Rhabdomyosarcoma: Advances in Molecular and Cellular Biology.

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS

Stereospecificity in glucose consumption: A new approach to martian life detection

In 1976, the Viking mission made a remarkable discovery: Martian soil was capable of decomposing an organic nutrient broth to carbon dioxide as if it contained live microorganisms. However, a biological interpretation of this finding is in apparent contradiction with the gas chromatograph-mass spectrometer aboard the Viking landers, which showed Martian soil to be devoid of indigenous organics. To reconcile these findings, it has been hypothesized that unknown abiotic oxidants, such as peroxide and superoxide, are present on Mars and that they were responsible for its soil reactivity. The objective of this research is to develop a life detection method that can distinguish biological reactivity from abiotic mimicry

Ability of γδ T cells to modulate the Foxp3 T cell response is dependent on adenosine.

Whether γδ T cells inhibit or enhance the Foxp3 T cell response depends upon their activation status. The critical enhancing effector in the supernatant is adenosine. Activated γδ T cells express adenosine receptors at high levels, which enables them to deprive Foxp3+ T cells of adenosine, and to inhibit their expansion. Meanwhile, cell-free supernatants of γδ T cell cultures enhance Foxp3 T cell expansion. Thus, inhibition and enhancement by γδ T cells of Foxp3 T cell response are a reflection of the balance between adenosine production and absorption by γδ T cells. Non-activated γδ T cells produce adenosine but bind little, and thus enhance the Foxp3 T cell response. Activated γδ T cells express high density of adenosine receptors and have a greatly increased ability to bind adenosine. Extracellular adenosine metabolism and expression of adenosine receptor A2ARs by γδ T cells played a major role in the outcome of γδ and Foxp3 T cell interactions. A better understanding of the functional conversion of γδ T cells could lead to γδ T cell-targeted immunotherapies for related diseases

The X-ray Cluster Normalization of the Matter Power Spectrum

The number density of galaxy clusters provides tight statistical constraints on the matter fluctuation power spectrum normalization, traditionally phrased in terms of sigma_8, the root mean square mass fluctuation in spheres with radius 8 h^-1 Mpc. We present constraints on sigma_8 and the total matter density Omega_m0 from local cluster counts as a function of X-ray temperature, taking care to incorporate and minimize systematic errors that plagued previous work with this method. In particular, we present new determinations of the cluster luminosity - temperature and mass - temperature relations, including their intrinsic scatter, and a determination of the Jenkins mass function parameters for the same mass definition as the mass - temperature calibration. Marginalizing over the 12 uninteresting parameters associated with this method, we find that the local cluster temperature function implies sigma_8 (Omega_m0/0.32)^alpha = 0.86+/-0.04 with alpha = 0.30 (0.41) for Omega_m0 < 0.32 (Omega_mo > 0.32) (68% confidence for two parameters). This result agrees with a wide range of recent independent determinations, and we find no evidence of any additional sources of systematic error for the X-ray cluster temperature function determination of the matter power spectrum normalization. The joint WMAP5 + cluster constraints are: Omega_m0 = 0.30+0.03/-0.02 and sigma_8 = 0.85+0.04/-0.02 (68% confidence for two parameters).Comment: 31 pages, 16 figures, accept for publication in ApJ 609, Jan. 10, 200

Magnesium isotopic composition of the oceanic mantle and oceanic Mg cycling

© The Author(s), 2017. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 206 (2017): 151-165, doi:10.1016/j.gca.2017.02.016.To constrain the Mg isotopic composition of the oceanic mantle, investigate Mg isotope fractionation of abyssal peridotites during seafloor alteration, and assess Mg budget in the oceans, a suite of 32 abyssal peridotite samples from the Gakkel Ridge and Southwest Indian Ridge (SWIR) was, for the first time, selected for high-precision Mg isotope analyses. Although most of these samples are extensively altered, largely by serpentinization and weathering, primary olivine, diopside and enstatite grains are preserved in some samples. Olivine grains from the least altered samples have δ26Mg varying from −0.30 to −0.12‰ (n = 7), whereas enstatite and diopside have δ26Mg varying from −0.27 to −0.16‰ (n = 7), and from −0.23 to −0.09‰ (n = 6), respectively. Whole-rock δ26Mg values range from −0.24 to 0.03‰ with an average of −0.12 ± 0.13‰ (2SD, n = 32). Strongly serpentinized peridotites have lower average δ26Mg values (δ26Mg = −0.19 ± 0.07‰, 2SD, n = 7) than weathering-dominated ones (δ26Mg = −0.10 ± 0.12‰, 2SD, n = 25). Calculated Mg isotopic compositions of fresh mantle peridotites vary from −0.29 to −0.13‰, beyond the previously reported range of the subcontinental lithospheric mantle (−0.25 ± 0.04‰) and the analytical uncertainty (±0.07‰, 2SD). Our study therefore indicates that the oceanic mantle may have similar but slightly heterogeneous Mg isotopic compositions to that of subcontinental lithospheric mantle. Secondary serpentinization does not fractionate Mg isotopes of abyssal peridotites, whereas low-T weathering and formation of clay can result in the enrichment of heavy Mg isotopes in abyssal peridotites. This study also demonstrates that fluid-rock interaction does not necessarily produce rocks with intermediate Mg isotopic compositions. Magnesium isotopes of the rocks thereafter are dependent on the secondary minerals formed. We also conclude that the release of light Mg isotopes into the ocean during alteration of abyssal peridotites can be an important influx of Mg for the seawater Mg budget. Abyssal peridotites with a heavy Mg isotopic signature can be recycled into the mantle in subduction zones and may thus result in heterogeneous Mg isotopic compositions of the oceanic mantle and heavy Mg isotopic compositions of arc magmas.This study was supported by grants from the National Science Foundation of China (grants 41473038 and 41503010), China Postdoctoral Science Foundation (2015M570145), National Science Foundation (EAR-1056713 and EAR-1340160) and project MOST104 -2745-M-002-001-ASP granted to SLC. Partial support for HJBD was provided by the US National Science Foundation (OCE-1434452)

Martian life detection with xylose enantiomers

Ability of Martian soil to degrade carbohydrates, shown by the Viking mission, has two interpretations. One possibility is that the soil harbors living microorganisms. Alternatively, the soil is sterile but chemically oxidizing, i.e. it is laden with photochemical oxidants. It was shown by REU research last summer that these two possibilities can be distinguished by the use of glucose enantiomers. Life is selective: Earth organisms use D-glucose, but ignore Lglucose. This stereo selectivity is absent in chemical reactions. The goal of this project is to test if xylose, a five carbon sugar, is also suitable for chiral life detection. Mixed microbial cultures were raised from various soils (Jordan, the Mojave Desert, and the Atacama Desert). Added D- and L-xylose were monitored over time. Results show that terrestrial microorganisms utilize only Dxylose, not L-xylose, confirming that like glucose, xylose is a suitable substrate for Martian life detection

Martian life detection with amino acid enantiomers

The Viking mission showed that Martian soil can degrade a heterotrophic medium to carbon dioxide as if live microorganisms were present. The result is considered inconclusive, however, because abiotic oxidants, such as superoxides, may also exist on Mars and would explain the Viking result. One way to resolve this ambiguity is to repeat the Viking experiment with a isomerically pure medium. The consumption of one isomer, either D or L, would indicate biological activity. Indiscriminate destruction of both isomers would indicate abiotic redox processes. This idea was validated for glucose by REU research last summer (Sun et al. 2009). The objective of this project is to test this idea with amino acids. Specifically, the consumption rates of D- and Lenantiomers will be compared for histidine, lysine, and serine in selected bacteria, archaea, and eukaryotic fungi and yeasts. Results with Bacillus revealed that in histidine, only the L-isomer was consumed while for serine and lysine, both the D- and L-isomers were utilized. If confirmed in other microorganisms, these results indicate that histidine is a suitable substrate for Martian life detection but serine and lysine are not

Targeted delivery of bleomycin to the brain using photo-chemical internalization of Clostridium perfringens epsilon prototoxin

Cells infiltrating into normal brain from malignant brain tumors are protected by the blood brain barrier (BBB) which prevents the delivery and limits the effects of anti-tumor agents. We have evaluated the ability of photochemical internalization (PCI) to limit the effects of an agent known to broadly open the BBB to a target region of the brain. The PCI-based relocation and activation of macromolecules into the cell cytosol has the advantage of minimal side effects since the effect is localized to the area exposed to light, allowing the access of chemotherapeutic agents only to these regions. Non tumor bearing inbred Fisher rats were treated with photosesitizer, and a nontoxic intraperitoneal dose of Clostridium perfringens epsilon prototoxin (ETXp) followed by light exposure. Post-contrast T1 MRI scans were used to monitor the degree BBB disruption. F98 tumor cells were implanted into the brains of other animals that were subsequently treated 24 h later with ETXp-PCI BBB opening followed by the i.p. administration of bleomycin (BLM). PCI delivery of ETXp at low fluence levels demonstrated significant MRI enhancement. No effect on the BBB was observed if photosesitizer and light was given in the absence ETXp. The survival of animals implanted with F98 tumor cells was significantly extended following ETXp-PCI BBB opening and BLM therapy compared to controls. PCI delivered ETXp was effective in opening the BBB in a limited region of the brain. ETXp-PCI mediated BBB opening clearly increased the efficacy of BLM therapy