Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate ...early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared "permanent" because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but not
-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.
Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying ...medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
3.
Ink4a/Arf expression is a biomarker of aging Krishnamurthy, Janakiraman; Torrice, Chad; Ramsey, Matthew R ...
The Journal of clinical investigation
114, Issue:
9
Journal Article
Peer reviewed
Open access
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined ...Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. HNSCC patient prognosis is closely related to the occurrence ...of tumor metastases, and collagen within the tumor microenvironment (TME) plays a key role in this process. Lysyl hydroxylase 2 (LH2), encoded by the Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) gene, catalyzes hydroxylation of telopeptidyl lysine (Lys) residues of fibrillar collagens which then undergo subsequent modifications to form stable intermolecular cross-links that change the biomechanical properties (i.e. quality) of the TME. While LH2-catalyzed collagen modification has been implicated in driving tumor progression and metastasis in diverse cancers, little is known about its role in HNSCC progression. Thus, using gain- and loss-of-function studies, we examined the effects of LH2 expression levels on collagen cross-linking and cell behavior in vitro and in vivo using a tractable bioluminescent imaging-based orthotopic xenograft model. We found that LH2 overexpression dramatically increases HNSCC cell migratory and invasive abilities in vitro and that LH2-driven changes in collagen cross-linking robustly induces metastasis in vivo. Specifically, the amount of LH2-mediated collagen cross-links increased significantly with PLOD2 overexpression, without affecting the total quantity of collagen cross-links. Conversely, LH2 knockdown significantly blunted HNSCC cells invasive capacity in vitro and metastatic potential in vivo. Thus, regardless of the total “quantity” of collagen crosslinks, it is the “quality” of these cross-links that is the key driver of HNSCC tumor metastatic dissemination. These data implicate LH2 as a key regulator of HNSCC tumor invasion and metastasis by modulating collagen cross-link quality and suggest that therapeutic strategies targeting LH2-mediated collagen cross-linking in the TME may be effective in controlling tumor progression and improving disease outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The epidermis has an essential function in creating a barrier against the external environment to retain proper fluid balance and block the entry of pathogens. When damage occurs to this barrier, the ...wound must quickly be sealed to avoid fluid loss, cleared of invading pathogens, and then keratinocytes must re-form an intact barrier. This requires complex integration of temporally and spatially distinct signals to execute orderly closure of the wound, and failure of this process can lead to chronic ulceration. Transcription factors serve as a key integration point for the myriad of information coming from the external environment, allowing for an orderly process of re-epithelialization. Importantly, transcription factors engage with and alter the chromatin structure around key target genes through association with different chromatin-modifying complexes. In this review, we will discuss the current understanding of how transcription is regulated during the initiation of re-epithelialization, and the exciting technological advances that will allow for a more refined mechanistic understanding of the re-epithelialization process.
Top squark with mass close to the top quark Buckley, Matthew R.; Plehn, Tilman; Ramsey-Musolf, Michael J.
Physical review. D, Particles, fields, gravitation, and cosmology,
07/2014, Volume:
90, Issue:
1
Journal Article
Peer reviewed
Open access
The most natural supersymmetric solution to the hierarchy problem prefers the scalar top partner to be close in mass to the top quark. Experimental searches exclude top squarks across a wide range of ...masses, but a gap remains when the difference between the masses of the stop and the lightest supersymmetric particle is close to the top mass. We propose to search for stops in this regime by exploiting the azimuthal angular correlation of forward tagging jets in (s)top pair production. As shown in earlier work, this correlation is sensitive to the spin of the heavy states, allowing one to distinguish between top and stop pair production. Here, we demonstrate that this angular information can give a statistically significant stop pair production signal in the upcoming LHC run. While the appropriate simulation including parton showering and detector simulation requires some care, we find stable predictions for the angular correlation using multijet merging.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated cytosine (5-methylcytosine) can be oxidized ...by the TET family of enzymes to 5-hydroxymethylcytosine (5-hmC), a key intermediate in the demethylation cycle, and 5-hmC levels are reduced in malignancies such as acute myeloid leukemia and melanoma. We constructed a tissue microarray of human cutaneous squamous cell carcinoma tumors and found a global reduction in 5-hmC levels compared with that in the adjacent skin. Using a murine K14-CreER system, we have found that loss of Tet2 promotes carcinogen-induced squamous cell carcinoma and cooperates with loss of Tp53 to drive spontaneous squamous cell carcinoma tumors in epithelial tissues. Analysis of changes in 5-hmC and gene expression after loss of Tet2 in the epidermis revealed focal alterations in 5-hmC levels and an increase in hair follicle transient amplifying cell genes along with a reduction in epidermal differentiation genes. These results show a role for TET2 in epidermal lineage specification, consistent with reported roles for TET enzymes in controlling lineage commitment in hematopoietic stem cells and embryonic stem cells and establishing TET2 as a bone fide tumor suppressor in squamous cell carcinoma.
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ROS as a tumour suppressor? Ramsey, Matthew R; Sharpless, Norman E
Nature cell biology,
200611, 2006-Nov, 2006-11-00, 20061101, Volume:
8, Issue:
11
Journal Article
Peer reviewed
Senescence is an important mechanism for suppressing mammalian tumours and it may also contribute to aging. A new study suggests that changes in the metabolism of oxygen radicals are important for ...establishing senescence and blocking cytokinesis to ensure senescent cells never divide again.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Identifying means of empirically modeling the human component of a coupled, human‐water system becomes critically important to further advances in sociohydrology. We develop a social‐psychological ...model of environmental decision making that addresses four key challenges of incorporating social science into integrated models. We use the model to explain preferences for three conservation policies designed to conserve and protect water resources and aquatic ecosystems in the Smoky Hill River Basin, a semiarid agricultural region in the Central U.S. Great Plains. Further, we compare the model's capacity to explain policy preferences among members of two groups in the River Basin: agricultural producers and members of nonfarming communities. We find that financial obligation is the strongest and most consistent explanation of support for conservation policies among members of both groups. We also find that policy support is grounded in cultural values—deeply held ideas about right and wrong. Environmental values are particularly important explanations of policy support. The constellations of values invoked to make decisions about policies, and the social‐psychological pathways linking values to policy support, can vary across policies and types of agents (farmers and nonfarmers). We discuss the implications of the results for future research in sociohydrology.
Key Points
A model of environmental decision making addresses four key challenges of incorporating social science into socio‐hydrological models
The model is applied to conservation policy support, and comparisons are made between members of farming and non‐farming populations
Financial obligation and environmental values are the most important explanations of policy support
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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