Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion

Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)–like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein- Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM- like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD

The spectrum of myelodysplastic syndromes post-solid organ transplantation: A single institutional experience

An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48–64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells.

Activation-induced cytidine deaminase (AID) is necessary for immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR) in T-dependent immune response in germinal centers (GCs). The structural similarity of AID with RNA-editing enzymes and its largely cytoplasmic location have fueled controversial views of its mode of interaction with DNA. We show that AID, a mature B-cell–restricted cytoplasmic antigen, is relocated into the nucleus in 2.5% of CDKN1B–, CCNB1– GC cells. The GC dark zone and the outer zone (OZ), but not the light zone, contain nuclear and cytoplasmic AID+ blasts. AID+ cells in the OZ are in contact with T cells and CD23– follicular dendritic cells. In addition, AID is expressed in extrafollicular large proliferating B cells, 14% of which have nuclear AID. GC and extrafollicular AID+ cells express E47 but not the inhibiting BHLH protein Id2. Outside the GC, AID+ B cells are in contact with T cells and show partial evidence of CD40 plus bcr stimulation-dependent signature (CCL22, JunB, cMYC, CD30) but lack early and late plasma cell markers. The distribution of nuclear AID is consistent with the topography of SHM and CSR inside the GC and in extrafollicular activated B cells

Influence of interferon-gamma Receptor 1 gene polymorphisms on the susceptibility to pulmonary tuberculosis among sudanese population

Background: A variety of genetic mutations are thought to be responsible for acquisition of different infections such as tuberculosis (TB). An obvious example for these variations is the link between pulmonary TB and polymorphisms within interferon-gamma receptor 1 (IFN-γ R1) gene. This project is designed to identify the role of IFN-γR1 gene polymorphism in the development of pulmonary TB among Sudanese patients attending several hospitals in Khartoum State. Methods: One hundred (n = 100) patients with active TB and fifty (n = 50) matched healthy controls were investigated for the association of two genetic polymorphisms within IFN-γR1 gene and their risk of developing pulmonary tuberculosis. Polymerase chain reaction (PCR) assay and PCR-restriction fragment length polymorphism were performed. Results: Migrated IFN-γR1 DNA bands representing genotypes and polymorphic alleles were identified. Molecular findings revealed that two genetic variants, namely, −56C and +295C deletion 12 within IFN-γR1 gene, were nonsignificantly linked with increased risk of development of pulmonary TB, P = 0.771 and 0.343, respectively. Two genetic variants within IFN-γR1 gene were examined for suggested role in inducing development of TB. Conclusion: The two genetic variants were found to have potential risk in association with active disease development among Sudanese patients. Further intensive research work involving use of large collection of samples should be conducted to verify these findings

Influence of interferon-gamma Receptor 1 gene polymorphisms on the susceptibility to pulmonary tuberculosis among sudanese population

Background: A variety of genetic mutations are thought to be responsible for acquisition of different infections such as tuberculosis (TB). An obvious example for these variations is the link between pulmonary TB and polymorphisms within interferon-gamma receptor 1 (IFN-γ R1) gene. This project is designed to identify the role of IFN-γR1 gene polymorphism in the development of pulmonary TB among Sudanese patients attending several hospitals in Khartoum State. Methods: One hundred (n = 100) patients with active TB and fifty (n = 50) matched healthy controls were investigated for the association of two genetic polymorphisms within IFN-γR1 gene and their risk of developing pulmonary tuberculosis. Polymerase chain reaction (PCR) assay and PCR-restriction fragment length polymorphism were performed. Results: Migrated IFN-γR1 DNA bands representing genotypes and polymorphic alleles were identified. Molecular findings revealed that two genetic variants, namely, −56C and +295C deletion 12 within IFN-γR1 gene, were nonsignificantly linked with increased risk of development of pulmonary TB, P = 0.771 and 0.343, respectively. Two genetic variants within IFN-γR1 gene were examined for suggested role in inducing development of TB. Conclusion: The two genetic variants were found to have potential risk in association with active disease development among Sudanese patients. Further intensive research work involving use of large collection of samples should be conducted to verify these findings

Synergistic effect of dry sludge from waste wash water of concreteplants and zeolitic by-product on the properties of ternary blendedordinary Portland cements

art. no 118493This paper analyses the use of two types of supplementary cementing materials,edry sludge from wastewash water of concrete plants and zeolitic by-productefor producing hardened cement paste speci-mens. X-ray powder diffraction, scanning electronic microscopy, energy-dispersive X-ray spectroscopy,and thermal analysis were used as investigation methods. Test results showed that the addition of drysludge reduced the compressive strength of hardened cement paste at both 7 and 28 days. In hardenedcement paste specimens where Portland cement was substituted with 5 %e30% of dry sludge thecompressive strength decreased significantly after 7 and 28 at days. After 28 days blended Portlandcement containing up to 10% of supplementary cementing materials ((SCM) - dry sludge and zeolitic by-product) demonstrated higher compressive strength than the reference specimen as a result of syner-gistic interactions, whereas higher replacement levels led to reduction in compressive strengthKauno technologijos universitetasVilniaus Gedimino technikos universitetasVytauto Didžiojo universitetasŽemės ūkio akademij