Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain.

Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these "dual-display" phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.

Using Near-Infrared Spectroscopy and Education to Support Older Adults with Diabetic Foot Ulcers to Age-in-Place: A Case Series.

ABSTRACT: The objective of this article is to demonstrate the added value of foot care provided by an RN with foot care training to older adults in their home by focusing on four older adults with diabetic foot ulcers. The RN used a mobile multispectral near-infrared spectroscopy device to enhance the assessment of the diabetic foot ulcers. The Mobile Seniors Wellness Network methodically engaged with English-speaking adults 55 years and older living within a 90-minute radius of the city's community health center. Older adults were referred to the research project through various sources. The participation group included 366 participants with varying holistic healthcare concerns and financial stressors that impacted their ability to age well in place. Over the course of visits by the RN and registered social worker, positive outcomes were facilitated through the collaboration of the participant and the multidisciplinary team, thus enhancing the individual's confidence to remain at home longer. In a time of ongoing provincial health crisis, it may be cost-effective to provide in-home support to those who want to age well in their communities by deploying a Mobile Seniors Wellness Network system throughout the province and enhancing the RN's assessment of feet with a portable and innovative technology tool.

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662-C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

Supplemental Protein and a Multinutrient Beverage Speed Wound Healing after Acute Sleep Restriction in Healthy Adults.

BACKGROUND: Physiologic and psychologic stress slow healing from experimental wounds by impairing immune function. OBJECTIVES: We aimed to determine whether supplemental protein and multinutrient supplementation improved wound healing markers after acute stress induced by acute sleep restriction. METHODS: In this single-blind, crossover study in generally healthy young adults (18 males/2 females; mean ± SD age: 19.7 ± 2.30 y), experimental wounds were created by removing the top layer of forearm blisters induced via suction after 48 h of 72-h sleep restriction (2-h nightly sleep), a protocol previously shown to delay wound healing. Skin barrier restoration (measured by transepidermal water loss) assessed wound healing ≤10 d postblistering, and local immune responses were evaluated by serial measurement of cytokine concentrations in fluid collected at wound sites for 48 h postblistering. Participants consumed controlled, isocaloric diets with either 0.900 g · kg-1 · d-1 protein plus placebo (PLA) or 1.50 g · kg-1 · d-1 protein plus multinutrient beverage [l-arginine: 20.0 g/d; l-glutamine: 30.0 g/d; omega-3 (n-3) fatty acids: 1.00 g/d; zinc sulfate: 24.0 mg/d; cholecalciferol: 800 IU/d; and vitamin C: 400 mg/d] (NUT) during sleep restriction and for 4 d afterwards. RESULTS: Skin barrier restoration (primary outcome) was shorter for NUT (median: 3.98 d; IQR: 1.17 d) than for PLA (median: 5.25 d; IQR: 1.05 d) (P = 0.001). Cytokines from wound fluid (secondary outcome) increased over time (main effect of time P ≤ 0.001), except IL-13 (P = 0.07); however, no effects of treatment were observed. CONCLUSIONS: Supplemental nutrition may promote wound healing after sleep restriction in healthy adults including military personnel, the latter of which also have a high incidence of wounds and infection.This trial was registered at clinicaltrials.gov as NCT03525184.

Next-generation of targeted AAVP vectors for systemic transgene delivery against cancer.

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.

Combination outreach and wellness intervention for distressed rural veterans: results of a multimethod pilot study.

We partnered with veteran-serving nonprofits in order to identify distressed rural veterans and provide them with a mental health workshop in community-based settings. Community organizations helped recruit veterans and provided space for 1-day (5-h) Acceptance and Commitment Therapy (ACT) group workshops conducted in rural locations. Qualitative interviews were conducted at 1- and 3-months post-intervention to assess acceptability. Quantitative measures were conducted at baseline, 1- and 3-months post-intervention to measure effectiveness. We successfully engaged community partners throughout every stage of the research and delivered workshops to thirty-one veterans in rural community-based locations. Veterans appreciated the structure, content, and environment of the workshops; most implemented ACT skills into their daily lives and some initiated new treatment following workshop participation. Quantitative measures showed improvements in functioning (Cohen's d ranging from .27 to .40), reintegration (Cohen's d = .45), meaning and purpose (Cohen's d = .40), and reductions in distress (Cohen's d ranging from .28 to .40) 3-months following workshop participation. Collaborating with rural veteran-serving nonprofit organizations holds promise for engaging hard-to-reach distressed veterans in mental health care.

Behavioral correlates of self-reported health status in US active duty military.

Trends and relationships between health behaviors and conditions in US active duty military and Coast Guard personnel are understudied. Self-reported data from the 2011 and 2015 Department of Defense Health Related Behaviors Surveys were analyzed to estimate associations between seven behaviors (reasons for not exercising; moderate, vigorous, and strength training exercise; alcohol intake; sleep; and smoking) and five health conditions (high blood pressure [BP], blood sugar [BG], cholesterol [CH]; overweight/obesity [OW]; or obesity [OB]). In 33,531 respondents, 14.8%, 1.7%, 13.6%, 65.5%, and 12.1% had high BP, BG, CH, OW, or OB, respectively. Respondents in 2015, versus 2011, had higher odds of BP, BG, OW, and OB. Compared to exercising as much as desired, citing a disability or injury, or work commitments as reasons for not exercising associated with higher odds of each condition. Longer sleep associated with lower odds of each condition except BG. Current and former smoking associated with higher odds of BP; former smoking also associated with higher odds of high CH and OW. Three behaviors contributing to the best predictive models of each condition resulted in associations of reasons for not exercising with all conditions; strength training for OW and OB; alcohol intake for BP and BG; sleep for BP and CH; and moderate exercise for BG. Disability and injury and time constraints limiting exercise were consistent markers of self-reported health conditions. Military-specific initiatives to promote strategies for overcoming barriers to exercising, continued emphasis on adequate sleep, and reduction of alcohol intake and smoking are warranted.

Are Playboy (and girl) Norms Behind the Relationship Problems Associated with Pornography Viewing in Men and Women?

Research has indicated that pornography viewing is related to romantic relationship problems. However, the correlations across past studies have been small. We tested a model in which playboy norm conformity (i.e. desires to have frequent sex with multiple partners) functions as a confound between pornography viewing constructs on three romantic relationship wellbeing indicators: Relationship satisfaction, relationship commitment, and infidelity proclivity. Results from men (n = 286) and women (n = 717) indicated that the significant inverse correlations between relationship satisfaction and relationship commitment with pornography viewing constructs becomes non-significant when playboy norm conformity is accounted. Further, the positive relationship between pornography viewing and infidelity proclivity also becomes non-significant in women (no initial connection between pornography viewing and infidelity proclivity was found in men). Though conformity to playboy norms was more strongly related to all romantic relationship wellbeing indicators across genders, pornography viewing frequency was still significantly inversely correlated with relationship satisfaction for women; though the effect size was small. Moderation analyses suggested that pornography viewing frequency was more strongly inversely correlated with relationship satisfaction for women than men. Cumulatively, our results suggest conformity to playboy norms is a significant confounding variable between pornography viewing and romantic relationship wellbeing.

Comparing integrative cognitive-affective therapy and guided self-help cognitive-behavioral therapy to treat binge-eating disorder using standard and naturalistic momentary outcome measures: A randomized controlled trial.

OBJECTIVE: Innovative treatments and outcome measures are needed for binge-eating disorder (BED). This randomized controlled trial compared Integrative Cognitive-Affective Therapy (ICAT-BED), an individual psychotherapy targeting momentary behavioral and emotional precipitants of binge eating, with an established cognitive-behavioral guided self-help (CBTgsh) treatment using standard and ecological momentary assessment (EMA) outcome measures. METHOD: A total of 112 participants were randomized to 17 weeks of treatment (21 sessions for ICAT-BED and 10 sessions for CBTgsh). Binge-eating frequency was assessed with the Eating Disorder Examination (EDE) as well as EMA using cell phone-based real-time, naturalistic assessment at end of treatment (EOT) and 6-month follow-up. Hypothesized maintenance mechanisms were assessed using self-report questionnaires. RESULTS: Binge-eating frequency as measured by the EDE and real-time assessment showed significant reductions at EOT and follow-up, with no significant differences between treatments. Hypothesized maintenance mechanisms, including emotion regulation, cognitive self-discrepancy, self-directed style, as well as measures of associated eating disorder psychopathology, depression, anxiety, impulsivity, and negative affect, showed similar improvement at EOT and follow-up with no differences between treatments. Abstinence rates at EOT (ICAT-BED: 57.1%; CBTgsh: 42.9%) and 6-month follow-up (ICAT-BED: 46.4%; CBTgsh: 42.9%) were not significantly different. Treatment retention was significantly higher for ICAT-BED (87.5%) than CBTgsh (71.4%). DISCUSSION: These findings suggest that ICAT-BED and CBTgsh were associated with similar improvements in binge eating, psychopathology, and putative maintenance mechanisms as measured by traditional self-report and momentary, naturalistic assessments and that these changes were generally sustained at 6-month follow-up.

Understanding Preferences for Addressing Spirituality Among Adults Seeking Outpatient Mental Health Care.

Focusing on 472 religiously heterogenous adult patients seeking psychotherapy at a university-based outpatient clinic, this brief report examined (1) these patients' preferences about clinicians appreciating their religion and/or spirituality (R/S) backgrounds (spiritually affirming) and addressing spiritual concerns in treatment (spiritually integrated) and (2) role of demographic factors and psychological functioning in predicting preferences for R/S integration. Analyses revealed that more than half of patients reported moderate or greater importance for spiritually affirming care and one-third hoped to address spiritual issues. Furthermore, these factors emerged as indicators of stronger preferences for R/S integration: female sex, racial minority status (African American, Native American), history of marriage (past and present), affiliation to organized religion (Christianity, Islam), and importance placed on R/S. In general, findings suggest that most patients seeking psychotherapy in a university-based clinic in southern Alabama might desire a spiritually affirming approach, and a smaller subset prefer an approach in which R/S is integrated into treatment.

Meropenem as an antidote for intentional valproic acid overdose.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug indicated for monotherapy and adjunctive therapy of seizures, and complex manic episodes associated with bipolar disorder [1]. While uncommon due to monitoring, VPA can cause toxicity at supratherapeutic levels [1, 2]. Traditional treatment for VPA toxicity is primarily supportive care, however activated charcoal, l-carnitine, and hemodialysis have been successful in removing free VPA [2]. An interaction between carbapenem antibiotics and VPA is well-established and listed in respective package inserts as a combination to be avoided due to decreased VPA efficacy [1, 3]. Recent literature suggests co-administration of meropenem with VPA reduces mean plasma VPA levels by 50-80% [4, 6]. This case report describes the successful use of carbapenems to intentionally lower toxic VPA levels in a 42 year old female that presented to the emergency department with VPA toxicity from an overdose with divalproex sodium.

Sleep restriction and cognitive load affect performance on a simulated marksmanship task.

Sleep restriction degrades cognitive and motor performance, which can adversely impact job performance and increase the risk of accidents. Military personnel are prone to operating under sleep restriction, and previous work suggests that military marksmanship may be negatively affected under such conditions. Results of these studies, however, are mixed and have often incorporated additional stressors (e.g. energy restriction) beyond sleep restriction. Moreover, few studies have investigated how the degree of difficulty of a marksmanship task impacts performance following sleep restriction. The purpose of the current experiment was to study the effects of sleep restriction on marksmanship while minimizing the potential influence of other forms of stress. A friend-foe discrimination challenge with greater or lesser degrees of complexity (high versus low load) was used as the primary marksmanship task. Active duty Soldiers were recruited, and allowed 2 h of sleep every 24 h over a 72-h testing period. Marksmanship tasks, cognitive assessment metrics and the NASA-Task Load Index were administered daily. Results indicated that reaction times to shoot foe targets and signal friendly targets slowed over time. In addition, the ability to correctly discriminate between friend and foe targets significantly decreased in the high-cognitive-load condition over time despite shot accuracy remaining stable. The NASA-Task Load Index revealed that, although marksmanship performance degraded, participants believed their performance did not change over time. These results further characterize the consequences of sleep restriction on marksmanship performance and the perception of performance, and reinforce the importance of adequate sleep among service members when feasible.

Glycaemic regulation, appetite and ex vivo oxidative stress in young adults following consumption of high-carbohydrate cereal bars fortified with polyphenol-rich berries.

Consumption of certain berries appears to slow postprandial glucose absorption, attributable to polyphenols, which may benefit exercise and cognition, reduce appetite and/or oxidative stress. This randomised, crossover, placebo-controlled study determined whether polyphenol-rich fruits added to carbohydrate-based foods produce a dose-dependent moderation of postprandial glycaemic, glucoregulatory hormone, appetite and ex vivo oxidative stress responses. Twenty participants (eighteen males/two females; 24 (sd 5) years; BMI: 27 (sd 3) kg/m2) consumed one of five cereal bars (approximately 88 % carbohydrate) containing no fruit ingredients (reference), freeze-dried black raspberries (10 or 20 % total weight; LOW-Rasp and HIGH-Rasp, respectively) and cranberry extract (0·5 or 1 % total weight; LOW-Cran and HIGH-Cran), on trials separated by ≥5 d. Postprandial peak/nadir from baseline (Δmax) and incremental postprandial AUC over 60 and 180 min for glucose and other biochemistries were measured to examine the dose-dependent effects. Glucose AUC0-180 min trended towards being higher (43 %) after HIGH-Rasp v. LOW-Rasp (P=0·06), with no glucose differences between the raspberry and reference bars. Relative to reference, HIGH-Rasp resulted in a 17 % lower Δmax insulin, 3 % lower C-peptide (AUC0-60 min and 3 % lower glucose-dependent insulinotropic polypeptide (AUC0-180 min) P<0·05. No treatment effects were observed for the cranberry bars regarding glucose and glucoregulatory hormones, nor were there any treatment effects for either berry type regarding ex vivo oxidation, appetite-mediating hormones or appetite. Fortification with freeze-dried black raspberries (approximately 25 g, containing 1·2 g of polyphenols) seems to slightly improve the glucoregulatory hormone and glycaemic responses to a high-carbohydrate food item in young adults but did not affect appetite or oxidative stress responses at doses or with methods studied herein.

Two days of calorie deprivation impairs high level cognitive processes, mood, and self-reported exertion during aerobic exercise: A randomized double-blind, placebo-controlled study.

Military personnel and emergency responders perform cognitively-demanding tasks during periods of sustained physical exertion and limited caloric intake. Cognitive function is preserved during short-term caloric restriction, but it is unclear if preservation extends to combined caloric restriction and physical exertion. According to the "reticular-activating hypofrontality" model, vigorous exertion impairs prefrontal cortex activity and associated functions. This double-blind, placebo-controlled, crossover study examined cognitive function during sustained exertion while volunteers were calorically-deprived. Twenty-three volunteers were calorie-depleted for two days on one occasion and fully-fed on another. They completed intermittent bouts of exercise at 40-65% VO2peak while prefrontal cortex-dependent tasks of cognitive control, mood, and perceived exertion were assessed. Calorie deprivation impaired accuracy on the task-switching task of set-shifting (p < .01) and decreased sensitivity on the go/no-go task of response inhibition (p < .05). Calorie deprivation did not affect risk taking on the Rogers risk task. During exercise, calorie deprivation, particularly on day 2, increased perceived exertion (p < .05) and impaired mood states of tension, depression, anger, vigor, fatigue, and confusion (all p < .01). Physical exertion during severe calorie deprivation impairs cognitive control, mood, and self-rated exertion. Reallocation of cerebral metabolic resources from the prefrontal cortex to structures supporting movement may explain these deficits.

Patterns of Treatment Disengagement and Personality Traits Associated With Posttraumatic Stress Disorder in Recent-Era U.S. Veterans Receiving Cognitive Processing Therapy.

Low treatment engagement is a barrier to implementation of empirically supported treatments for posttraumatic stress disorder (PTSD) among veterans. Understanding personality traits that predict dropout may help focus attempts to improve engagement. The current study included 90 veterans who served in recent conflicts in Iraq and/or Afghanistan and participated in a trial of cognitive processing therapy for PTSD. Goals were to characterize (a) personality correlates of PTSD, (b) patterns of engagement (i.e., attendance and homework completion), and (c) personality correlates of reduced engagement. Higher levels of PTSD symptoms were associated with a range of characteristics, including affective lability, r = .44 p < .001; anxiety, r = .38, p < .001; identity problems, r = .57, p < .001; intimacy problems, r = .34, p = .001; low affiliation, r = .33, p = .002; oppositionality, r = .36, p = .001; restricted expression, r = .35, p = .001; and suspiciousness, r = .50, p < .001. Notably, veterans with worse PTSD symptoms endorsed more cognitive dysregulation, r = .40, p < .001; and less insecure attachment, r = .14, p = .190, than expected. Only 52.2% of veterans completed the 12-session course of treatment and 31.0% of participants completed fewer than six sessions. Personality traits did not predict attendance or homework completion. Disengagement continues to be a significant issue in trauma-focused treatment for veterans with PTSD. Understanding veteran-level factors, such as personality traits, may be useful considerations for future research seeking to understand and improve engagement.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Patrones de desconexión del tratamiento y rasgos de personalidad asociados con el trastorno de estrés postraumático en Recientes Veteranos Estadounidenses que reciben terapia de procesamiento cognitivo DESCONEXIÓN DEL TRATAMIENTO Y PERSONALIDAD EN VETERANOS El bajo compromiso con el tratamiento es una barrera para la implementación de tratamientos con apoyo empírico para el trastorno de estrés postraumático (TEPT) entre los veteranos. Comprender los rasgos de personalidad que predicen el abandono puede ayudar a enfocar los intentos de mejorar el compromiso con el tratamiento en esta población. El estudio actual incluyó una muestra de 90 veteranos que habían servido en conflictos recientes en Irak y / o Afganistán y que estaban inscritos en el ensayo de terapia de procesamiento cognitivo para el TEPT. Los objetivos principales del estudio fueron (a) describir los correlatos de la personalidad y el TEPT de los veteranos, (b) caracterizar los patrones de compromiso (es decir, la asistencia y la finalización de la tarea), y (c) identificar los rasgos de personalidad asociados con el poco compromiso . Los niveles más altos de síntomas de TEPT se asociaron con una amplia gama de problemas de personalidad, incluida la labilidad afectiva, ansiedad, desregulación cognitiva, problemas de identidad, problemas de intimidad, baja afiliación, oposicionismo, expresión restringida y desconfianza. En particular, los veteranos con niveles más altos de síntomas de TEPT mostraron más desregulación cognitiva y menos problemas con el apego inseguro de lo esperado. Solo el 52.2% de los veteranos completaron el curso de tratamiento de 12 sesiones. Casi un tercio de los participantes (31.0%) completó menos de seis sesiones. Los rasgos de personalidad no fueron predictivos de la asistencia o la finalización de la tarea en el presente estudio. El abandono del tratamiento con apoyo empírico sigue siendo un problema importante en el tratamiento centrado en el trauma para los veteranos con TEPT. Comprender los factores a nivel de veteranos, como los rasgos de personalidad, puede ser una consideración útil para futuras investigaciones que buscan comprender y mejorar el compromiso con el tratamiento.

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas.

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.

Outbreak of diarrhetic shellfish poisoning associated with consumption of mussels, United Kingdom, May to June 2019.

We report on six cases of diarrhetic shellfish poisoning following consumption of mussels harvested in the United Kingdom. Dinophysis spp. in the water column was found to have increased rapidly at the production site resulting in high levels of okadaic acid-group lipophilic toxins in the flesh of consumed mussels. Clinicians and public health professionals should remain aware of algal-derived toxins being a potential cause of illness following seafood consumption.

Self-reported health behaviors, including sleep, correlate with doctor-informed medical conditions: data from the 2011 Health Related Behaviors Survey of U.S. Active Duty Military Personnel.

BACKGROUND: Health behaviors and cardiometabolic disease risk factors may differ between military and civilian populations; therefore, in U.S. active duty military personnel, we assessed relationships between demographic characteristics, self-reported health behaviors, and doctor-informed medical conditions. METHODS: Data were self-reported by 27,034 active duty military and Coast Guard personnel who responded to the 2011 Department of Defense Health Related Behaviors Survey. Multivariate linear and logistic regressions were used to estimate cross-sectional associations between (1) demographic characteristics (age, sex, service branch, marital status, children, race/ethnicity, pay grade) and self-reported behaviors (exercise, diet, smoking, alcohol, sleep); (2) demographic characteristics and doctor-informed medical conditions (hypertension, hypercholesterolemia, low high density lipoprotein (HDL) cholesterol, hyperglycemia) and overweight/obesity; and (3) behaviors and doctor-informed medical conditions. RESULTS: Among respondents (age 29.9 ± 0.1 years, 14.7% female), females reported higher intake than men of fruit, vegetables, and dairy; those with higher education reported higher intakes of whole grains; those currently married and/or residing with children reported higher intake of starches. Older age and female sex were associated with higher odds (ORs 1.25 to 12.54 versus the youngest age group) of overweight/obesity. Older age and female sex were also associated with lower odds (ORs 0.29 to 0.65 versus male sex) of doctor-informed medical conditions, except for blood glucose, for which females had higher odds. Those currently married had higher odds of high cholesterol and overweight/obesity, and separated/divorced/widowed respondents had higher odds of high blood pressure and high cholesterol. Short sleep duration (< 5 versus 7-8 h/night) was associated with higher odds (ORs 1.36to 2.22) of any given doctor-informed medical condition. Strength training was associated with lower probability of high cholesterol, high triglycerides, and low HDL, and higher probability of overweight/obesity. Dietary factors were variably associated with doctor-informed medical conditions and overweight/obesity. CONCLUSIONS: This study observed pronounced associations between health behaviors-especially sleep-and medical conditions, thus adding to evidence that sleep is a critical, potentially modifiable behavior within this population. When possible, adequate sleep should continue to be promoted as an important part of overall health and wellness throughout the military community.

Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.

Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.