Targeting IGF2-IGF1R Signaling to Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy.

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. RESULTS: Transcriptome analysis identified IGF2 as one of the top secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8+cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. CONCLUSION: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Primary care and community partnerships to promote age-friendly care for Hispanic older adults.

BACKGROUND: Healthcare and community collaborations have the potential to address health-related social needs. We examined the implementation of an educational initiative and collaborative intervention between a geriatric clinic and Area Agency on Aging (AAA) to enhance age-friendly care for a Hispanic patient population. METHODS: As part of a Health Resources and Services Administration (HRSA)-funded Geriatric Workforce Enhancement Program, a geriatric clinic partnered with AAA to embed an English- and Spanish-speaking Social Service Coordinator (SSC). The SSC met with patients during new and annual visits or by referral to address What Matters and Mentation in the patient's primary language, provide education, and make social service referrals. Patients aged 60 and older, who received SSC services during a 12-month period, were defined as the intervention group (n = 112). Using a retrospective chart review, we compared them to a non-intervention group (n = 228) that received primary care. We examined available demographic and clinical data within the age-friendly areas of What Matters and Mentation. Measures included cognitive health screenings, advance care planning, patient education, and community referrals. RESULTS: Most of the intervention groups were eligible for AAA services and had the opportunity for service referrals to address identified needs. A higher proportion of patients within the intervention group completed screenings for cognitive health and advance care planning discussions. CONCLUSION: Interagency partnerships between ambulatory care settings and community-based organizations have the potential to expand access to linguistically and culturally competent age-friendly primary care for older adults.

Integrating Fall Prevention Strategies into EMS Services to Reduce Falls and Associated Healthcare Costs for Older Adults.

Purpose: The purpose of this study is to detail the implementation of fall prevention initiatives through emergency medical services (EMS) and associated outcomes. Methods: Paramedics with MedStar Mobile Healthcare utilized the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) fall prevention model to screen and direct intervention through 9-1-1 emergency response, High Utilization Group (HUG), and 30-day Hospital Readmission Avoidance (HRA) programs. Outcomes from 9-1-1 calls measured the number of older adults screened for falls and identified risk factors. The HUG and HRA programs measured change in quality of life with EuroQol-5D, referral service utilization, falls, emergent healthcare utilization, and hospital readmission data. Analysis included costs associated with reduced healthcare usage. Results: Emergency paramedics provided fall risk screening for 50.5% (n=45,090) of adults aged 65 and older and 59.3% were at risk of falls, with 48.1% taking medications known to increase the risk of falls. Services provided through the HUG and HRA programs, along with additional needed referral services, resulted in a 37.2% reduction in fall-related 9-1-1 calls and a 29.5% increase in overall health status related to quality of life. Analysis of the HUG program revealed potential savings of over $1 million with a per-patient enrolled savings of $19,053. The HRA program demonstrated a 16.4% hospital readmission rate, in comparison to a regional average of 30.2%, and a cost-savings of $4.95 million or $15,618 per enrolled patient. Conclusion: Implementation of the STEADI model into EMS services provides an effective and cost-saving model for addressing fall prevention for older adults, provides meaningful and impactful improvement for older adults, and could serve as a model for other EMS programs.

This study explored the feasibility and impact of implementing an evidence-based fall prevention model into emergency medical services for older adults. The outcomes resulted in an efficient and effective manner to screen older adults for falls during emergency response services and connect high-risk older adults with in-home follow-up care from community paramedics. In addition, fall prevention services were provided for vulnerable adults following a recent discharge from hospital care. These initiatives to address fall prevention resulted in a majority of older adults receiving preventive fall risk screening during emergency response calls, significant changes in quality of life measures for adults with multiple comorbidities and fall risk, and significant potential cost savings in reduced healthcare services.

Nutrition association with skin integrity and pressure injury in critically ill pediatric patients.

BACKGROUND: Current research highlights the positive impact of nutrition therapy, particularly enteral nutrition, in critical illness. However, little attention is given to the impact of nutrition on skin integrity during critical illness. Skin integrity is at risk in critically ill children owing to necessary clinical therapies and challenges of providing nutrition therapy. METHODS: We conducted a narrative literature review with three main thematic concepts to drive our literature search: the association of nutrition therapy with (1) skin integrity; (2) injury, wounds, and wound healing; and (3) differences of skin color. Using pertinent search and subject terms, PubMed, CINAHL, EMBASE, and SCOPUS databases were searched, yielding 316 articles. After removal of duplicates, articles were reviewed based on inclusion and exclusion criteria defined by the authors; only eight articles met the defined criteria to inform this review. RESULTS: Large and important gaps exist in the current literature regarding an association between nutrition therapy, skin injury, and wound healing. Little to no attention was found for associations with skin color. The resulting narrative review addresses these topics and subtopics with additional references included that are independent of the original search strategy. CONCLUSIONS: A dearth of evidence exists describing associations between nutrition and disruption of skin integrity in pediatric critical illness. Children with dark skin are at increased risk, as manifestation and identification of disruption to skin integrity may not be recognized. Research is needed to describe these associations and the impact of nutrition on skin integrity, including differences of skin color.

Lessons Learned from Age-Friendly, Team-Based Training.

According to the Institute of Medicine, immediate steps must be taken across the United States to educate and train the healthcare workforce to work collaboratively to address the needs of the growing older adult population. The Geriatric Practice Leadership Institute (GPLI) was designed to support professional teams working in acute and post-acute care in transforming their organization into a designated Age-Friendly Health System. The program was built around the Institute for Healthcare Improvement's Age-Friendly Health Systems 4Ms framework. This framework focuses on What Matters, Medication, Mentation, and Mobility (the 4Ms) in supporting care for older adults. The GPLI program is an online, seven-month team-based program with four to seven participants from one organization per team. Additionally, each team selected, developed, and completed a quality improvement project based on Age-Friendly Health Systems 4Ms. The curriculum also includes organizational culture, leadership, and interprofessional team-building modules. Using a post-completion survey, the experiences of 41 participants in the GPLI program were assessed. All respondents found the information in the program 'very' or 'extremely' valuable, and their executive sponsor 'very' or 'extremely' valuable in supporting their team's involvement and project. The GPLI program has trained over 200 healthcare professionals and teams that have successfully implemented projects across their organizations.

Central Auditory Processing Dysfunction in Service Members and Veterans: Treatment Considerations and Strategies.

PURPOSE: Military risk factors such as blast exposure, noise exposure, head trauma, and neurotoxin exposure place Service members and Veterans at risk for deficits associated with auditory processing dysfunction. However, there is no clinical guidance specific to the treatment of auditory processing deficits in this unique population. We provide an overview of available treatments and their limited supporting evidence for use in adults, emphasizing the need for multidisciplinary case management and interdisciplinary research to support evidence-based solutions. METHOD: We explored relevant literature to inform the treatment of auditory processing dysfunction in adults, with emphasis on findings involving active or former military personnel. We were able to identify a limited number of studies, pertaining primarily to the treatment of auditory processing deficits through the use of assistive technologies and training strategies. We assessed the current state of the science for knowledge gaps that warrant additional study. CONCLUSIONS: Auditory processing deficits often co-occur with other military injuries and may pose significant risk in military operational and occupational settings. Research is needed to advance clinical diagnostic and rehabilitative capabilities, guide treatment planning, support effective multidisciplinary management, and inform fitness-for-duty standards. We emphasize the need for an inclusive approach to the assessment and treatment of auditory processing concerns in Service members and Veterans and for evidence-based solutions to address complex military risk factors and injuries.

Whole-Genome Sequencing to Predict Antimicrobial Susceptibility Profiles in Neisseria gonorrhoeae.

BACKGROUND: Neisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates. METHODS: Susceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility. RESULTS: A total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 µg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 µg/mL. CONCLUSIONS: Single marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials.

Prospective measurements of hearing threshold during military rifle training with in-ear, protected, noise exposure monitoring.

Although a causal relationship exists between military occupational noise exposure and hearing loss, researchers have struggled to identify and/or characterize specific operational noise exposures that produce measurable changes in hearing function shortly following an exposure. Growing evidence suggests that current standards for noise-exposure limits are not good predictors of true hearing damage. In this study, the aim was to capture the dose-response relationship during military rifle training exercises for noise exposure and hearing threshold. To capture exposure, a wearable system capable of measuring impulse noise simultaneously on-body and in-ear, behind hearing protection was used. To characterize hearing threshold changes, portable audiometry was employed within 2 h before and after exposure. The median 8-h time-weighted, protected, free-field equivalent in-ear exposure was 87.5 dBA at one site and 80.7 dBA at a second site. A significant dose-response correlation between in-ear noise exposure and postexposure hearing threshold changes across our population ( R = 0.40 , p = 0.0281) was observed. The results demonstrate an approach for establishing damage risk criteria (DRC) for in-ear, protected measurements based on hearing threshold changes. While an in-ear DRC does not currently exist, it may be critical for predicting the risk of injury for noise environments where protection is mandatory and fit status can vary.

Is jet fuel exposure associated with central auditory nervous system difficulties: An exploratory study in military personnel.

Central auditory nervous system dysfunction (CANSD) can manifest as hearing difficulty in the absence of audiometric abnormalities. Effects of noise or jet fuel exposure on the CANS are documented in animal models and humans. This study screened military personnel using the modified Amsterdam Inventory for Auditory Disability (mAIAD) to assess whether concurrent jet fuel and noise (JFN) exposures potentiate central auditory difficulties compared to noise only exposures. A total of 48 age- and sex-matched participants were recruited: 24 military bulk fuel specialists (JFN) and 24 military personnel without jet fuel exposure. All participants completed the mAIAD, the Noise Exposure Questionnaire, and basic audiological testing. Results revealed non-significant differences in pure-tone thresholds between groups, but the JFN group had higher noise exposures. Additionally, the JFN group revealed consistently lower mAIAD scores compared to the noise only group. Interestingly, a JFN stratified subgroup reporting more listening difficulty exhibited statistically significant lower mAIAD scores in the speech intelligibility in noise subdomain. These preliminary data suggest that jet fuel exposure may potentiate noise-induced CANSD, such as speech-in-noise difficulties. Such difficulties may be more prominent among specific military personnel with combined exposures. Hearing conservation programs could add CANSD screening by use of the mAIAD.

Histone modifiers at the crossroads of oncolytic and oncogenic viruses.

Cancer is a disease caused by loss of regulatory processes that control the cell cycle, resulting in increased proliferation. The loss of control can deregulate both tumor suppressors and oncogenes. Apart from cell intrinsic gene mutations and environmental factors, infection by cancer-causing viruses also induces changes that lead to malignant transformation. This can be caused by both expression of oncogenic viral proteins and also by changes in cellular genes and proteins that affect the epigenome. Thus, these epigenetic modifiers are good therapeutic targets, and several epigenetic inhibitors are approved for the treatment of different cancers. In addition to small molecule drugs, biological therapies, such as antibodies and viral therapies, are also increasingly being used to treat cancer. An HSV-1-derived oncolytic virus is currently approved by the US FDA and the European Medicines Agency. Similarly, an adenovirus-based therapeutic is approved for use in China for some cancer types. Because viruses can affect cellular epigenetics, the interaction of epigenome-targeting drugs with oncogenic and oncolytic viruses is a highly significant area of investigation. Here, we will review the current knowledge about the impact of using epigenetic drugs in tumors positive for oncogenic viruses or as therapeutic combinations with oncolytic viruses.

NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy.

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy. EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy. RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit. CONCLUSIONS: NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.

Distortion product otoacoustic mapping measured pre- and post-loud sound exposures.

OBJECTIVE: Sampling distortion product otoacoustic emissions (DPOAEs) at multiple f2/f1 ratios and f2 frequency values produces a DPOAE "map." This study examined the efficacy of DPOAE mapping compared with pure tone audiometry and standard DPOAEs for detecting noise effects in subjects exposed to loud sound. DESIGN: A map significance score was developed as a single measure of map change. Significance scores were evaluated before and after exposure to: loud music (LM), controlled noise (CN), and firing range noise (FR) in three separate sets of subjects. Scores were compared to audiometry and standard DPOAE results in the LM study. STUDY SAMPLE: The LM and CN exposure studies involved 22, and 20 healthy young subjects respectively with normal hearing. Eight Marines were studied before and after FR exposure. RESULTS: After LM exposure, audiometry showed significant changes at 1, 2, 4, and 6 kHz. Standard DPOAE measures were also significantly different at several frequencies. Map significance scores detected changes more effectively and showed the distribution of DPOAE alterations. CONCLUSIONS: Map significance scores detected changes after noise exposure more reliably than audiometry and standard DPOAEs. Additionally, maps showed a diffuse response to sound exposure perhaps explaining why individual DP-grams appear less sensitive.

Portable eye-tracking as a reliable assessment of oculomotor, cognitive and reaction time function: Normative data for 18-45 year old.

Eye movements measured by high precision eye-tracking technology represent a sensitive, objective, and non-invasive method to probe functional neural pathways. Oculomotor tests (e.g., saccades and smooth pursuit), tests that involve cognitive processing (e.g., antisaccade and predictive saccade), and reaction time tests have increasingly been showing utility in the diagnosis and monitoring of mild traumatic brain injury (mTBI) in research settings. Currently, the adoption of these tests into clinical practice is hampered by a lack of a normative data set. The goal of this study was to construct a normative database to be used as a reference for comparing patients' results. Oculomotor, cognitive, and reaction time tests were administered to male and female volunteers, aged 18-45, who were free of any neurological, vestibular disorders, or other head injuries. Tests were delivered using either a rotatory chair equipped with video-oculography goggles (VOG) or a portable virtual reality-like VOG goggle device with incorporated infrared eye-tracking technology. Statistical analysis revealed no effects of age on test metrics when participant data were divided into pediatric (i.e.,18-21 years, following FDA criteria) and adult (i.e., 21-45 years) groups. Gender (self-reported) had an effect on auditory reaction time, with males being faster than females. Pooled data were used to construct a normative database using 95% reference intervals (RI) with 90% confidence intervals on the upper and lower limits of the RI. The availability of these RIs readily allows clinicians to identify specific metrics that are deficient, therefore aiding in rapid triage, informing and monitoring treatment and/or rehabilitation protocols, and aiding in the return to duty/activity decision. This database is FDA cleared for use in clinical practice (K192186).

Normative data for ages 18-45 for ocular motor and vestibular testing using eye tracking.

OBJECTIVE: Eye tracking technology has been employed in assessing ocular motor and vestibular function following vestibular and neurologic conditions, including traumatic brain injury (TBI). Assessments include tests that provide visual and motion (rotation) stimuli while recording horizontal, vertical, and torsional eye movements. While some of these tests have shown diagnostic promise in previous studies, their use in clinical practice is limited by the lack of normative data. The goal of this study was to construct normative reference ranges to be used when comparing patients' results. METHODS: Optokinetic response, subjective visual horizontal and vertical, and rotation tests were administered to male and female volunteers, ages 18-45, who were free from neurological, vestibular disorders, or other head injuries. Tests were administered using either a rotatory chair or a portable virtual reality-like goggle equipped with video-oculography. RESULTS: Reference values for eye movements in response to different patterns of stimuli were analyzed from 290 to 449 participants. Analysis of gender (self-reported) or age when grouped as pediatric (late adolescent; 18-21 years of age) and adult (21-45 years of age) revealed no effects on the test metrics. Data were pooled and presented for each test metric as the 95% reference interval (RI) with 90% confidence intervals (CI) on upper and lower limits of the RI. CONCLUSIONS: This normative database can serve as a tool to aid in diagnosis, treatment, and/or rehabilitation protocols for vestibular and neurological conditions, including mild TBI (mTBI). This database has been cleared by the FDA for use in clinical practice (K192186). LEVEL OF EVIDENCE: 2b.

Eating Competence and Dietary Intake of Sexual and Gender Minority College Students.

Sexual and gender minority college students are underrepresented in nutrition research and may face unique challenges related to eating which impact their overall diet quality. We assessed the differences in eating competence and dietary intake between sexual and gender minority (SGM) and cisgender heterosexual (CH) college students. Participants (n = 2645) reported sexual orientation, gender identity and completed the Eating Competence Satter Inventory (ecSI 2.0™ through an online questionnaire. Three-day food records examined dietary intake. Intake was compared to recommendations for nutrients of public health concern. Chi-square and ANCOVA examined differences between eating competence and dietary intake. There were no differences in total ecSI 2.0™ scores. Subscale scores for Eating Attitudes and Contextual Skills were significantly higher in CH vs. SGM students (13.4 ± 0.1 vs. 12.4 ± 0.4 p = 0.01 and 10.7 ± 0.1 vs. 9.9 ± 0.3, p = 0.01, respectively). Most students (40.8%) met one nutrient recommendation. The proportion of students meeting nutrient recommendations were similar for SGM and CH. SGM populations may struggle with attitudes and eating behaviors. Dietary intake of SGM and CH students were similarly inadequate when compared to recommendations.

Sustained Reduction of Nasal Pressure Injuries in the Neonatal Intensive Care Unit With the Use of Bubble Continuous Positive Airway Pressure: A Quality Improvement Project.

PURPOSE: The purpose of this interprofessional team-driven quality improvement project was to implement a Bubble continuous positive airway pressure (CPAP) Skincare Protocol proactively to prevent potential device-related pressure injuries. PARTICIPANTS AND SETTING: The setting was a level 3, 60-bed single patient room neonatal intensive care unit (NICU) located within a Midwest urban academic medical center with more than 200 healthcare providers. Prior to the beginning of this project, the NICU had been using the CPAP apparatus that had documented 6 nasal pressure injuries over a 6-month period. Because of ease of use, the NICU moved to using Bubble CPAP (BCPAP), which is known to place patients at a higher risk of nasal pressure injuries due to the way the apparatus sits inside the nares. APPROACH: An evidence-based practice model provided the guiding framework for the development of our BCPAP Skincare Protocol. Knowing that the unit had already documented nasal pressure injuries, the interprofessional-devised protocol was developed to decrease the risk of nasal injuries with the use of BCPAP in premature infants. The protocol was disseminated via an all-healthcare provider educational program. OUTCOMES: During the first 3 months postprotocol implementation period, one stage 2 nasal injury was noted and immediately treated and healed without incident. During the next 24-month, postimplementation period, there were zero nasal pressure injuries reported. IMPLICATIONS FOR PRACTICE: The healthcare providers found that using an interprofessional team approach in developing and implementing an evidence-based BCPAP Skincare Protocol reduced the incidence of nasal pressure injuries associated with the use of BCPAP in the NICU.

The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS).

Although many regional multiple sclerosis (MS) databases existed in the United States and Canada, there was no single clinician-derived registry that examined this disease as a group across the North American continent. This distinction is important because information that results from such a database can potentially give perspectives about MS that cannot be derived from any single regional registry. A partnership was forged between the pharmaceutical industry and the Consortium of Multiple Sclerosis Centers (CMSC) to create a registry of patients with MS from Canada and the United States, including Puerto Rico. Case report forms were created to collect physician-derived information, and the Patient-Reported Outcomes Measurement Information System (PROMIS) was selected to capture patient-reported outcomes. As of November 2021, 754 of 1000 patients have been enrolled. Completion of recruitment is expected by the end of 2021. Twenty-five centers are participating, with an expected total of 30, including five centers from Canada. Clinical status, health economic outcomes, magnetic resonance images, and, soon, biomarkers relevant to understanding relapses and progression are collected. The short-term goal is to understand and better treat MS disease progression, and the long-term goal is its prevention. The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is one of few clinician/patient-generated registries that examines MS across North America, including Puerto Rico. Information derived from the natural history studies should help physicians, the pharmaceutical industry, and regulatory bodies understand MS better and improve quality of life for patients with MS worldwide.

ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors.

Histone deacetylase inhibitors (HDACi) are largely ineffective in the treatment of solid tumors. In this study, we describe a new class of protein disulfide isomerase (PDI) inhibitors that significantly and synergistically enhance the antitumor activity of HDACi in glioblastoma and pancreatic cancer preclinical models. RNA-sequencing screening coupled with gene silencing studies identified ATF3 as the driver of this antitumor synergy. ATF3 was highly induced by combined PDI and HDACi treatment as a result of increased acetylation of key histone lysine residues (acetylated histone 3 lysine 27 and histone 3 lysine 18) flanking the ATF3 promoter region. These chromatin marks were associated with increased RNA polymerase II recruitment to the ATF3 promoter, a synergistic upregulation of ATF3, and a subsequent apoptotic response in cancer cells. The HSP40/HSP70 family genes DNAJB1 and HSPA6 were found to be critical ATF3-dependent genes that elicited the antitumor response after PDI and HDAC inhibition. In summary, this study presents a synergistic antitumor combination of PDI and HDAC inhibitors and demonstrates a mechanistic and tumor suppressive role of ATF3. Combined treatment with PDI and HDACi offers a dual therapeutic strategy in solid tumors and the opportunity to achieve previously unrealized activity of HDACi in oncology. SIGNIFICANCE: This study uses a first-in-class PDI inhibitor entering clinical development to enhance the effects of epigenetic drugs in some of the deadliest forms of cancer.

Novel Use of a Gas Analyzer Can Reliably Predict the Arterial Oxygen among Emergency Department Patients Undergoing Rapid Sequence Intubation.

BACKGROUND: To our knowledge, no study has assessed the correlation of fraction of inspired oxygen (FiO2) and end-tidal oxygen (EtO2) values obtained from a gas analyzer during the preoxygenation period of rapid sequence intubation (RSI) to predict partial pressure of oxygen (PaO2) among patients requiring intubation in the emergency department (ED). OBJECTIVE: The purpose of this study was to determine whether a simple equation using EtO2 and FiO2 at time of induction could reliably estimate minimal PaO2 in ED patients undergoing RSI. METHODS: We conducted an observational pilot study performed in an adult ED utilizing a gas analyzer to obtain EtO2 and FiO2 values in ED patients undergoing RSI from data collectors blinded to our objective. The Pearson correlation coefficient was calculated between the equation's predicted PaO2 and the PaO2 drawn from an arterial blood gas shortly after intubation. A Bland-Altman plot analysis was performed to identify any additional bias. RESULTS: Seventy-five patients were enrolled. The equation's mean predicted minimal PaO2 and mean PaO2 from an arterial blood gas within 3 min after intubation was 178 mm Hg (95% confidence interval [CI] 145-211 mm Hg) and 209 mm Hg (95% CI 170-258 mm Hg), respectively. The Pearson correlation coefficient between the predicted minimal PaO2 and post-intubation PaO2 demonstrated a strong correlation (r2 = 0.89). The Bland-Altman plot indicated no bias affecting the correlation between the predicted and actual PaO2. CONCLUSIONS: Among ED patients undergoing RSI, the use of a gas analyzer to measure EtO2 and FiO2 can provide a reliable measure of the minimal PaO2 at the time of induction during the RSI phase of preoxygenation.

Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction.

RATIONALE: Increasing prevalence of obesity and its associated risk with cardiovascular diseases demands a better understanding of the contribution of different cell types within this complex disease for developing new treatment options. Previous studies could prove a fundamental role of FTO (fat mass and obesity-associated protein) within obesity; however, its functional role within different cell types is less understood. OBJECTIVES: We identify endothelial FTO as a previously unknown central regulator of both obesity-induced metabolic and vascular alterations. METHODS AND RESULTS: We generated endothelial Fto-deficient mice and analyzed the impact of obesity on those mice. While the loss of endothelial FTO did not influence the development of obesity and dyslipidemia, it protected mice from high-fat diet-induced glucose intolerance and insulin resistance by increasing AKT (protein kinase B) phosphorylation in endothelial cells and skeletal muscle. Furthermore, loss of endothelial FTO prevented the development of obesity-induced hypertension by preserving myogenic tone in resistance arteries. In Fto-deficient arteries, microarray analysis identified upregulation of L-Pgds with significant increases in prostaglandin D2 levels. Blockade of prostaglandin D2 synthesis inhibited the myogenic tone protection in resistance arteries of endothelial Fto-deficient mice on high-fat diet; conversely, direct addition of prostaglandin D2 rescued myogenic tone in high-fat diet-fed control mice. Myogenic tone was increased in obese human arteries with FTO inhibitors or prostaglandin D2 application. CONCLUSIONS: These data identify endothelial FTO as a previously unknown regulator in the development of obesity-induced metabolic and vascular changes, which is independent of its known function in regulation of obesity.