Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures

Mild hyperhomocysteinemia is caused by B vitamin deficiencies. We hypothesize that these biochemical derangements detrimentally affect spermatogenesis. Therefore, the aim of this study was to investigate the folate, cobalamin, pyridoxine, and homocysteine concentrations in blood and seminal plasma and the associations between these biomarkers and semen parameters in men participating in an in vitro fertilization or intracytoplasmic sperm injection program. From 73 men (median age [range]: 37 years [28-53]), blood and semen samples were obtained for the determination of serum and red blood cell (RBC) folate, serum total cobalamin, whole-blood pyridoxal-5'-phosphate, plasma total homocysteine (tHcy), and serum total testosterone. Semen analysis included sperm concentration, motility, and morphology according to World Health Organization criteria. The B vitamins and tHcy concentrations were significantly correlated in blood but not in seminal plasma. The serum and RBC folate concentrations were significantly correlated also with the total folate concentration in seminal plasma (r = .44; P < .001 and r = .39; P < .001, respectively). Likewise, the total cobalamin concentration in serum and seminal plasma was significantly correlated (r = .55; P = .001). Of interest is that the total cobalamin concentration in seminal plasma was significantly correlated with the sperm concentration (r = .42; P < .001). This is in contrast to the absence of significant associations between the other vitamins and tHcy in blood and seminal plasma and any of the semen parameters. These findings suggest that folate and cobalamin are transferred from the blood to the male reproductive organs and emphasize the role of cobalamin in spermatogenesis in human

Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice

Primary lymphoma of the central nervous system (CNS, PCNSL) is a specific diffuse large B cell lymphoma entity arising in and confined to the CNS. Despite extensive research since many decades, the pathogenetic mechanisms underlying the remarkable tropism of this peculiar malignant hematopoietic tumor remain still to be elucidated. In the present review, we summarize the present knowledge on the genotypic and phenotypic characteristics of the tumor cells of PCNSL, give an overview over deregulated molecular pathways in PCNSL and present recent progress in the field of preclinical modeling of PCNSL in mice. With regard to the phenotype, PCNSL cells resemble late germinal center exit IgM+IgD+ B cells with blocked terminal B cell differentiation. They show continued BCL6 activity in line with ongoing activity of the germinal center program. This together with the pathways deregulated by genetic alterations may foster B cell activation and brisk proliferation, which correlated with the simultaneous MYC and BCL2 overexpression characteristic for PCNSL. On the genetic level, PCNSL are characterized by ongoing aberrant somatic hypermutation that, besides the IG locus, targets the PAX5, TTF, MYC, and PIM1 genes. Moreover, PCNSL cells show impaired IG class switch due to s mu region deletions, and PRDM1 mutations. Several important pathways, i.e., the B cell receptor (BCR), the toll-like receptor, and the nuclear factor-kappa B pathway, are activated frequently due to genetic changes affecting genes like CD79B, SHIP, CBL, BLNK, CARD11, MALT1, BCL2, and MYD88. These changes likely foster tumor cell survival. Nevertheless, many of these features are also present in subsets of systemic DLBLC and might not be the only reasons for the peculiar tropism of PCNSL. Here, preclinical animal models that closely mimic the clinical course and neuropathology of human PCNSL may provide further insight and we discuss recent advances in this field. Such models enable us to understand the pathogenetic interaction between the malignant B cells, resident cell populations of the CNS, and the associated inflammatory infiltrate. Indeed, the immunophenotype of the CNS as well as tumor cell characteristics and intracerebral interactions may create a micromilieu particularly conducive to PCNSL that may foster aggressiveness of tumor cells and accelerate the fatal course of disease. Suitable animal models may also serve as a well-defined preclinical system and may provide a useful tool for developing new specific therapeutic strategies