155 research outputs found
Hypertensive disorders during pregnancy in pre-gestational diabetic women
Pre-gestational diabetes is often compounded by hypertensive disease of pregnancy. In this study, women diagnosed as suffering from pre-gestational diabetes mellitus (pre-DM) were subdivided into two groups: those found to be suffering from some form of hypertension during their pregnancy (n=18); and those who did not develop hypertension (n=75). The maternal characteristics and perinatal outcome of the two groups were statistically correlated. The results showed that type of diabetes was the only statistically significant correlate to the likelihood to develop hypertension. The infant was more likely to have a higher mean birth weight in pre-DM women with hypertension than those without. Perinatal morbidity and mortality did not show any significant differences.peer-reviewe
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Photo-biomodulation of human skin fibroblast sub-populations: a systematic approach for the optimization of optical treatment parameters
The thesis presents a rational path for the optimization of the selection of optical treatment parameters in photobiomodulation of human skin fibroblasts. The project begins with an extensive analysis of 90 bibliographic reports in photobiomodulation published between 1985 and 2015, and revealed major inconsistencies in optical parameters selected for clinical applications. Seeking greater clarity for optimal parameter choice, a systematic approach to disentangle the multiple factors underpinning the response of human dermal fibroblasts in vitro to visible and near-infra red (NIR) light was employed. Light-based devices were constructed to specifically and systematically screen the optical parameter window (i.e. wavelength, irradiance and dose) observed in literature. Additionally, critical culture and treatment conditions that have dramatic impact on the outcome of specific light treatment of these human skin dermal cells were identified. In particular, environmental oxygen concentration, cell confluency and serum concentration were all found to have a great effect on the response of dermal fibroblasts to light. In parallel, the induction of reactive oxygen species (ROS) by short visible wavelengths on two dermal fibroblast sub-populations or lineage, reticular and papillary, was monitored by live-cell imaging. The ROS species were found to be created in or close to mitochondria. Lastly, gene expression studies revealed a strong impact of short visible wavelengths, as compared to long and NIR wavelengths on both subpopulations of human dermal fibroblasts. In particular, blue light (450 nm) specifically down-regulated proliferation, metabolism and protein synthesis molecular pathways. At the protein level, 450-nm light inhibited the production of procollagen I in human reticular and papillary fibroblasts in a dose-dependent manner. Gene expression results were in agreement i.e., the same light parameter down-regulated collagen fiber genes, integrins and up-regulated collagenase MMP1. This thesis concludes with a chapter presenting a characterization of the accuracy of a potential translation tool for the prediction of optical photon density inside human skin.Marie SkĹodowska-Curie Actions
Photobiomodulation of human dermal fibroblasts in vitro: decisive role of cell culture conditions and treatment protocols on experimental outcome
YesPhotobiomodulation-based (LLLT) therapies show tantalizing promise for treatment of skin diseases. Confidence in this approach is blighted however by lamentable inconsistency in published experimental designs, and so complicates interpretation. Here we interrogate the appropriateness of a range of previously-reported treatment parameters, including light wavelength, irradiance and radiant exposure, as well as cell culture conditions (e.g., serum concentration, cell confluency, medium refreshment, direct/indirect treatment, oxygen concentration, etc.), in primary cultures of normal human dermal fibroblasts exposed to visible and near infra-red (NIR) light. Apart from irradiance, all study parameters impacted significantly on fibroblast metabolic activity. Moreover, when cells were grown at atmospheric O2 levels (i.e. 20%) short wavelength light inhibited cell metabolism, while negligible effects were seen with long visible and NIR wavelength. By contrast, NIR stimulated cells when exposed to dermal tissue oxygen levels (approx. 2%). The impact of culture conditions was further seen when inhibitory effects of short wavelength light were reduced with increasing serum concentration and cell confluency. We conclude that a significant source of problematic interpretations in photobiomodulation reports derives from poor optimization of study design. Further development of this field using in vitro/ex vivo models should embrace significant standardization of study design, ideally within a design-of-experiment setting
Does blue light restore human epidermal barrier function via activation of Opsin during cutaneous wound healing?
YesBackground and Objective
Visible light has beneficial effects on cutaneous wound healing, but the role of potential photoreceptors in human skin is unknown. In addition, inconsistency in the parameters of blue and red lightâbased therapies for skin conditions makes interpretation difficult. Red light can activate cytochrome c oxidase and has been proposed as a wound healing therapy. UVâblue light can activate Opsin 1âSW, Opsin 2, Opsin 3, Opsin 4, and Opsin 5 receptors, triggering biological responses, but their role in human skin physiology is unclear.
Materials and Methods
Localization of Opsins was analyzed in situ in human skin derived from face and abdomen by immunohistochemistry. An ex vivo human skin wound healing model was established and expression of Opsins confirmed by immunohistochemistry. The rate of wound closure was quantitated after irradiation with blue and red light and mRNA was extracted from the regenerating epithelial tongue by laser microâdissection to detect changes in Opsin 3 (OPN3) expression. Retention of the expression of Opsins in primary cultures of human epidermal keratinocytes and dermal fibroblasts was confirmed by qRTâPCR and immunocytochemistry. Modulation of metabolic activity by visible light was studied. Furthermore, migration in a scratchâwound assay, DNA synthesis and differentiation of epidermal keratinocytes was established following irradiation with blue light. A role for OPN3 in keratinocytes was investigated by gene silencing.
Results
Opsin receptors (OPN1âSW, 3 and 5) were similarly localized in the epidermis of human facial and abdominal skin in situ. Corresponding expression was confirmed in the regenerating epithelial tongue of ex vivo wounds after 2 days in culture, and irradiation with blue light stimulated wound closure, with a corresponding increase in OPN3 expression. Expression of Opsins was retained in primary cultures of epidermal keratinocytes and dermal fibroblasts. Both blue and red light stimulated the metabolic activity of cultured keratinocytes. Low levels of blue light reduced DNA synthesis and stimulated differentiation of keratinocytes. While low levels of blue light did not alter keratinocyte migration in a scratch wound assay, higher levels inhibited migration. Gene silencing of OPN3 in keratinocytes was effective (87% reduction). The rate of DNA synthesis in OPN3 knockdown keratinocytes did not change following irradiation with blue light, however, the level of differentiation was decreased.
Conclusions
Opsins are expressed in the epidermis and dermis of human skin and in the newly regenerating epidermis following wounding. An increase in OPN3 expression in the epithelial tongue may be a potential mechanism for the stimulation of wound closure by blue light. Since keratinocytes and fibroblasts retain their expression of Opsins in culture, they provide a good model to investigate the mechanism of blue light in wound healing responses. Knockdown of OPN3 led to a reduction in early differentiation of keratinocytes following irradiation with blue light, suggesting OPN3 is required for restoration of the barrier function. Understanding the function and relationship of different photoreceptors and their response to specific light parameters will lead to the development of reliable lightâbased therapies for cutaneous wound healing.European Commission 7th Framework Programme for Research and Technical Development - Marie Curie Innovative Training Networks (ITN), Grant agreement no.: 60788
PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML
Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110ι, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ
New Mass and Radius Constraints on the LHS 1140 Planets -- LHS 1140 b is Either a Temperate Mini-Neptune or a Water World
The two-planet transiting system LHS 1140 has been extensively observed since
its discovery in 2017, notably with , HST, TESS, and ESPRESSO, placing
strong constraints on the parameters of the M4.5 host star and its small
temperate exoplanets, LHS 1140 b and c. Here, we reanalyse the ESPRESSO
observations of LHS 1140 with the novel line-by-line framework designed to
fully exploit the radial velocity content of a stellar spectrum while being
resilient to outlier measurements. The improved radial velocities, combined
with updated stellar parameters, consolidate our knowledge on the mass of LHS
1140 b (5.600.19 M) and LHS 1140 c (1.910.06 M)
with unprecedented precision of 3%. Transits from , HST, and TESS are
jointly analysed for the first time, allowing us to refine the planetary radii
of b (1.7300.025 R) and c (1.2720.026 R).
Stellar abundance measurements of refractory elements (Fe, Mg and Si) obtained
with NIRPS are used to constrain the internal structure of LHS 1140 b. This
planet is unlikely to be a rocky super-Earth as previously reported, but rather
a mini-Neptune with a 0.1% H/He envelope by mass or a water world with a
water-mass fraction between 9 and 19% depending on the atmospheric composition
and relative abundance of Fe and Mg. While the mini-Neptune case would not be
habitable, a water-abundant LHS 1140 b potentially has habitable surface
conditions according to 3D global climate models, suggesting liquid water at
the substellar point for atmospheres with relatively low CO concentration,
from Earth-like to a few bars.Comment: 31 pages, 18 figures, accepted for publication in ApJ
Evidence of maternal QTL affecting growth and obesity in adult mice
Most quantitative trait loci (QTL) studies fail to account for the effect that the maternal genotype may have on an individualâs phenotypes, even though maternal effect QTL have been shown to account for considerable variation in growth and obesity traits in mouse models. Moreover, the fetal programming theory suggests that maternal effects influence an offspringâs adult fitness, although the genetic nature of fetal programming remains unclear. Within this context, our study focused on mapping genomic regions associated with maternal effect QTL by analyzing the phenotypes of chromosomes 2 and 7 subcongenic mice from genetically distinct dams. We analyzed 12 chromosome 2 subcongenic strains that spanned from 70 to 180Â Mb with CAST/EiJ donor regions on the background of C57BL/6Â J, and 14 chromosome 7 subcongenic strains that spanned from 81 to 111Â Mb with BALB/cByJ donor regions on C57BL/6ByJ background. Maternal QTL analyses were performed on the basis of overlapping donor regions between subcongenic strains. We identified several highly significant (PÂ <Â 5Â ĂÂ 10â4) maternal QTL influencing total body weight, organ weight, and fat pad weights in both sets of subcongenics. These QTL accounted for 1.9-11.7% of the phenotypic variance for growth and obesity and greatly narrowed the genomic regions associated with the maternal genetic effects. These maternal effect QTL controlled phenotypic traits in adult mice, suggesting that maternal influences at early stages of development may permanently affect offspring performance. Identification of maternal effects in our survey of two sets of subcongenic strains, representing approximately 5% of the mouse genome, supports the hypothesis that maternal effects represent significant sources of genetic variation that are largely ignored in genetic studies
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by
the American Lebanese Syrian Associated Charities of St. Jude Childrenâs Research
Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrickâs
Foundation Scholar Award (to C.G.M.); by a St. Baldrickâs Consortium Award (S.P.H.),
by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and
C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma
Society Special Fellow Award and Alexâs Lemonade Stand Foundation Young Investigator
Awards (K.R.), by an Alexâs Lemonade Stand Foundation Award (M.L.) and by
National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01
CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract
HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN
Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171
(The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and
C.G.M.); and grants to the COG: U10 CA98543 (Chairâs grant and supplement to
support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24
CA114766 (Specimen Banking). This project has been funded in whole or in part with
Federal funds from the National Cancer Institute, National Institutes of Health, under
Contract Number HHSN261200800001E
Deregulation of DUX4 and ERG in acute lymphoblastic leukemia
Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function
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