Objective
To determine if multispectral narrow‐band imaging (mNBI) can be used for automated, quantitative detection of oropharyngeal carcinoma (OPC).
Study Design
Prospective cohort study.
Methods
...Multispectral narrow‐band imaging and white light endoscopy (WLE) were used to examine the lymphoepithelial tissues of the oropharynx in a preliminary cohort of 30 patients (20 with biopsy‐proven OPC, 10 healthy). Low‐level image features from five patients were then extracted to train naïve Bayesian classifiers for healthy and malignant tissue.
Results
Tumors were classified by color features with 65.9% accuracy, 66.8% sensitivity, and 64.9% specificity under mNBI. In contrast, tumors were classified with 52.3% accuracy (P = 0.0108), 44.8% sensitivity (P = 0.0793), and 59.9% specificity (P = 0.312) under WLE. Receiver operating characteristic analysis yielded areas under the curve (AUC) of 72.3% and 54.6% for classification under mNBI and WLE, respectively (P = 0.00168). For classification by both color and texture features, AUC under mNBI increased (80.1%, P = 0.00230) but did not improve under WLE (below 55% for both models, P = 0.180). Cross‐validation with five folds yielded an AUC above 80% for both mNBI models and below 55% for both WLE models (P = 0.0000410 and 0.000116).
Conclusion
Compared to WLE, mNBI significantly enhanced the performance of a naïve Bayesian classifier trained on low‐level image features of oropharyngeal mucosa. These findings suggest that automated clinical detection of OPC might be used to enhance surgical vision, improve early diagnosis, and allow for high‐throughput screening.
Level of Evidence
NA. Laryngoscope, 2514–2520, 2018
ABSTRACT Tissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as ...systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.
Fibrosis is intimately linked to wound healing and is one of the largest causes of wound-related morbidity. While scar formation is the normal and inevitable outcome of adult mammalian cutaneous ...wound healing, scarring varies widely between different anatomical sites. The spectrum of craniofacial wound healing spans a particularly diverse range of outcomes. While most craniofacial wounds heal by scarring, which can be functionally and aesthetically devastating, healing of the oral mucosa represents a rare example of nearly scarless postnatal healing in humans. In this review, we describe the typical wound healing process in both skin and the oral cavity. We present clinical correlates and current therapies and discuss the current state of research into mechanisms of scarless healing, toward the ultimate goal of achieving scarless adult skin healing.
Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is ...limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.
Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that ...myeloid cell-derived TGF-β1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of
abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-β1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.
CRISPR germline editing therapies (CGETs) hold unprecedented potential to eradicate hereditary disorders. However, the prospect of altering the human germline has sparked a debate over the safety, ...efficacy, and morality of CGETs, triggering a funding moratorium by the NIH. There is an urgent need for practical paths for the evaluation of these capabilities. We propose a model regulatory framework for CGET research, clinical development, and distribution. Our model takes advantage of existing legal and regulatory institutions but adds elevated scrutiny at each stage of CGET development to accommodate the unique technical and ethical challenges posed by germline editing.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, PRFLJ, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue ...prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.
Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer ...matrix, termed hyaluronan elastin‐like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue‐derived, epithelial‐only intestinal organoids. HELP enables the encapsulation of dissociated patient‐derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal‐derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G’ ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10−3–1 × 10−3 m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal‐derived products or synthetic polyethylene glycol for potential clinical translation.
A tunable, designer matrix, termed hyaluronan elastin‐like protein (HELP) that enables the formation, differentiation, and passaging of adult primary tissue‐derived organoids is reported. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization.
While ligand clustering is known to enhance integrin activation, this insight has been difficult to apply to the design of implantable biomaterials because the local and global ligand densities that ...enable clustering-enhanced integrin signaling were unpredictable. Here, two general design principles for biomaterial ligand clustering are elucidated. First, clustering ligands enhances integrin-dependent signals when the global ligand density, i.e., the ligand density across the cellular length scale, is near the ligand's effective dissociation constant (KD,eff). Second, clustering ligands enhances integrin activation when the local ligand density, i.e., the ligand density across the length scale of individual focal adhesions, is less than an overcrowding threshold. To identify these principles, we fabricated a series of elastin-like, electrospun fabrics with independent control over the local (0 to 122 000 ligands μm(-2)) and global (0 to 71 000 ligand μm(-2)) densities of an arginine-glycine-aspartate (RGD) ligand. Antibody blocking studies confirmed that human umbilical vein endothelial cell adhesion to these protein-engineered biomaterials was primarily due to αVβ3 integrin binding. Clustering ligands enhanced cell proliferation, focal adhesion number, and focal adhesion kinase expression near the ligand's KD,eff of 12 000 RGD μm(-2). Near this global ligand density, cells on ligand-clustered fabrics behaved similarly to cells grown on fabrics with significantly larger global ligand densities but without clustering. However, this enhanced ligand-clustering effect was not observed above a threshold cut-off concentration. At a local ligand density of 122 000 RGD μm(-2), cell division, focal adhesion number, and focal adhesion kinase expression were significantly reduced relative to fabrics with identical global ligand density and lesser local ligand densities. Thus, when clustering results in overcrowding of ligands, integrin receptors are no longer able to effectively engage with their target ligands. Together, these two insights into the cellular responses to ligand clustering at the cell-matrix interface may serve as design principles when developing future generations of implantable biomaterials.
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