Rates of bronchopulmonary dysplasia in very low birth weight neonates: a systematic review and meta-analysis.

IMPORTANCE: Large-scale estimates of bronchopulmonary dysplasia (BPD) are warranted for adequate prevention and treatment. However, systematic approaches to ascertain rates of BPD are lacking. OBJECTIVE: To conduct a systematic review and meta-analysis to assess the prevalence of BPD in very low birth weight (≤ 1,500 g) or very low gestational age (< 32 weeks) neonates. DATA SOURCES: A search of MEDLINE from January 1990 until September 2019 using search terms related to BPD and prevalence was performed. STUDY SELECTION: Randomized controlled trials and observational studies evaluating rates of BPD in very low birth weight or very low gestational age infants were eligible. Included studies defined BPD as positive pressure ventilation or oxygen requirement at 28 days (BPD28) or at 36 weeks postmenstrual age (BPD36). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently conducted all stages of the review. Random-effects meta-analysis was used to calculate the pooled prevalence. Subgroup analyses included gestational age group, birth weight group, setting, study period, continent, and gross domestic product. Sensitivity analyses were performed to reduce study heterogeneity. MAIN OUTCOMES AND MEASURES: Prevalence of BPD defined as BPD28, BPD36, and by subgroups. RESULTS: A total of 105 articles or databases and 780,936 patients were included in this review. The pooled prevalence was 35% (95% CI, 28-42%) for BPD28 (n = 26 datasets, 132,247 neonates), and 21% (95% CI, 19-24%) for BPD36 (n = 70 studies, 672,769 neonates). In subgroup meta-analyses, birth weight category, gestational age category, and continent were strong drivers of the pooled prevalence of BPD. CONCLUSIONS AND RELEVANCE: This study provides a global estimation of BPD prevalence in very low birth weight/low gestation neonates.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

Mixed-Reality Simulation for a Pediatric Transport Team: A Pilot Study.

OBJECTIVE: Transport medicine requires a complex set of skills including fast-paced medical decision making, in-depth medical knowledge, procedural competence, interpersonal and communication skills, leadership, and professionalism. There has been a call for more training in these areas. Simulation-based training can be a way to acquire these necessary skills and bridge the gap to higher-quality transport care. The purpose of this study was to develop a novel mixed-reality simulation program to enhance medical and communication skills for a pediatric transport team. METHODS: A mixed-reality simulation program using standardized patients portraying family members and high-fidelity manikins to simulate a medical emergency was developed and implemented for a pediatric transport team. Ten nurses, 9 respiratory therapists, and 8 emergency medical technicians participated. Pre-post self-perceptions of skill and program quality were assessed prospectively. RESULTS: Team members rated the overall program quality highly, with a median 5 on a 5-point Likert scale. There was a statistically significant change in pre- versus postprogram self-perceptions of skill in the areas of communication (premedian = 3 vs. postmedian = 4, 5-point Likert scale, P < .001). CONCLUSION: Mixed-reality simulation programs can enhance standard technical skills training by providing an additional relational element. Such programs are translatable to other institutions.

Therapeutic hypothermia after out-of-hospital cardiac arrest in children.

BACKGROUND: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

NCI Cancer Research Data Commons: Resources to Share Key Cancer Data.

Since 2014, the NCI has launched a series of data commons as part of the Cancer Research Data Commons (CRDC) ecosystem housing genomic, proteomic, imaging, and clinical data to support cancer research and promote data sharing of NCI-funded studies. This review describes each data commons (Genomic Data Commons, Proteomic Data Commons, Integrated Canine Data Commons, Cancer Data Service, Imaging Data Commons, and Clinical and Translational Data Commons), including their unique and shared features, accomplishments, and challenges. Also discussed is how the CRDC data commons implement Findable, Accessible, Interoperable, Reusable (FAIR) principles and promote data sharing in support of the new NIH Data Management and Sharing Policy. See related articles by Brady et al., p. 1384, Pot et al., p. 1396, and Kim et al., p. 1404.

Cefazolin vs Second-line Antibiotics for Surgical Site Infection Prevention After Total Joint Arthroplasty Among Patients With a Beta-lactam Allergy.

Background: Cefazolin is a first-line agent for prevention of surgical site infections (SSIs) after total joint arthroplasty. Patients labeled allergic to beta-lactam antibiotics frequently receive clindamycin or vancomycin perioperatively due to the perceived risk of a hypersensitivity reaction after exposure to cefazolin. Methods: This single-system retrospective review included patients labeled allergic to penicillin or cephalosporin antibiotics who underwent a primary total hip and/or knee arthroplasty between January 2020 and July 2021. A detailed chart review was performed to compare the frequency of SSI within 90 days of surgery and interoperative hypersensitivity reactions (HSRs) between patients receiving cefazolin and patients receiving clindamycin and/or vancomycin. Results: A total of 1128 hip and/or knee arthroplasties from 1047 patients were included in the analysis (cefazolin n = 809, clindamycin/vancomycin n = 319). More patients in the clindamycin and/or vancomycin group had a history of cephalosporin allergy and allergic reactions with immediate symptoms. There were fewer SSIs in the cefazolin group compared with the clindamycin and/or vancomycin group (0.9% vs 3.8%; P < .001) including fewer prosthetic joint infections (0.1% vs 1.9%). The frequency of interoperative HSRs was not different between groups (cefazolin = 0.2% vs clindamycin/vancomycin = 1.3%; P = .06). Conclusions: The use of cefazolin as a perioperative antibiotic for infection prophylaxis in total joint arthroplasty in patients labeled beta-lactam allergic is associated with decreased postoperative SSI without an increase in interoperative HSR.

Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a devastating lung condition that develops in premature newborns exposed to prolonged mechanical ventilation and supplemental oxygen. Significant morbidity and mortality are associated with this costly disease and effective therapies are limited. Mesenchymal stem/stromal cells (MSCs) are multipotent cells that can repair injured tissue by secreting paracrine factors known to restore the function and integrity of injured lung epithelium and endothelium. Most preclinical studies showing therapeutic efficacy of MSCs for BPD are administered either intratracheally or intravenously. The purpose of this study was to examine the feasibility and effectiveness of human cord tissue-derived MSC administration given via the intranasal route. Human umbilical cord tissue MSCs were isolated, characterized, and given intranasally (500 000 cells per 20 µL) to a hyperoxia-induced rat model of BPD. Lung alveolarization, vascularization, and pulmonary vascular remodeling were restored in animals receiving MSC treatment. Gene and protein analysis suggest the beneficial effects of MSCs were attributed, in part, to a concerted effort targeting angiogenesis, immunomodulation, wound healing, and cell survival. These findings are clinically significant, as neonates who develop BPD have altered alveolar development, decreased pulmonary vascularization and chronic inflammation, all resulting in impaired tissue healing. Our study is the first to report the intranasal delivery of umbilical cord Wharton's jelly MSCs in experimental BPD is feasible, noninvasive, and an effective route that may bear clinical applicability.

Identification of Cosalane as an Inhibitor of Human and Murine CC-Chemokine Receptor 7 Signaling via a High-Throughput Screen.

CC-chemokine receptor 7 (CCR7) is a G protein-coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states. Due to its therapeutic relevance and absence of available CCR7 inhibitors, we undertook a high-throughput screen (HTS) to identify small-molecule antagonists of the receptor. Here, we describe a robust HTS approach using a commercially available ß-galactosidase enzyme fragment complementation system and confirmatory transwell chemotaxis assays. This work resulted in the identification of several compounds with activity against CCR7. The most potent of these was subsequently determined to be cosalane, a cholesterol derivative previously designed as a therapeutic for human immunodeficiency virus. Cosalane inhibited both human and murine CCR7 in response to both CCL19 and CCL21 agonists at physiologic concentrations. Furthermore, cosalane produced durable inhibition of the receptor following a cellular incubation period with subsequent washout. Overall, our work describes the development of an HTS-compatible assay, completion of a large HTS campaign, and demonstration for the first time that cosalane is a validated CCR7 antagonist. These efforts could pave the way for new approaches to address CCR7-associated disease processes.

Performing the Brain Death Examination and the Declaration of Pediatric Brain Death.

Declaration of brain death is a clinical diagnosis made by the absence of neurological function in a comatose patient secondary to a known irreversible cause. Brain death determination is not an infrequent process in pediatric intensive care units. It is important that pediatric intensive care providers understand the definition of brain death and intensivists are able to implement brain death testing. The following is a narration detailing the process of brain death determination by physical examination. First, the prerequisites that determine patients' eligibility for brain death testing will be outlined. Next, each part of the physical exam, including the apnea test, will be described in detail. Finally, how the declaration of brain death is made is stated. In addition, special considerations and ancillary testing will be briefly highlighted.

A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides.

The pharmacological effectiveness of oligonucleotides has been hampered by their tendency to remain entrapped in endosomes, thus limiting their access to cytosolic or nuclear targets. We have previously reported a group of small molecules that enhance the effects of oligonucleotides by causing their release from endosomes. Here, we describe a second novel family of oligonucleotide enhancing compounds (OECs) that is chemically distinct from the compounds reported previously. We demonstrate that these molecules substantially augment the actions of splice switching oligonucleotides (SSOs) and antisense oligonucleotides (ASOs) in cell culture. We also find enhancement of SSO effects in a murine model. These new compounds act by increasing endosome permeability and causing partial release of entrapped oligonucleotides. While they also affect the permeability of lysosomes, they are clearly different from typical lysosomotropic agents. Current members of this compound family display a relatively narrow window between effective dose and toxic dose. Thus, further improvements are necessary before these agents can become suitable for therapeutic use.

Hydrogen bonding is the prime determinant of carboxyl pKa values at the N-termini of alpha-helices.

Experimentally determined mean pK(a) values of carboxyl residues located at the N-termini of alpha-helices are lower than their overall mean values. Here, we perform three types of analyses to account for this phenomenon. We estimate the magnitude of the helix macrodipole to determine its potential role in lowering carboxyl pK(a) values at the N-termini. No correlation between the magnitude of the macrodipole and the pK(a) values is observed. Using the pK(a) program propKa we compare the molecular surroundings of 18 N-termini carboxyl residues versus 233 protein carboxyl groups from a previously studied database. Although pK(a) lowering interactions at the N-termini are similar in nature to those encountered in other protein regions, pK(a) lowering backbone and side-chain hydrogen bonds appear in greater number at the N-termini. For both Asp and Glu, there are about 0.5 more hydrogen bonds per residue at the N-termini than in other protein regions, which can be used to explain their lower than average pK(a) values. Using a QM-based pK(a) prediction model, we investigate the chemical environment of the two lowest Asp and the two lowest Glu pK(a) values at the N-termini so as to quantify the effect of various pK(a) determinants. We show that local interactions suffice to account for the acidity of carboxyl residues at the N-termini. The effect of the helix dipole on carboxyl pK(a) values, if any, is marginal. Backbone amide hydrogen bonds constitute the single biggest contributor to the lowest carboxyl pK(a) values at the N-termini. Their estimated pK(a) lowering effects range from about 1.0 to 1.9 pK(a) units.

Development of a Comprehensive Communication Skills Curriculum for Pediatrics Residents.

BACKGROUND: Effective communication is an essential element of medical care and a priority of medical education. Specific interventions to teach communication skills are at the discretion of individual residency programs. OBJECTIVE: We developed the Resident Communication Skills Curriculum (RCSC), a formal curriculum designed to teach trainees the communication skills essential for high-quality practice. METHODS: A multidisciplinary working group contributed to the development of the RCSC, guided by an institutional needs assessment, literature review, and the Accreditation Council for Graduate Medical Education core competencies. The result was a cohesive curriculum that incorporates didactic, role play, and real-life experiences over the course of the entire training period. Methods to assess curricular outcomes included self-reporting, surveys, and periodic faculty evaluations of the residents. RESULTS: Curricular components have been highly rated by residents (3.95-3.97 based on a 4-point Likert scale), and residents' self-reported communication skills demonstrated an improvement over the course of residency in the domains of requesting a consultation, providing effective handoffs, handling conflict, and having difficult conversations (intern median 3.0, graduate median 4.0 based on a 5-point Likert scale, P ≤ .002). Faculty evaluations of residents have also demonstrated improvement over time (intern median 3.0, graduate median 4.5 based on a 5-point Likert scale, P < .001). CONCLUSIONS: A comprehensive, integrated communication skills curriculum for pediatrics residents was implemented, with a multistep evaluative process showing improvement in skills over the course of the residency program. Positive resident evaluations and informal comments from faculty support its general acceptance. The use of existing resources makes this curriculum feasible.

Death receptor signaling and autoimmunity.

In recent years, it has become clear that self-nonself discrimination by the immune system is driven not so much by the specificities of the antigen receptors themselves, but by ligand-receptor systems that sense the presence of foreign pathogens (toll-like receptors) and those that regulate the balance between cellular proliferation and programmed cell death (tumor necrosis factor [TNF] family ligands and receptors). Interestingly, these two receptor families share a number of common signaling pathways, mediated by the cytoplasmic proteins containing death domains and TRAF domains, which trigger the complementary processes of programmed cell death and inflammation. Both humans and mice with genetic defects in the TNF-receptor family member Fas accumulate abnormal lymphocytes and develop systemic autoimmunity. These findings highlighted the importance of this TNF-receptor family member in the homeostasis of the immune system. In particular, the Fas receptor has been shown to be important in immunoreceptor-mediated apoptosis of activated T and B lymphocytes. Six members of the TNF-receptor superfamily share a common signaling domain with Fas, termed the death domain, that directly links these receptors to the apoptotic machinery of the cell, and, collectively, these receptors have been designated as "death receptors."We are currently investigating a number of important unresolved issues in this field, including: (1). how susceptibility to apoptosis through death receptors is regulated, (2). how Fas and related death receptors function in the maintenance of self-tolerance and homeostasis in the major cell types of the immune system, and (3). recently described nonapoptotic lymphocyte activation signals that use components of death receptor signaling.

Using simulation to address hierarchy-related errors in medical practice.

OBJECTIVE: Hierarchy, the unavoidable authority gradients that exist within and between clinical disciplines, can lead to significant patient harm in high-risk situations if not mitigated. High-fidelity simulation is a powerful means of addressing this issue in a reproducible manner, but participant psychological safety must be assured. Our institution experienced a hierarchy-related medication error that we subsequently addressed using simulation. The purpose of this article is to discuss the implementation and outcome of these simulations. METHODS: Script and simulation flowcharts were developed to replicate the case. Each session included the use of faculty misdirection to precipitate the error. Care was taken to assure psychological safety via carefully conducted briefing and debriefing periods. Case outcomes were assessed using the validated Team Performance During Simulated Crises Instrument. Gap analysis was used to quantify team self-insight. Session content was analyzed via video review. RESULTS: Five sessions were conducted (3 in the pediatric intensive care unit and 2 in the Pediatric Emergency Department). The team was unsuccessful at addressing the error in 4 (80%) of 5 cases. Trends toward lower communication scores (3.4/5 vs 2.3/5), as well as poor team self-assessment of communicative ability, were noted in unsuccessful sessions. Learners had a positive impression of the case. CONCLUSIONS: Simulation is a useful means to replicate hierarchy error in an educational environment. This methodology was viewed positively by learner teams, suggesting that psychological safety was maintained. Teams that did not address the error successfully may have impaired self-assessment ability in the communication skill domain.

Filtration improves the performance of a high-throughput screen for anti-mycobacterial compounds.

The tendency for mycobacteria to aggregate poses a challenge for their use in microplate based assays. Good dispersions have been difficult to achieve in high-throughput screening (HTS) assays used in the search for novel antibacterial drugs to treat tuberculosis and other related diseases. Here we describe a method using filtration to overcome the problem of variability resulting from aggregation of mycobacteria. This method consistently yielded higher reproducibility and lower variability than conventional methods, such as settling under gravity and vortexing.

A simulation-based curriculum to address relational crises in medicine.

INTRODUCTION: Preparing health care professionals for challenging communication tasks such as delivering bad news to patients and families is an area where a need for improved teaching has been identified. OBJECTIVES: We developed a simulation-based curriculum to enhance the skills of health care professionals, with an emphasis on the communication of difficult or bad news, which we termed relational crises. METHODS: Our approach was based on a review of existing simulation-based curricula, with the addition of unique features, including a learner-focused needs assessment to shape curriculum development, use of 360-degree evaluations, and provision of written feedback. Development and implementation of our curriculum occurred in 3 phases. Phase I involved a multidisciplinary needs assessment, creation of a clinical scenario based on needs assessment results, and training of standardized patients. In Phase II we implemented the curriculum with 36 pediatric and internal medicine-pediatrics residents, 20 nurses, and 1 chaplain. Phase III consisted of the provision of written feedback for learners, created from the 360-degree evaluations compiled from participants, observers, faculty, and standardized patients. RESULTS: Participants felt the scenarios were realistic (average rating of 4.7 on a 5-point Likert scale) and improved their practice and preparedness for these situations (average rating, 4.75/5 and 4.18/5, respectively). Our curriculum produced a statistically significant change in participants' pre- and postcurriculum self-reported perceptions of skill (2.42/5 vs. 3.23/5, respectively, P < .001) and level of preparedness (2.91/5 vs. 3.72/5, respectively, P < .001). DISCUSSION: A simulation-based curriculum using standardized patients, learner-identified needs, 360-degree evaluations, and written feedback demonstrated a statistically significant change in participants' self-perceived skills and preparedness for communicating difficult news in pediatrics.

Development of a high-throughput assay for identifying inhibitors of TBK1 and IKKε.

IKKε and TBK1 are noncanonical IKK family members which regulate inflammatory signaling pathways and also play important roles in oncogenesis. However, few inhibitors of these kinases have been identified. While the substrate specificity of IKKε has recently been described, the substrate specificity of TBK1 is unknown, hindering the development of high-throughput screening technologies for inhibitor identification. Here, we describe the optimal substrate phosphorylation motif for TBK1, and show that it is identical to the phosphorylation motif previously described for IKKε. This information enabled the design of an optimal TBK1/IKKε substrate peptide amenable to high-throughput screening and we assayed a 6,006 compound library that included 4,727 kinase-focused compounds to discover in vitro inhibitors of TBK1 and IKKε. 227 compounds in this library inhibited TBK1 at a concentration of 10 µM, while 57 compounds inhibited IKKε. Together, these data describe a new high-throughput screening assay which will facilitate the discovery of small molecule TBK1/IKKε inhibitors possessing therapeutic potential for both inflammatory diseases and cancer.

Inhibition of NFkappaB by the natural product Withaferin A in cellular models of Cystic Fibrosis inflammation.

Cystic Fibrosis (CF) is one of the most common autosomal genetic disorders in humans. This disease is caused by mutations within a single gene, coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The phenotypic hallmark of CF is chronic lung infection and associated inflammation from opportunistic microbes such as Pseudomonas aeruginosa (PA), Haemophilus influenzae, and Staphylococcus aureus. This eventually leads to deterioration of lung function and death in most CF patients. Unfortunately, there is no approved therapy for correcting the genetic defect causal to the disease. Hence, controlling inflammation and infection in CF patients are critical to disease management. Accordingly, anti-inflammatory agents and antibiotics are used to manage chronic inflammation and infection in CF patients. However, most of the anti-inflammatory agents in CF have severe limitations due to adverse side effects, and resistance to antibiotics is becoming an even more prominent problem. Thus, new agents that can be used to control chronic inflammation in CF are needed in the absence of a cure for the disease. Activation of the transcription factor NFkappaB through Toll-like receptors (TLR) following bacterial infection is principally involved in regulating lung inflammation in CF. NFkappaB regulates the transcription of several genes that are involved in inflammation, anti-apoptosis and anti-microbial activity, and hyper-activation of this transcription factor leads to a potent inflammatory response. Thus, NFkappaB is a potential anti-inflammatory drug target in CF. Screening of several compounds from natural sources in an in vitro model of CF-related inflammation wherein NFkappaB is activated by filtrates of a clinically isolated strain of PA (PAF) led us to Withaferin A (WFA), a steroidal lactone from the plant Withania Somnifera L. Dunal. Our data demonstrate that WFA blocks PAF-induced activation of NFkappaB as determined using reporter assays, IL-8 measurements and high-content fluorescent imaging of NFkappaB subunit p65 translocation. Since the airways of CF patients can be specifically targeted for delivery of therapeutics, we propose that WFA should be further studied as an anti-inflammatory agent in models of CF related inflammation mediated by NFkappaB.

A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2.

Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.