had a significantly higher level of HbF compared to HbA patients (p = 0.035). SCA in-patients had significantly increased levels of zinc, but a reduced 8-OHdG than SCA out-patients compared to control group (p \u3c 0.05). HbF correlated significantly (r = 0.318, p \u3c 0.038) with zinc in SCA out-patients. Micronutrients are essential in maintaining the redox status in SCA out-patients and HbF can influence some micronutrients

Coagulation factors and natural anticoagulants as surrogate markers of preeclampsia and its subtypes: A case-control study in a Ghanaian population

Preeclampsia (PE) is associated with endothelial injury and hemostatic abnormalities. However, the diagnostic role of coagulation parameters and natural anticoagulants in predicting PE has not been explored in Ghana. This study assessed plasma levels of these factors as surrogate markers of PE and its subtypes. This case-control study included 90 women with PE (cases) and 90 normotensive pregnant women (controls). Blood samples were drawn for the estimation of complete blood count and coagulation tests. The prothrombin time (PT), activated partial thromboplastin time (APTT), and the calculation of the international normalized ratio (INR) were determined by an ACL elite coagulometer while the levels of protein C (PC), protein S (PS), antithrombin III (ATIII), and D-dimers were also measured using the solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) method. All statistical analyses were performed using the R Language for Statistical Computing. Results showed significantly (p \u3c .05) shortened APTT (28.25 s) and higher D-dimer levels (1219.00 ng/mL) among PE women, as well as low levels of PC (1.02 g/mL), PS (6.58 g/mL), and ATIII (3.99 ng/mL). No significant difference was found in terms of PT and INR. From the receiver operating characteristic analysis, PC, PS, and ATIII could significantly predict PE and its subtypes at certain cutoffs with high accuracies (area under the curve [AUC] ≥ 0.70). Most women with PE are in a hypercoagulable state with lower natural anticoagulants. PC, PS, and ATIII are good predictive and diagnostic markers of PE and its subtypes (early-onset PE [EO-PE] and late-onset PE [LO-PE]) and should be explored in future studies

Biomarkers of oxidative stress and its nexus with haemoglobin variants and adverse foeto-maternal outcome among women with preeclampsia in a Ghanaian population: A multi-centre prospective study

Introduction Haemoglobin variants and preeclampsia (PE) are associated with adverse fatal events of which oxidative stress may be an underlying factor. Oxidative stress (OS) among preeclamptic women with haemoglobin variants has been well established. It is, however, unclear whether haemoglobin variants induce OS to aggravate the risk of adverse foeto-maternal outcomes in pregnant women with preeclampsia. We measured the levels of OS biomarkers and determined the association between haemoglobin variants, and adverse foeto-maternal outcomes among pregnant women with PE. Methods This multi-centre prospective study recruited 150 PE women from three major health facilities in both Bono and Bono east regions of Ghana from April to December 2019. Haemoglobin variants; HbAS, HbSS, HbSC, HbCC, and HbAC were determined by haemoglobin electrophoresis. OS biomarkers such as malondialdehyde (MDA), catalase (CAT), vitamin C, and uric acid (UA) along with haematological and biochemical parameters were estimated using standard protocol. Adverse pregnancy complications (APCs) such as post-partum haemorrhage (PPH), HELLP (Haemolysis, Elevated liver enzymes, Low platelet count) syndrome, preterm delivery, neonatal intensive care unit (NICU) admission, and neonatal jaundice were recorded. Results Of the 150 pregnant women with preeclampsia, the distribution of haemoglobin AA, AS, AC, CC, SS and SC phenotypes were 66.0%, 13.3%, 12.7%, 3.3%, 3.3% and 1.3%, respectively. The most prevalent foeto-maternal outcomes among PE women were NICU admission (32.0%) followed by PPH (24.0%), preterm delivery (21.3%), HELLP syndrome (18.7%), and neonatal jaundice (18.0%). Except for vitamin C level which was significantly higher in patients with at least a copy of Haemoglobin S variant than those with at least a copy of Haemoglobin C variant (5.52 vs 4.55; p = 0.014), levels of MDA, CAT, and UA were not statistically significantly different across the various haemoglobin variants. Multivariate logistic regression model showed that participants with HbAS, HbAC, having at least a copy of S or C and participants with HbCC, SC, SS had significantly higher odds of neonatal jaundice, NICU admission, PPH and HELLP syndrome compared to participants with HbAA. Conclusion Reduced levels of vitamin C are common among preeclamptics with at least one copy of the HbC variant. Haemoglobin variants in preeclampsia contribute to adverse foeto-maternal outcomes with Haemoglobin S variants being the most influencing factor for PPH, HELLP, preterm labour, NICU admission, and neonatal jaundice

Quality of glycemic control in type 2 diabetes mellitus (T2DM) and its association with markers of coagulation and inhibitors of fibrinolysis: A case–control study in the upper west region, Ghana

Background and Aims: Type 2 diabetes mellitus (T2DM) individuals are at a higher risk of developing diabetes complications, with approximately 80% complication-related mortality. The increased morbidity and mortality among T2DM patients are partly due to dysregulated hemostasis. This study determined the quality of glycemic control in T2DM and its association with markers of coagulation and inhibitors of fibrinolysis. Methods: This case–control study recruited 90 participants involving: 30 T2DM patients with good glycemic control, 30 with poor glycemic control, and 30 nondiabetic subjects as controls at a Municipal Hospital in Ghana. Fasting blood glucose, glycated hemoglobin, activated partial thromboplastin time (APTT), prothrombin time (PT), calculated international normalized ratio (INR), and full blood count (FBC) were determined for each respondent. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI) were determined using the solid-phase sandwich enzyme-linked immunosorbent assay method. Data were analyzed using R language software. Results: Plasma PAI-1 antigen levels were significantly higher in the participants with poor glycemic control as compared to participants with good glycemic control (p \u3c 0.0001). There was no significant difference in plasma TAFI levels between the participants with poor glycemic control as compared to participants with good glycemic control (p = 0.900). T2DM patients had significantly shorter APTT, PT, and INR than controls (p \u3c 0.05). At a cut-off of ≥ 161.70 pg/μL, PAI was independently associated with increasing odds (adjusted odds ratio = 13.71, 95% confidence interval: 3.67–51.26, p \u3c 0.0001) of poor glycemic control and showed the best diagnostic accuracy for poor glycemic control (area under the curve = 0.85, p \u3c 0.0001). Conclusion: PAI-1 levels were significantly increased in T2DM with poor glycemic control and emerged as the best predictor for poor glycemic control. Good glycemic management to control the plasma levels of PAI-1 is required to prevent hypercoagulability and thrombotic disorders

Reference intervals for selected haematological and biochemical parameters among apparently healthy adults in different eco-geographical zones in Ghana.

BackgroundDue to the influence of gender, race/genetics, age, lifestyle habits and geography on the references intervals (RIs), the Clinical and Laboratory Standards Institute (CLSI) recommends the determination of population-specific RIs. Ghana continues to depend on pre-established RIs from other countries which poses the risk of misdiagnoses and wrong treatment. This study presents the haemato-biochemical RIs from four eco-geographical zones in Ghana.MethodsIn this population-based cross-sectional study, a total of 1227 randomly selected healthy voluntary blood donors from the four eco-geographic zones (Coastal Savannah, Rain Forest, Savannah and Transitional) were enrolled and screened. Based on the CLSI Guidance Document C28A2992, the data of eligible participants were used to non-parametrically determine the RIs for the haemato-biochemical parameters at the 2.5th and 97.5th percentiles. Comparison of analytes by gender was done by Wilcoxon rank sum test and eco-geographic differences were assessed using the Kruskal-Wallis with the Dunn post hoc multiple comparison tests.ResultsThere were statistically significant differences in most of the haematological parameters (RBC, Hb, HCT, MCV, PLT, WBC; p-values ConclusionThis study reports significant inter-sex and inter-geographical differences in haemato-biochemical RIs in Ghana as well as differences in RIs with both the RIs accompanying the analyzers and those of other countries. Determining RIs representative of populations and including them in the report systems of laboratories to ensure effective and efficient healthcare service delivery is thus recommended

Interplay between foetal haemoglobin, micronutrients and oxidative stress biomarkers in sickle cell anaemia children

Foetal haemoglobin (HbF) has been speculated to have an impact on the quantity of micronutrients and the latter also have a role to play in oxidative stress (OS) in sickle cell anaemia (SCA). No previous study in Ghana has examined the interplay of these factors together among SCA children. This study compared the levels of OS biomarkers (8-hydroxy-deoxyguanosine [8-OHdG] total antioxidant capacity [TAC]) and micronutrients (zinc and copper), and their relationship with HbF in SCA and sickle cell negative, apparently healthy children. This case-control study recruited 58 SCA (out-patients [n = 42] and in-patients [n = 16]) children aged 1–14 years as cases and 62 sickle cell negative children as controls from the Sickle Cell Unit at the Eastern Regional Hospital, Ghana. The micronutrients were measured using the atomic absorption spectrophotometer (AAS) whereas OS biomarkers and HbF were assayed using enzyme-linked immunosorbent assay (ELISA). SCA out-patients had a significantly higher level of HbF compared to HbA patients (p = 0.035). SCA in-patients had significantly increased levels of zinc, but a reduced 8-OHdG than SCA out-patients compared to control group (p < 0.05). HbF correlated significantly (r = 0.318, p < 0.038) with zinc in SCA out-patients. Micronutrients are essential in maintaining the redox status in SCA out-patients and HbF can influence some micronutrients