Showing papers by "Yoram Cohen published in 2013"

Ovarian follicle burnout: A universal phenomenon?

Abstract: The ovarian follicle reserve is maintained in a delicate state of homeostasis aimed at preserving the majority of follicles in a dormant state. Key regulatory factors in follicle activation and quiescence include the PI3K/PTEN/Akt signaling pathway in the oocyte, as well as external paracrine inhibitory factors such as anti-Mullerian hormone (AMH) (Fig. 1A). Mice with oocyte-specific deletion of one or more elements in the PI3K/PTEN/Akt pathway, or AMH-knockout mice, exhibit premature activation and rapid depletion of ovarian follicle reserve.1 Figure 1. (A) During normal follicular development, the ovary is in a state of equilibrium. The primordial follicles (PMFs) are under balanced regulation by the PI3K/PTEN/Akt pathway and suppressive factors produced by growing follicles ensure ... Disturbance of ovarian homeostasis has been shown to be a mechanism of follicle loss in the case of iatrogenic ovotoxicity. We recently showed that ovotoxic chemotherapy agent cyclophosphamide (Cy) triggers upregulation of the PI3K pathway, initiating a wave of follicle recruitment and growth and, ultimately, burnout of the ovarian follicle reserve.2 In addition, Cy also induced apoptosis in growing follicles within 24 h of exposure. Co-treatment with immunomodulator, AS101, reduced both apoptosis of growing follicles and activation of the PI3K/PTEN/Akt pathway, thereby reducing follicle activation and loss. We further demonstrated that AMH expression levels (as measured by qRT-PCR) dropped to below control levels as early as 12 h post Cy treatment, reflecting the loss of growing follicles at this time point. AMH levels in Cy-treated ovaries remained lower than control levels up to 3 d post-Cy; however, between 3 and 7 d post treatment, AMH expression in Cy-treated ovaries increased not just to equivalent levels to PBS treated mice, but to twice the relative expression and maintained for at least 14 d post-treatment.3 This increase in AMH levels reflects the increase in early growing follicles as a result of Cy-induced follicle activation. The reduction in AMH expression together with the activation of the PI3K pathway, which occur within 24 h of Cy treatment, combine to create a “window of unregulated growth” of the dormant primordial follicle population. This is a new understanding of the mechanisms of ovotoxicity that carries significant implications, reaching further than cancer treatments. This observation is supported by additional studies that have suggested that primordial follicle activation via the PI3K/PTEN/Akt pathway is also the mechanism behind ovarian follicle loss seen after exposure to a number of other environmental carcinogens and ovotoxins. Of particular interest is the implication of the “burnout” phenomenon for ovarian tissue transplantation. Ovarian tissue cryopreservation is a widely used strategy for fertility preservation in young patients with a high risk of ovarian failure after cancer treatment.4 However, the duration of graft survival following ovarian tissue transplantation is extremely variable, in some cases as short as a few months, largely due to massive loss of primordial follicles that occurs following grafting.5 In addition the vast majority of large follicles in the graft are lost during processing, freezing, and thawing, leaving the ovarian reserve unregulated. Our recent observations on follicle dynamics post-ovarian tissue transplantation show that recovered grafts have higher ratios of growing to total follicles and higher levels of proliferation staining than non-transplanted control tissue, and that this is seen to a greater degree in thinner grafts, which have fewer large follicles.6 This data strongly suggests that ovarian tissue grafts undergo a similar process of follicle activation and “burnout” to that seen following Cy treatment (Fig. 1B). It is likely that the removal of follicles from their normal physiological environment disturbs the ovarian homeostasis. The absence of larger follicles in the ovarian cortical strips in particular results in a decrease in the secretion of inhibitory signaling factor AMH,7 leading to follicle activation. The implications of imbalances in ovarian homeostasis may also extend to the normal physiological state. Age-related changes to the ovarian environmental milieu may have important effects on the regulation of follicle activation. With increasing age, the numbers of all follicles in the ovary decrease, and the decrease in the number of growing follicles results in an age-related decline in AMH levels.8 AMH levels do not only reflect the decline in ovarian follicle reserve, they also indicate a decrease in inhibition exerted on the same population of follicles. This may explain the age-related dynamics of ovarian reserve, which show a fairly constant rate of decline in follicle number until age 35–37, when there is an acceleration of follicle loss. We hypothesize that with age-related reduction in follicle inhibition, follicle activation is accelerated, resulting in increased ovarian follicle loss. In our study, we showed that co-administration of AS101 attenuated follicle burnout via its effect on the PI3k pathway and by reducing apoptosis in growing follicles. This raises the possibility that other agents that act on this crucial activation pathway may have the potential to reduce follicle burnout and preserve ovarian follicle reserve in the face of ovotoxic treatments or ovarian tissue transplantation.

Modeling of the diffusion MR signal in calibrated model systems and nerves

Abstract: Diffusion NMR is a powerful tool for gleaning microstructural information on opaque systems. In this work, the signal decay in single-pulsed-field gradient diffusion NMR experiments performed on a series of phantoms of increasing complexity, where the ground truth is known a priori, was modeled and used to identify microstructural features of these complex phantoms. We were able to demonstrate that, without assuming the number of components or compartments, the modeling can identify the number of restricted components, detect their sizes with an accuracy of a fraction of a micrometer, determine their relative populations, and identify and characterize free diffusion when present in addition to the components exhibiting restricted diffusion. After the accuracy of the modeling had been demonstrated, this same approach was used to study fixed nerves under different experimental conditions. It seems that this approach is able to characterize both the averaged axon diameter and the relative population of the different diffusing components in the neuronal tissues examined.

Target-specific ligands and gadolinium-based complexes for imaging of dopamine receptors: synthesis, binding affinity, and relaxivity.

Abstract: Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this pa...

q-Space diffusion MRI (QSI) of the disease progression in the spinal cords of the Long Evans shaker: diffusion time and apparent anisotropy

Abstract: q-Space diffusion MRI (QSI) was used to study the spinal cords of Long Evans shaker (les) rats, a model of dysmyelination, and their age-matched controls at different maturation stages. Diffusion was measured parallel and perpendicular to the fibers of the spinal cords of the two groups and at different diffusion times. The results showed that QSI is able to detect the dysmyelination process that occurs in this model in the different stages of the disease. The differences in the diffusion characteristics of the spinal cords of the two groups were found to be larger when the diffusion time was increased from 22 to 100 ms. We found that the radial mean displacement is a much better parameter than the QSI fractional anisotropy (FA) to document the differences between the two groups. We observed that the degree of myelination affects the diffusion characteristics of the tissues, but has a smaller effect on FA. All of the extracted diffusion parameters that are affected by the degree of myelination are affected in a diffusion time-dependent fashion, suggesting that the terms apparent anisotropy, apparent fractional anisotropy and even apparent root-mean-square displacement (rmsD) are more appropriate.

resistance A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin

Abstract: CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well-characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin resistant (doses 80-185 mg/week) and 8 sensitive patients (7-13 mg/week) and 99 unselected controls (8-105 mg/week). We identified a coding VKORC1 Asp36Tyr polymorphism in 7/15 resistant compared to 0/8 sensitive patients (p=0.026). Carriers of Asp36Tyr in the control group (8/99) required significantly higher warfarin doses of 80.9±10.1 mg/week compared to 42.7±7.5 mg/week in non-carriers (F=9.79, p=0.002). Asp36Tyr was significantly associated with doses of >70mg/week (OR=13.0 [95%CL1.3-124.2]), while doses of 20-70mg/week were associated with Asp36Tyr (partial r 2 =0.11; p=0.004), CYP2C9*2/*3 (r 2 =0.08; p=0.01) and VKORC1*2/*3 markers (r 2 =0.05; p=0.05). All Asp36Tyr carriers also had VKORC1*1 tag-SNPs indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high-end of the warfarin dosing range. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.