Role of sphingosine-1-phosphate phosphohydrolase 1 in the regulation of resistance artery tone

Sphingosine-1-phosphate (S1P), which mediates pleiotropic actions within the vascular system, is a prominent regulator of microvascular tone. By virtue of its S1P-degrading function, we hypothesized that S1P-phosphohydrolase 1 (SPP1) is an important regulator of tone in resistance arteries. Hamster gracilis muscle resistance arteries express mRNA encoding SPP1. Overexpression of SPP1 (via transfection of a SPP1(wt)) reduced resting tone, Ca2+ sensitivity, and myogenic vasoconstriction, whereas reduced SPP1 expression (antisense oligonucleotides) yielded the opposite effects. Expression of a phosphatase-dead mutant of SPP1 (SPP1(H208A)) had no effect on any parameter tested, suggesting that catalytic activity of SPP1 is critical. The enhanced myogenic tone that follows overexpression of S1P-generating enzyme sphingosine kinase 1 (Sk1(wt)) was functionally antagonized by coexpression with SPP1(wt) but not SPP1(H208A). SPP1 modulated vasoconstriction in response to 1 to 100 nmol/L exogenous S1P, a concentration range that was characterized as S1P2-dependent, based on the effect of S1P(2) inhibition by antisense oligonucleotides and 1 mumol/L JTE013. Inhibition of the cystic fibrosis transmembrane regulator (CFTR) (1) restored S1P responses that were attenuated by SPP1(wt) overexpression; (2) enhanced myogenic vasoconstriction; but (3) had no effect on noradrenaline responses. We conclude that SPP1 is an endogenous regulator of resistance artery tone that functionally antagonizes the vascular effects of both Sk1(wt) and S1P2 receptor activation. SPP1 accesses extracellular S1P pools in a manner dependent on a functional CFTR transport protein. Our study assigns important roles to both SPP1 and CFTR in the physiological regulation of vascular tone, which influences both tissue perfusion and systemic blood pressure.     

Squamous cutaneous epithelial cell carcinoma in two CML patients with progressive disease under imatinib treatment

Imatinib (glivec), formerly known as STI571) effectively blocks the ATP-binding site of the bcr/abl fusion protein thereby inactivating selectively the tyrosine kinase activity of bcr/abl. Therefore, it is a promising drug in Philadelphia chromosome positive chronic myeloid leukemia showing high hematologic and cytogenetic response rates combined with a mild toxicity profile. Here we report two cases of squamous cell carcinoma of the skin, which appeared in the photo-exposed areas in two elderly patients treated for advanced chronic myeloid leukemia with imatinib. The role of chemotherapy, chronic sun exposure and of possible additional risk factors such as human papillomavirus infection is discussed.     

Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets

The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a previously unidentified kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium. Our results show that the integrated spectrum of the planet and the moon closely resembles that of a single object in strong chemical disequilibrium. We derive a firm limit on the maximum spectral resolution that can be obtained for both directly imaged and transiting planets. The spectral resolution of even idealized space-based spectrographs that might be achievable in the next several decades is in general insufficient to break the degeneracy. Both chemical species can only be definitively confirmed in the same object if absorption features of both chemicals can be unambiguously identified and their combined depth exceeds 100%.With almost a thousand confirmed exoplanets [Open Exoplanet Catalogue (1)], the prospects of detecting signs of a biosphere on a body outside our own solar system are more promising than ever before. However, there are still huge technological and theoretical challenges to overcome before one can hope to make a clear detection of life on an exoplanet. In this article, we discuss one of these complications, the possibility of false positives due to the presence of an exomoon orbiting the exoplanet.There are many ways that life on an exoplanet might affect the planet’s appearance, ranging from deliberate signals from intelligent civilizations (2) to subtler signs of simple life. To characterize an extrasolar world as fully as possible, we ideally would measure its spectrum as a function of time in both the optical and the infrared parts of the spectrum (e.g., refs. 3–6). For example, spectral evidence of water could suggest that a planet might be habitable. It has also been suggested that an intriguing indication of life might be an increase in the planet’s albedo toward the infrared part of the spectrum, which on Earth can be associated with vegetation (7). However, these features alone would not be smoking-gun proof of the presence of life. The terms “biomarker” and “biosignature” generally refer to chemicals or combinations of chemicals that could be produced by life and that could not be (or are unlikely to be) produced abiotically; hereafter, we use these terms interchangeably. If biosignature gases are detected in the spectrum of an exoplanet, the probability that they actually indicate life depends both on the prior probability of life (8) and on the probability that the observed spectroscopic feature could be produced abiotically. The latter possibility is the subject of this paper.Byproducts of metabolism are often thought of as the most promising biomarker (9–15). More specifically, an extreme thermodynamic disequilibrium of two molecules in the atmosphere is considered a biosignature (16–18). An example of two such species is the simultaneous presence of O₂ and a reduced gas such as CH₄. It is important to point out that a disequilibrium in a planet’s atmosphere should not be considered as clear evidence for life. [Also note that the Earth might have never had a phase of strong, observable O₂/CH₄ disequilibrium (19).] There is a long list of abiotic sources that could also create a disequilibrium such as impacts (20), photochemistry (21), and geochemistry (14).In this article, we describe a previously unidentified scenario for a possible false positive biosignature. If the exoplanet hosts a moon that has an atmosphere itself, the simultaneous observation of the planet and moon modifies the observed spectrum (see also refs. 22 and 23) and can produce a signal that looks like a disequilibrium in one atmosphere but is in fact created by two atmospheres blended together. It might be extremely difficult to discern that an exoplanet even has a moon, let alone that one component of a two-chemical biosignature comes from the moon instead of the planet.The outline of this article is as follows. We first describe our model atmospheres and present simulated spectra. Using those synthetic spectra, we show that the combined spectrum from an oxygen-rich atmosphere such as that of the Earth and a methane-rich atmosphere such as that of Titan indeed looks like it could have come from a single atmosphere with a strong disequilibrium. We then calculate a strong upper limit on the spectral resolution of such a system as observed from Earth under ideal conditions with a plausibly sized space telescope. Our estimate shows that the spectral resolution for such a system is unlikely to exceed ∼1,600 with foreseeable technology. Given this maximum possible resolution, discriminating between a single planet and a planet–moon system is in general unlikely to be possible.^† Nevertheless, we conclude with a summary and a positive outlook with two possibilities that can provide genuine biosignatures. The first possibility is to find a single chemical species that is sufficient to indicate life. The second one requires the unambiguous identification of both species’ absorption features and the combined depth of the features needs to exceed 100%.     

A perivascular niche in the bone marrow hosts quiescent and proliferating tumorigenic colorectal cancer cells

Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.     

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.