Outcome of COVID-19 in Egyptian living-donor kidney transplant recipients and relation to maintenance immunosuppressive drugs: a pilot study.

Coronavirus disease 2019 (COVID-19) in kidney transplant recipients is a subject of much debate and became of interest to nephrologists amidst the pandemic. The main concerns are the influence of the chronic use of immunosuppressive drugs, the viral-related risk of acute rejection, and the long-term outcome of allograft function. This single-center prospective study included kidney transplant recipients with COVID-19 infection. Patients were maintained on immunosuppressive regimens. The severity of disease was defined as oxygen saturation < 94%, the need for hospitalization and/or hemodialysis, the occurrence of acute kidney injury (AKI), and mortality. Seventeen patients (54.8%) required hospital admission, four patients needed hemodialysis (12.9%), twelve patients (38.7%) had AKI, and three patients died (9.7%). Oxygen saturation < 94% showed a positive correlation with the presence of diabetes (p value 0.031) and a negative correlation with the maintenance steroid dose (p value 0.046). A negative correlation existed between the need for hemodialysis and average Cyclosporin level (p value 0.019) and between the need for hospitalization and average Tacrolimus level (p value 0.046). Severity of disease was associated with the presence of lymphopenia (p value 0.042), the cumulative steroid dose (p value 0.001), increased serum levels of LDH (p value 0.010), Ferritin (p value 0.020), AST (p value 0.047), and ALT (p value 0.006) and D-dimer levels more than 0.5 mg/L (p value 0.038). This study highlighted that the immunocompromised state of renal transplant recipients may not be regarded as a disadvantage in the setting of COVID-19 infection. Studies on a larger scale are needed to validate these results.

Impact of Epithelial-Mesenchymal Transition on the Immune Landscape in Breast Cancer.

The impact of epithelial-mesenchymal transition (EMT) signature on the immune infiltrate present in the breast cancer tumor microenvironment (TME) is still poorly understood. Since there is mounting interest in the use of immunotherapy for the treatment of subsets of breast cancer patients, it is of major importance to understand the fundamental tumor characteristics which dictate the inter-tumor heterogeneity in immune landscapes. We aimed to assess the impact of EMT-related markers on the nature and magnitude of the inflammatory infiltrate present in breast cancer TME and their association with the clinicopathological parameters. Tissue microarrays were constructed from 144 formalin-fixed paraffin-embedded invasive breast cancer tumor samples. The protein expression patterns of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM were examined by immunohistochemistry (IHC). The inflammatory infiltrate in the TME was assessed semi-quantitatively on hematoxylin and eosin (H&E)-stained whole sections and was characterized using IHC. The inflammatory infiltrate was more intense in poorly differentiated carcinomas and triple-negative carcinomas in which the expression of E-cadherin and GRHL2 was reduced, while EpCAM was overexpressed. Most EMT-related markers correlated with plasma cell infiltration of the TME. Taken together, our findings reveal that the EMT signature might impact the immune response in the TME.

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis.

Breast cancer is a heterogeneous disease comprising the estrogen receptor (ER)-positive luminal subtype which is subdivided into luminal A and luminal B and ER-negative breast cancer which includes the triple-negative subtype. This study has four aims: 1) to examine whether Minichromosome Maintenance (MCM)2, MCM4, and MCM6 can be used as markers to differentiate between luminal A and luminal B subtypes; 2) to study whether MCM2, MCM4, and MCM6 are highly expressed in triple-negative breast cancer, as there is an urgent need to search for surrogate markers in this aggressive subtype, for drug development purposes; 3) to compare the prognostic values of these markers in predicting relapse-free survival; and 4) to compare the three approaches used for scoring the protein expression of these markers by immunohistochemistry (IHC). MCM2, MCM4, MCM6, and MKI67 mRNA expression was first studied using in silico analysis of available breast cancer datasets. We next used IHC to evaluate their protein expression on tissue microarrays using three scoring methods. MCM2, MCM4, and MCM6 can help in distinction between luminal A and luminal B whose therapeutic management and clinical outcomes are different. MCM2, MCM4, MCM6, and Ki-67 are highly expressed in breast cancer of high histological grades that comprise clinically aggressive tumors such as luminal B, HER2-positive, and triple-negative subtypes. Low transcript expression of these markers is associated with increased probability of relapse-free survival. A positive relationship exists among the three scoring methods of each of the four markers. An independent validation cohort is needed to confirm their clinical utility.

Association of genetic polymorphism of pre-microRNA-146a rs2910164 and serum high-mobility group box 1 with febrile seizures in Egyptian children.

Interaction between immune-inflammatory process and genetic factors might be implicated in the pathogenesis of febrile seizures. Pre-microRNA (miR)-146a rs2910164 polymorphism is postulated to modulate expression of miR-146a whose anti-inflammatory role involves regulation of high-mobility group box 1. Our aim is to examine whether rs2910164 polymorphism influences serum high-mobility group box 1 levels and whether an association exists between both and febrile seizures. The study included 136 children, divided into 4 groups. Real-time polymerase chain reaction was used for detection of rs2910164 polymorphism and high-mobility group box 1 was measured using enzyme-linked immunosorbent assay. High-mobility group box 1 levels were higher in febrile seizure patients compared to the other groups. Rs2910164 polymorphism was not associated with increased risk of febrile seizures. Rs2910164 polymorphism might be accompanied by an upregulation of the proinflammatory process as it might be associated with an increase in high-mobility group box 1 and leukocytic count.

MEFV mutations in Egyptian children with systemic-onset juvenile idiopathic arthritis.

BACKGROUND AND OBJECTIVES: Systemic-onset juvenile idiopathic arthritis (SoJIA) is a chronic auto-inflammatory disease of childhood, with a complex genetic trait, which is characterized by arthritis associated with systemic manifestations. Familial Mediterranean fever (FMF) is another auto-inflammatory disorder that is monogenic. There are speculations as to whether Mediterranean fever (MEFV) mutations are among the genetic determinants of SoJIA. Our aim was to explore the frequency and clinical significance of MEFV mutations in Egyptian SoJIA patients. A group of healthy children were assigned to the control group in an attempt to estimate the carrier rate of MEFV mutations in Egypt. METHODS: Eighty-four children were recruited in this study; 54 children, age (mean ± standard deviation; 8.31 ± 2.85 years), diagnosed as having SoJIA with no typical symptoms of FMF; 30 healthy age- and gender-matched children served as the control group. All recruited children were screened for 12 common MEFV mutations using a reverse hybridization assay of biotinylated PCR products. RESULTS: SoJIA patients had a significantly higher frequency of MEFV mutations (66.7 %) than in the healthy control population (16.7 %). V726A was the leading mutation in SoJIA patients, with an allelic frequency of 15.74 %, followed by E148Q, with an allelic frequency of 7.4 %. Children who were carriers of MEFV mutations had an 18 times higher risk of developing SoJIA than wild-type carriers [odds ratio 18.0 (95 % CI 5-69), P < 0.01]. E148Q was the leading mutation, present in 13.3 % of healthy controls. CONCLUSION: These findings suggest that MEFV mutations may be responsible for auto-inflammatory diseases other than FMF, and patients with SoJIA, especially those with a positive family history of FMF or SoJIA, should be screened for MEFV mutations in countries where FMF is frequent.

Is there a role for MDR1, EPHX1 and protein Z gene variants in modulation of warfarin dosage? a study on a cohort of the Egyptian population.

BACKGROUND: There is considerable inter-individual variability in warfarin dosages necessary to achieve target therapeutic anticoagulation. Polymorphisms in genes, which master warfarin pharmacokinetics and pharmacodynamics, might influence warfarin dose variation. Genes encoding drug transporters, such as human multidrug resistance (MDR1), as well as epoxide hydrolase 1 (EPHX1), which is a putative subunit of the vitamin K epoxide reductase, and Protein Z (PZ), which is a vitamin K-dependent plasma glycoprotein, are among those candidate genes. OBJECTIVE: The purpose of this study was to investigate the contribution of MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms in warfarin dose variation in a cohort of the Egyptian population. METHODS: Eighty-four patients whose international normalized ratio (INR) was in the range of 2-3, 41 males and 43 females, with a mean (±SD) age of 40.9 (13.3) years were recruited into this study. MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Primarily, linear regression analysis, including the variables age, gender, MDR1 C3435T, EPHX1 H139R and combined MDR1 C3435T, EPHX1 H139R and PZ A-13G genotypes, was used to assess the effective factors for warfarin maintenance dose. Secondly, the previously examined cytochrome P450 (CYP) 2C9 A1075C and vitamin K epoxide reductase complex subunit 1 (VKORC1) C1173T were added to the regression analysis. RESULTS: Warfarin dose/week was not influenced by each of the MDR1 C3435T, EPHX1 H139R, and PZ A-13G gene polymorphisms when examined separately. However, when these single nucleotide polymorphisms (SNPs) were combined, MDR1 TT/EPHX1 RH,RR/PZ AA subjects showed statistically significant increase in warfarin dose/week when compared with MDR1 CC/EPHX1 RH,RR/PZ AA subjects [median (25th-75th percentiles): 49.0 (42.0-59.5) vs. 35.0 (24.5-42.0) mg/week, respectively] (p = 0.014). In contrast, in the presence of wild-type EPHX1 HH, there was a decrease in warfarin dose/week in MDR1 TT subjects when compared with CT and CC subjects [median (25th-75th percentiles): 22.0 (17.5-30.6), 42.0 (35.0-49.0) and 42.0 (28.0-54.3) mg/week, respectively] (p = 0.005 and 0.030, respectively). Age had a significant contribution (p = 0.048) to the overall variability in warfarin dose. Calculated weekly dose = 52.928 - (0.289 × age) + (9.709 × combined genotype). The multivariate linear regression equation of warfarin maintenance dose accounted for about 8 % of variation in dose (R (2) = 0.079), age accounted for 5 % of variation, while combined genotypes added the extra 3 %. However, the new regression equation accounted for 20.9 % of variation in dose. Age accounted for 5 %, while VKORC1 C1173T accounted for an extra 13 % of variation and MDR1 C3435T accounted for the remaining 3 % of variation. Calculated dose = 64.909 - (0.282 × age) - (13.390 × VKORC1) - (7.164 × MDR1). Correlation analysis showed a close and significant relationship between the calculated and actual warfarin dose (r = 0.457; p < 0.0005). CONCLUSION: Warfarin dose/week was significantly influenced by the combined MDR1 C3435T and EPHX1 H139R gene polymorphism since no polymorphism of PZ A-13G SNP was detected in our studied Egyptian population. Future studies with larger sample size will be needed to confirm our findings before definitive conclusions can be made.