BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number <26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by ‘low FMR1 alleles''. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (<26, 26–34, and >34 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n=368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted.     

Anti-CSF-1 treatment is effective to prevent carcinoma invasion induced by monocyte-derived cells but scarcely by microglia

The mononuclear phagocytic system is categorized in three major groups: monocyte-derived cells (MCs), dendritic cells and resident macrophages. During breast cancer progression the colony stimulating factor 1 (CSF-1) can reprogram MCs into tumor-promoting macrophages in the primary tumor. However, the effect of CSF-1 during colonization of the brain parenchyma is largely unknown.Thus, we analyzed the outcome of anti-CSF-1 treatment on the resident macrophage population of the brain, the microglia, in comparison to MCs, alone and in different in vitro co-culture models. Our results underline the addiction of MCs to CSF-1 while surprisingly, microglia were not affected. Furthermore, in contrast to the brain, the bone marrow did not express the alternative ligand, IL-34. Yet treatment with IL-34 and co-culture with carcinoma cells partially rescued the anti-CSF-1 effects on MCs. Further, MC-induced invasion was significantly reduced by anti-CSF-1 treatment while microglia-induced invasion was reduced to a lower extend. Moreover, analysis of lung and breast cancer brain metastasis revealed significant differences of CSF-1 and CSF-1R expression.Taken together, our findings demonstrate not only differences of anti-CSF-1 treatment on MCs and microglia but also in the CSF-1 receptor and ligand expression in brain and bone marrow as well as in brain metastasis.     

Cell fate specification along the anterior-posterior axis of the intermediate mesoderm.

The vertebrate intermediate mesoderm (IM) is highly patterned along the anterior-posterior (A-P) axis. In the chick embryo, the kidney tissue, which is a derivative of the IM, is generated only from IM located posterior to the sixth somite axial level, which also marks the border between cranial and trunk segments. The cellular and molecular mechanisms that govern the formation of the anterior border of the kidney morphogenetic field are currently unknown. In this study, we asked whether specific A-P patterning information is conveyed by the movement of cells through the primitive streak (PS) at different time points that consequently affects the expression of kidney genes, or by the environment that these cells encounter during their migration to the IM. In this study, we show that kidney-inductive signals are present along the whole axis, including anterior non-kidney-generating regions. These inductive signals are generated by tissues that are located medial to the anterior IM. We also demonstrate that cells that migrate through the PS of early embryonic stages (Hamburger and Hamilton stage 3-4 and earlier), which will give rise to anterior nonkidney IM, are competent to respond to these inductive factors. This prospective anterior IM tissue loses its competence to respond to kidney inducing signals during its migration from the PS to its final location in the anterior IM. We present here a model in which changes in cell competence determine the formation of the anterior border of kidney gene expression and discuss the possible evolutionary implications of this developmental mechanism.     

Combined plerixafor and granulocyte colony‐stimulating factor for harvesting high‐dose hematopoietic stem cells: Possible niche for plerixafor use in pediatric patients

PB is a source of HSC, especially for autologous HCT in solid tumors. However, there is a risk of failing to achieve the target number of SC after mobilization with growth factors alone in patients who were heavily pretreated with chemotherapy or those in need for tandem transplants. SC were harvested from seven pediatric patients with solid tumors who were in need of autologous HCT following combination GCSF and plerixafor. Six of them received plerixafor after failing to achieve enough SC with GCSF only, while the seventh patient received the combined protocol upfront. All seven patients achieved the target number of SC according to their treatment protocol. There were no adverse events. All patients underwent autologous HCT using the harvested HSC and achieved full engraftment. A protocol for harvesting autologous HCT using GCSF and plerixafor is feasible and safe in children with solid tumors who had been heavily pretreated with chemotherapy or needed tandem transplants.     

The influence of nacre surface and its modification on bone apposition: a bone development model in rats

BACKGROUND: Bone graft substitutes are currently used individually or in various combinations in reconstructing bone defects. Nacre, marine mineralized structure, was recently proposed as a very biocompatible and osteoinductive material for use in periodontal and implant surgery. Our aim was to investigate the interaction between natural nacre and fresh bone marrow, during bone development, in an ectopic site of DA rats. Surface modifications of nacre were tested. METHODS: Demineralized bone matrix (DBM) cylinders (demineralized cortex of diaphysis) prepared from rat femurs were filled with fresh marrow, which was removed from other 2-month old DA rat femurs. Natural nacre particle or nacre which was treated with HCl, phosphate buffer saline (PBS), and Ca(OH)2 to modify its surface was placed into the DBM cylinders. The cylinders were implanted subcutaneously at the thoracic region of growing DA rats. After 4 weeks the cylinders were surgically removed, fixed in buffered formalin, and x-rayed. Scans of the microradiographs and histological evaluation of the DBM cylinders including bone developed at the interface of nacre and its surface modifications were compared to marrow controls. RESULTS: The results show that natural nacre is a poor conductive biomaterial in a bone developmental environment. Nacre surface treated with Ca(OH)2 and PBS was found to be most biocompatible. In this group, new bone was apposed directly on the nacre surface and the total amount of bone was highest in comparison to other treatment groups. CONCLUSIONS: This study does not support previous observations that nacre is osseoinductive. Our model system seems to be very sensitive and capable of testing interaction between surface modifications of biomaterials and fresh marrow in the process of new bone development.     

Strain relaxation of fibroblasts in the marginal periodontium is the common trigger for alveolar bone resorption: a novel hypothesis

In summary, the present commentary proposes a hypothesis that alveolar bone remodeling and bone loss in periodontitis, periodontal surgery, and in orthodontic tooth movement is triggered by a common "strain relaxation" signaling pathway of gingival and periodontal fibroblasts. The abrupt splitting, degradation, or relaxation of collagen fibers in the marginal periodontium produces a "strain relaxation" signal in the local fibroblasts which reside on these fibers, activating an ECM-integrin-cytoskeleton pathway. A cascade of cellular reactions which lead to osteoclastic bone resorption starting on the inner aspect (periodontal) of the alveolar bone then persists. A novel therapeutic approach is suggested here by using locally delivered drugs intervening in the cell contractile apparatus.