Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically ...hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
Water scarcity afflicts societies worldwide. Anticipating water shortages is vital because of water’s indispensable role in social-ecological systems. But the challenge is daunting due to ...heterogeneity, feedbacks, and water’s spatial-temporal sequencing throughout such systems. Regional system models with sufficient detail can help address this challenge. In our study, a detailed coupled human–natural system model of one such region identifies how climate change and socioeconomic growth will alter the availability and use of water in coming decades. Results demonstrate how water scarcity varies greatly across small distances and brief time periods, even in basins where water may be relatively abundant overall. Some of these results were unexpected and may appear counterintuitive to some observers. Key determinants of water scarcity are found to be the cost of transporting and storing water, society’s institutions that circumscribe human choices, and the opportunity cost of water when alternative uses compete.
Concepts of simplicity and complexity in modeling have been explored in papers, editorials, and talks. The concept is not well understood because there are at least two flavors of simplicity. ...Modelers envision simplicity (i.e., elegant simplicity) as the sought‐after goal in modeling, but naïve simplicity, which is the focus of this paper, is commonly unrecognized and dangerous. The problem is that naïve or simple ideas are often mistaken for settled science and come with the prospect of being more wrong than right. The concept of the so‐called simplicity cycle, in relation to classical problems of carbon‐14 age and salinity in closed‐basin lakes, is used to illustrate these points. The emerging problems of water‐mosquitoes‐diseases show the value of mapping new problems to the simplicity cycle. Researchers can “know what they do not know” and avoid the dangers of naïve simplicity.
Article impact statement: This paper discusses issues of simplicity/complexity and explains how to avoid the problems naïve simplicity and potential research pitfalls.
The human airway epithelium is regenerated by basal cells. Thus, basal cell therapy has the potential to cure cystic fibrosis (CF) lung disease. We previously reported that the human basal cells ...repopulated the mouse airway epithelium after transplantation, and we estimated that 60 million cells would be needed to treat a human patient. To further develop cell therapy, we compared the proliferation potential of non‐CF and CF tissue‐derived bronchial basal cells. Three methods were used: regenerative cell frequency, burst size, and cell division frequency. Second, we used a serial passage strategy to determine if CF basal cells could be amplified to the estimated therapeutic dose. These studies evaluated that tissue‐derived bronchial basal cells and the basal cells that were recovered by brushing bronchial airways or the nasal respiratory epithelium. Finally, we used the limiting dilution method to isolate non‐CF and CF basal cell clones. The proliferation assays and the air‐liquid‐interface differentiation method were used to determine if cell amplification altered the proliferation and/or differentiation potential of clonal isolates. We demonstrate that: (a) non‐CF and CF basal cell proliferation is similar, (b) CF basal cells can be amplified to a therapeutic cell dose, and (c) amplified non‐CF and CF basal cell clones differentiate normally. Despite these encouraging findings, we also find that the cell amplification process depletes the regenerative basal cell pool. Analysis of basal cell clones indicates that serial passage selects for long‐lived basal cells and raise the possibility that prospective isolation of these stem‐like cells will improve the efficacy of cell replacement therapy. Stem Cells Translational Medicine 2019;8:225&235
A cell therapy that utilizes the airway epithelial stem/progenitor cells (basal cells) has the potential to cure cystic fibrosis (CF) lung disease. However, it is not known if CF lung disease compromises basal cell function. This study demonstrated that CF and non‐CF basal cell function is equivalent and indicates the feasibility of CF transmembrane conductance regulator gene editing and autologous cell therapy.
Fire-prone landscapes present many challenges for both managers and policy makers in developing adaptive behaviors and institutions. We used a coupled human and natural systems framework and an ...agent-based landscape model to examine how alternative management scenarios affect fire and ecosystem services metrics in a fire-prone multiownership landscape in the eastern Cascades of Oregon. Our model incorporated existing models of vegetation succession and fire spread and information from original empirical studies of landowner decision making. Our findings indicate that alternative management strategies can have variable effects on landscape outcomes over 50 years for fire, socioeconomic, and ecosystem services metrics. For example, scenarios with federal restoration treatments had slightly less high-severity fire than a scenario without treatment; exposure of homes in the wildland-urban interface to fire was also slightly less with restoration treatments compared to no management. Treatments appeared to be more effective at reducing high-severity fire in years with more fire than in years with less fire. Under the current management scenario, timber production could be maintained for at least 50 years on federal lands. Under an accelerated restoration scenario, timber production fell because of a shortage of areas meeting current stand structure treatment targets. Trade-offs between restoration outcomes (e.g., open forests with large fire-resistant trees) and habitat for species that require dense older forests were evident. For example, the proportional area of nesting habitat for northern spotted owl (Strix occidentalis) was somewhat less after 50 years under the restoration scenarios than under no management. However, the amount of resilient older forest structure and habitat for white-headed woodpecker (Leuconotopicus albolarvatus) was higher after 50 years under active management. More carbon was stored on this landscape without management than with management, despite the occurrence of high-severity wildfire. Our results and further applications of the model could be used in collaborative settings to facilitate discussion and development of policies and practices for fire-prone landscapes.
Congenital or acquired tracheal lesions alter airway epithelial structure and can lead to long-segment tracheal defects. Tissue engineered tracheal grafts (TETG) have the potential to cure such ...defects; however, clinical applications have been plagued with numerous complications including delayed graft epithelialization. The knowledge that epithelial cells migrate from native tissue to the TETG raises the possibility that TETG performance can be improved by increasing the rate of epithelialization.
We developed a model that can be used quantify epithelial migration in clinically-relevant conditions.
Existing histological analyses determined the differentiation status of the normal and injured human tracheal epithelium and were used to identify in vitro culture conditions that mimic these parameters. The classical scratch assay was adapted to permit analysis of migratory velocity as a function of differentiation status. Migration of undifferentiated (UD), partially-differentiated (PD), and well-differentiated (WD) epithelia was quantified.
The normal and injured epithelium can be modeled using human cells that are cultured using a modified air-liquid-interface culture system. PD cell cultures are similar to the remodeled epithelium; whereas; WD cultures are similar to the normal epithelium. Preliminary results indicate that PD cells migrate more rapidly than WD cells and that PD and WD cells migrate more rapidly than UD cells.
Pending verification of these results, we suggest that epithelial migration is significantly altered by differentiation status. Thus, efforts to improve TETG epithelialization should use model systems that faithfully-represent the differentiation state of the native tissue.
The objective of this study was to determine if pre-operative oral midazolam administration decreased postoperative oral fluid intake after tonsillectomy with or without adenoidectomy.
A ...retrospective chart review identified 104 patients who were undergoing tonsillectomy with and without adenoidectomy who were not given midazolam preoperatively and 182 who were given midazolam preoperatively. Indications for tonsillectomy with or without adenoidectomy included obstructive sleep apnea, recurrent acute streptococcal pharyngotonsillitis, and, in selected cases, periodic fever with aphthous stomatitis, pharyngitis and adenopathy. All patients were evaluated in the pre-operative area by the attending anesthesiologist, who then determined whether or not he/she felt the patient would benefit from premedication with oral midazolam prior to surgery. Patients whom the attending anesthesiologist judged would benefit from midazolam were then given a 0.12–1.06 mg/kg dose (mean 0.35 mg/kg, STD 0.12), at the discretion of the anesthesiologist. Various methods were used to perform tonsillectomy, such as coblation and electrocautery, at the discretion of the otolaryngologist. Results were not stratified by surgical technique. Oral fluid intake was calculated by establishing the time of return to the floor from surgery and determining the documented oral fluid intake for the next 12 h. Oral fluid intake per kg per hour was then calculated. The amount of midazolam given was documented.
There was no significant difference in oral fluid intake by group when adjusting for age and weight, F(1, 282) = 0.383, p = 0.537. Also, there was no significant difference in ml/kg/hr by group when adjusting for age and weight, F(1, 282) = 2.813, p = 0.095.
There was no significant difference in oral fluid intake between the no midazolam and midazolam groups, indicating that clinicians can continue to use their judgement in administering midazolam to select anxious patients prior to tonsillectomy with or without adenoidectomy. Future work could include multi-center retrospective reviews or a randomized placebo-controlled trial to examine more carefully the effects of midazolam on postoperative oral fluid intake.
Level IV.
Although several surgical landmarks have been proposed to localize the recurrent laryngeal nerve (RLN), there is still no reliable landmark.BackgroundAlthough several surgical landmarks have been ...proposed to localize the recurrent laryngeal nerve (RLN), there is still no reliable landmark.To validate the reliability of a novel reference point at the intersection of the inferior border of the cricopharyngeal muscle and the inferior cornu of thyroid cartilage for locating the RLN.AimsTo validate the reliability of a novel reference point at the intersection of the inferior border of the cricopharyngeal muscle and the inferior cornu of thyroid cartilage for locating the RLN.Cadaver dissection study in the academic department of otolaryngology-head and neck surgery.Study DesignCadaver dissection study in the academic department of otolaryngology-head and neck surgery.Sixty-four RLNs in cadavers were assessed, and measurements of different surgical landmarks in conjunction with the proposed surgical landmark were obtained. Descriptive statistics, Pearson’s chi-squared test, and Student’s t-test were performed to analyze the data using GraphPad Prism (version 9.4.1; Dotmatics, Boston, Massachusetts, USA).MethodsSixty-four RLNs in cadavers were assessed, and measurements of different surgical landmarks in conjunction with the proposed surgical landmark were obtained. Descriptive statistics, Pearson’s chi-squared test, and Student’s t-test were performed to analyze the data using GraphPad Prism (version 9.4.1; Dotmatics, Boston, Massachusetts, USA).The average distance from the proposed landmark to the RLN was 2.3 ± 0.85 mm. The RLN was located just posterior to the reference point in 95.31% of the cadavers. The RLN passed under the inferior constrictor muscle in 90.63% of the cadavers. There was no statistically significant difference between right- and left-sided RLNs in terms of their relation with the reference point.ResultsThe average distance from the proposed landmark to the RLN was 2.3 ± 0.85 mm. The RLN was located just posterior to the reference point in 95.31% of the cadavers. The RLN passed under the inferior constrictor muscle in 90.63% of the cadavers. There was no statistically significant difference between right- and left-sided RLNs in terms of their relation with the reference point.The proposed reference point can be used as a reliable landmark to locate the RLN. This reference point may help surgeons during difficult thyroidectomy surgeries by providing an additional anatomical landmark.ConclusionThe proposed reference point can be used as a reliable landmark to locate the RLN. This reference point may help surgeons during difficult thyroidectomy surgeries by providing an additional anatomical landmark.
Objective
Significant morbidity and mortality are associated with clinical use of synthetic tissue‐engineered tracheal grafts (TETG). Our previous work focused on an electrospun polyethylene ...terephthalate and polyurethane (PET/PU) TETG that was tested in sheep using a long‐segment tracheal defect model. We reported that graft stenosis and limited epithelialization contributed to graft failure. The present study determined if the epithelialization defect could be attributed to: 1) postsurgical depletion of native airway basal stem/progenitor cells; 2) an inability of the PET/PU‐TETG to support epithelial migration; or 3) compromised basal stem/progenitor cell proliferation within the PET/PU environment.
Study Design
Experimental.
Methods
Basal stem/progenitor cell frequency in sheep that underwent TETG implantation was determined using the clone‐forming cell frequency (CFCF) method. A novel migration model that mimics epithelial migration toward an acellular scaffold was developed and used to compare epithelial migration toward a control polyester scaffold and the PET/PU scaffold. Basal stem/progenitor cell proliferation within the PET/PU scaffold was evaluated using the CFCF assay, doubling‐time analysis, and mitotic cell quantification.
Results
We report that TETG implantation did not decrease basal stem/progenitor cell frequency. In contrast, we find that epithelial migration toward the PET/PU scaffold was significantly less extensive than migration toward a polyester scaffold and that the PET/PU scaffold did not support basal stem/progenitor cell proliferation.
Conclusions
We conclude that epithelialization of a PET/PU scaffold is compromised by poor migration of native tissue‐derived epithelial cells and by a lack of basal stem/progenitor cell proliferation within the scaffold.
Level of Evidence
NA
Abstract
Background: Education about metastatic breast cancer can help caregivers by providing tools to deal with the psychosocial effects of the disease. This analysis explores metastatic breast ...cancer caregivers’ experiences related to participation in Cancer Support Community’s national evidence-based educational program, Frankly Speaking About Cancer: Metastatic Breast Cancer. This comprehensive psychosocial education program, created for people diagnosed with metastatic breast cancer and their caregivers, provides information about current treatments, side-effect management, and social and emotional challenges of an advanced breast cancer diagnosis. Methods: Caregivers who attended 67 workshops across the country between 2014 and 2019 completed program evaluations and provided self-reported data on factors including pre- and post-workshop knowledge, workshop satisfaction, confidence levels, and intentions for patient-provider communication post-workshop. In total, 305 caregivers of patients with metastatic breast cancer attending in-person Frankly Speaking About Cancer: Metastatic Breast Cancer workshops nationwide completed a survey assessing their experiences and learnings as a result of the educational workshops. Descriptive analyses and pre-and post-workshop comparisons were conducted to assess workshop outcomes. Results: Caregivers were predominantly White (79%) and female (75%) and averaged 64.2 years old (s.d.=12.5). 75% strongly identified as caregivers and 69% were strongly involved in coordinating the patient’s care (rated a ‘4’ or ‘5’ on a 5-point scale for both). Most participants in the caregiving capacity (87%) reported experiencing emotional distress due to their loved one’s cancer. The workshop was well-received, with 92% recommending the workshop to others facing similar issues. Most caregivers (77%) reported gaining a “high or very high” level of knowledge about metastatic breast cancer, which was a significant increase compared with pre-workshop levels (42%; χ²= 13.4, p <.05). Caregivers were likely to report that they gained confidence to participate in treatment decision-making with their loved one’s health care team (79%) and to ask questions about side effects of metastatic breast cancer and its treatment (82%) as a result of participating in the workshop. Lastly, 92% of caregivers reported that because of the workshops, they felt better prepared to emotionally cope with their metastatic breast cancer caregiving experience. Discussion: Results suggest that comprehensive information and supportive services are highly relevant in meeting the psychosocial needs of cancer caregivers. Increased understanding of informational and emotional support service utilization can inform provision of services and programs addressing the emotional and informational needs of caregivers.
Citation Format: Claire Saxton, Kirstin Fearnley, Maria B. Gonzalo, Cynthia Schwartz. Metastatic breast cancer caregiver participation in a psychoeducational cancer support program: Results from the frankly speaking about cancer: Metastatic breast cancer evidence-based educational workshops abstract. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-17-01.
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