Freeing the performer's mind: A network analysis of music performance anxiety, negative affect, self-consciousness and mindfulness among music performers.

Music performance anxiety (MPA) is a common damaging phenomenon in musicians' careers. Mindfulness stands as a promising construct to prevent MPA. However, the relationships between mindfulness and MPA are scarcely explored, alongside other relevant attention-based (e.g., self-consciousness) or emotion-based constructs (e.g., negative affect). This study explores the relationships between these constructs. A sample of 151 musicians was assessed to explore the relationships between these constructs. Self-reports of mindfulness, MPA, negative affect, and self-consciousness were applied. We implemented network analysis following a general (second-order) and specific (first-order) framework. Networks showed dispositional mindfulness as negatively associated with negative affect and MPA in both general and facet levels, while mindfulness in past performances was only negatively associated with negative affect. MPA was positively associated with negative affect and self-consciousness. Mindfulness displayed light or no associations with self-consciousness. Therefore, mindfulness seems to be a relevant construct toward MPA. We propose a preliminary model to improve mindfulness research and interventions applied to music performers. We also outline limitations and future directions.

Passionate healthcare workers in demanding intensive care units: its relationship with daily exhaustion, secondary traumatic stress, empathy, and self-compassion.

This study focuses on Intensive Care Units (ICU) and aims to test whether daily job demands are related to daily emotional exhaustion and secondary traumatic stress (STS) after work through the experience of passion at work and whether personal resources in ICU, such as empathy and self-compassion, moderate these relationships. A diary study was designed to assess day-level job demands, passion, empathy, self-compassion at work; and day-level emotional exhaustion and STS after work. The sample was 97 healthcare workers from ICU from different Spanish hospitals being selected by the snowball technique. This sample was assessed 5 days x two moments per day through a diary questionnaire. The multilevel analysis showed a negative mediational effect of harmonious passion between daily job demands and both emotional exhaustion and STS. Also, in predicting emotional exhaustion, a moderator effect of empathy on harmonious passion was found, as well as a moderator effect of self-compassion on obsessive passion. In predicting STS, a direct positive effect was found in empathy. Our findings highlight the vocational work of these healthcare workers, considering job demands as challenging and enhancing their harmonious passion to overcome the drawbacks. Moreover, empathy revealed to have a negative effect whereas self-compassion the contrary. Thus, increase the awareness on these personal resources and how to train them could be considered as valuable preventative measures.

Foaming of PLA Composites by Supercritical Fluid-Assisted Processes: A Review.

Polylactic acid (PLA) is a well-known and commercially available biopolymer that can be produced from different sources. Its different characteristics generated a great deal of interest in various industrial fields. Besides, its use as a polymer matrix for foam production has increased in recent years. With the rise of technologies that seek to reduce the negative environmental impact of processes, chemical foaming agents are being substituted by physical agents, primarily supercritical fluids (SCFs). Currently, the mass production of low-density PLA foams with a uniform cell morphology using SCFs as blowing agents is a challenge. This is mainly due to the low melt strength of PLA and its slow crystallization kinetics. Among the different options to improve the PLA characteristics, compounding it with different types of fillers has great potential. This strategy does not only have foaming advantages, but can also improve the performances of the final composites, regardless of the implemented foaming process, i.e., batch, injection molding, and extrusion. In addition, the operating conditions and the characteristics of the fillers, such as their size, shape factor, and surface chemistry, play an important role in the final foam morphology. This article proposes a critical review on the different SCF-assisted processes and effects of operating conditions and fillers on foaming of PLA composites.

TREATMENT PATTERNS AND 2-YEAR VISION OUTCOMES WITH BEVACIZUMAB IN DIABETIC MACULAR EDEMA: An Analysis From a Large U.S. Integrated Health Care System.

PURPOSE: To assess health care utilization and vision outcomes over 2 years in patients receiving bevacizumab treatment in clinical practice for diabetic macular edema. METHODS: Patients with newly diagnosed diabetic macular edema who received an intravitreal bevacizumab injection within 12 months of initial diagnosis were identified from Kaiser Permanente's 350,000 patients with diabetes mellitus treated between 2008 and 2013. Snellen best-corrected visual acuity (BCVA), number of intravitreal injections, and patient characteristics were abstracted from the electronic record. The main outcome measure was change in BCVA. RESULTS: Three hundred and nine patients met the inclusion criteria and had 2 years of follow-up after their first bevacizumab injection. These patients had a mean of 3.1 injections (range, 1-17) during the 2-year follow-up. Mean BCVA improvement was 5.4 letters at 12 months and 5.3 letters at 24 months. Only 29.8% of patients demonstrated ≥3 lines of vision improvement from baseline, whereas 12.3% had ≥3 lines of vision loss from baseline at 24 months. CONCLUSION: This is the largest U.S. clinical practice-based study of bevacizumab use in diabetic macular edema. Consistent with national studies, the frequency of injection was low. Average BCVA improvement was lower than in anti-vascular endothelial growth factor trials. Significant BCVA improvement was achieved in approximately 30% of patients with newly diagnosed diabetic macular edema.

Exposure to Gastric Acid-Suppression Therapy Is Associated With Health Care- and Community-Associated Clostridium difficile Infection in Children.

OBJECTIVE: The aim of the study was to determine whether gastric acid-suppression therapy is associated with Clostridium difficile infection (CDI) in both inpatient and outpatient pediatric populations. METHODS: We conducted a retrospective case-control study at a 200-bed academic pediatric hospital and associated outpatient clinics during 2005-2010. We defined cases as children 1 to 18 years of age with a first positive test for C difficile toxin A/B, and matched each case to 2 controls without C difficile. We conducted chart review to elicit selected comorbidities and exposure to gastric acid-suppression therapy and antibiotics in the preceding 3 months of the infection or encounter date. We used bivariate and multivariable logistic regression to evaluate the association between antacid use and CDI, controlling for potential confounders. RESULTS: We identified 138 children with health care- or community-associated CDIs and 276 controls. The use of any acid suppression therapy was more common in cases compared with controls (34% vs 20%, P = 0.002). When adjusted for demographic variables and comorbidities, gastric acid-suppression therapy remained significantly associated with CDI (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.0-3.1). Antibiotic use (aOR 1.7, 95% CI 1.1-2.7) and immunosuppressed state were also associated with CDI in our adjusted model (aOR 2.5, 95% CI 1.2-5.2). CONCLUSIONS: Gastric acid-suppression therapy was associated with both health care- and community-associated CDIs in children. Larger pediatric studies are necessary to determine the role of proton pump inhibitors specifically in causing CDI in children.

Improving public health through state health improvement planning: a framework for action.

BACKGROUND: State health improvement plans (SHIPs) identify priorities for making the greatest impacts on health promotion and disease prevention, specific to the needs of state populations. Both SHIPs and the state health assessments on which they are based are prerequisites for Public Health Accreditation Board national accreditation. OBJECTIVE: To identify and evaluate existing SHIPs to develop guidance to support health departments in the state health improvement planning process. DESIGN: In 2010, the Association of State and Territorial Health Officials (ASTHO) conducted a comprehensive search for existing SHIPs. A systematic evaluation of existing SHIPS was accomplished by means of primary source document review using a standardized data collection form. Using data derived from these SHIPs and guidance from a workgroup of practitioners, ASTHO developed the ASTHO SHIP Guidance and Resources (SHIP Guidance) Framework. RESULTS: The search yielded 25 states (49%) having a SHIP completed or in progress. Fifteen states (29%) had no SHIP but had a Healthy People plan, and 10 states (20%) had no SHIP or Healthy People plan. No information was available for 1 state. Findings were reviewed, evaluated, and incorporated into the SHIP Guidance. The SHIP Guidance provides a framework for the implementation, monitoring, and evaluation of a SHIP process using 12 key steps. CONCLUSIONS: As public health/health care integration and accreditation readiness activity grows, multisector engagement through a SHIP will continue to be a priority for state public health and improving health outcomes. The SHIP Guidance provides a systematic, flexible approach for states conducting or updating state health assessments and SHIPs.

Sudden-Onset Back Pain and Intermittent Dyspnea While Eating: A Case of Pediatric Achalasia.

A 14-year-old girl with a history of asthma was hospitalized because of sudden-onset back pain around her thoracic region that spread to her chest and abdomen. She had been experiencing dysphagia and breathing difficulties for two years, especially after overeating, which often resulted in vomiting undigested food. CT imaging revealed a severely dilated esophagus narrowing at the gastroesophageal junction, suggestive of type 1 achalasia. Further testing confirmed the diagnosis, with an esophageal manometry showing a lack of esophageal contractions and sphincter relaxation. She then underwent a laparoscopic Heller myotomy with relief to her symptoms. This case underscores the rarity of pediatric-onset achalasia with significant esophageal dilation and secondary airway compression, presenting with unusual musculoskeletal and respiratory symptoms. Timely diagnosis and treatment are crucial to prevent worsening and complications.

Studying daily fluctuations of emotional effort among nurses of intensive care units: the establishment of latent profiles and its relationship with daily secondary traumatic stress and vitality.

Introduction: Nursing professionals working in Intensive Care Units (ICU) face significant challenges that can result in secondary traumatic stress (STS). These challenges stem from witnessing patients' suffering and managing difficult tasks (i.e. communication with patients' relatives). Furthermore, these professionals encounter emotional demands, such as emotional effort, which is the dissonance between the emotion felt and the emotion that should be expressed to meet work expectations. Consequently, we aimed to investigate whether different profiles exist concerning nurses' levels of emotional effort over a five-day period and whether these profiles are related to daily STS and vitality. Methods: The sample comprised 44 nursing professionals from ICUs in Spanish hospitals. They were assessed daily, using a package of questionnaires twice per day for five working days: a) immediately after their shift and b) at a later time after working. Results: The findings revealed three distinct profiles based on emotional effort levels: high (Profile 1), moderate (Profile 2), and low (Profile 3). These profiles were found to be negative predictors for both daily shattered assumptions and symptomatology. Discussion: This study underscores the importance of assessing daily emotional demands in an ICU setting. Such assessments are crucial for establishing preventive measures to help nursing professionals manage lower-level emotional demands.

Rationale and design of the KP ENRICH trial: A food is medicine intervention in low-income high-risk adults with diabetes within Kaiser Permanente.

BACKGROUND: Food insecurity is associated with poor glycemic control and increased risk for diabetes-related complications. The clinical benefit of addressing these challenges through a medically supportive grocery prescription (GRx) program in patients with type 2 diabetes mellitus (T2D) remains unclear. We report the aims and design of a randomized clinical trial to evaluate the effectiveness of a 6-month GRx intervention on hemoglobin A1c (HbA1c) levels among low-income adults with T2D. METHODS: The Kaiser Permanente Evaluating Nutritional Interventions in Food-Insecure High-Risk Adults (KP ENRICH) Study is a pragmatic randomized trial enrolling 1100 participants within Kaiser Permanente Northern California and Southern California, two integrated health care delivery systems serving >9 million members. Medicaid-insured adults with T2D and baseline HbA1c ≥7.5% will be randomized at a 1:1 ratio to either GRx, delivered as $100 per month for select items from among a curated list of healthful food groups in an online grocery ordering and home-delivery platform along with biweekly digital nutrition educational materials, or control, consisting of free membership and deliveries from the online grocery platform but without curated food groups or purchasing dollars. The primary outcome is 6-month change in HbA1c. Secondary outcomes include 12-month change in HbA1c, and 6- and 12-month change in medical resource utilization, food security, nutrition security, dietary habits, diabetes-related quality of life, and dietary self-efficacy. CONCLUSIONS: The results of this large randomized clinical trial of GRx will help inform future policy and health system-based initiatives to improve food and nutrition security, disease management, and health equity among patients with T2D.

Personalizing Digital Health: Adapting Health Technology Systems to Meet the Needs of Different Older Populations.

The ageing of the population is growing significantly and will challenge healthcare systems. Chronic diseases in the older population require a change in service delivery, and new technologies can be a key element in ensuring the viability and sustainability of these systems. However, the generation gap and the physical and cognitive decline commonly associated with the older generation are barriers to the transition to these models of care. Despite this, there has been a trend towards digital healthcare, which has many potential benefits for the older population. Numerous studies have assessed the acceptability of new technologies for older people in healthcare. These studies highlight the importance of perceived usefulness, compatibility, ease of use and personalisation of the technology. Personalisation is necessary to ensure that the system is useful for users, and different characteristics such as country of origin, gender, age, or comfort with the technology should be taken into account. A person-centred approach in the development of new health technology systems is essential to ensure that applications can be better tailored to the needs of different ageing populations. Many organisations have dedicated time and resources to ensure a person-centred approach in the development of new health technology systems, and putting the individual first is the best way forward in digital health. This article presents the work carried out in this regard in the framework of the European TeNDER project together with an analysis of the results obtained in terms of satisfaction, usefulness, and usability from end-users. The dynamic and continuous process carried out throughout the TeNDER project translates the needs reported by users, as far as personalisation of interactions is concerned. All end-users held a positive opinion about the usability and usefulness of the system.

Polymer Supercritical CO2 Foaming under Peculiar Conditions: Laser and Ultrasound Implementation.

The two-step batch foaming process of solid-state assisted by supercritical CO2 is a versatile technique for the foaming of polymers. In this work, it was assisted by an out-of-autoclave technology: either using lasers or ultrasound (US). Laser-aided foaming was only tested in the preliminary experiments; most of the work involved US. Foaming was carried out on bulk thick samples (PMMA). The effect of ultrasound on the cellular morphology was a function of the foaming temperature. Thanks to US, cell size was slightly decreased, cell density was increased, and interestingly, thermal conductivity was shown to decrease. The effect on the porosity was more remarkable at high temperatures. Both techniques provided micro porosity. This first investigation of these two potential methods for the assistance of supercritical CO2 batch foaming opens the door to new investigations. The different properties of the ultrasound method and its effects will be studied in an upcoming publication.

Amino acid metabolism in primary bone sarcomas.

Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care.

Factors Affecting Compliance with Diabetic Retinopathy Screening: A Qualitative Study Comparing English and Spanish Speakers.

Purpose: The purpose of this study was to understand individual-, social-, and system-level factors that affect compliance with recommended diabetic retinopathy (DR)-evaluations, and how these factors vary between English and Spanish speakers. Patients and Methods: We conducted a qualitative study using semi-structured interviews. Study subjects included Kaiser Permanente Southern California members with type II diabetes mellitus at least aged 26 years who spoke English or Spanish. Patients were divided into groups based on their adherence with DR evaluations. Our main outcome measure was the major themes expressed by patients that explained their compliance with DR evaluation. Results: Fifty-one participants were enrolled: 30 English speakers (11 nonadherent, 19 adherent) and 21 Spanish speakers (8 nonadherent, 13 adherent). Adherent patients were more likely to have had experience with diabetes and identify as being responsible for their own care. Substantially more non-adherent patients suggested that beliefs and attitudes were the reasons people missed retinopathy appointments. More English-speaking participants tended to be self-directed in managing their healthcare, whereas more Spanish speakers relied on others for help. English speakers also noted better relationships with their physicians. Spanish speakers outlined problems with insurance coverage and costs as barriers. Conclusion: These data suggest two specific intervention strategies that eye care providers could implement to improve adherence with diabetic retinopathy screening and follow up: incorporating a person with DR-related visual loss into the team of staff delivering diabetes support programs and communication campaigns including specific messaging to address fears related to vision loss.

Racial/Ethnic Disparities in Parent Activation: Implications for Developing Interventions Addressing Early Childhood Obesity.

OBJECTIVE: Examine racial/ethnic differences in parent activation and associations with child obesity risk behaviors in low-income families. METHODS: Cross-sectional survey study of 300 low-income Black, Latinx, and White parents of patients aged 2 to 5 years receiving primary care within 2 health care systems (Systems 1 & 2). In-person and phone surveys were conducted. Parent activation, defined as parents' knowledge, confidence, and willingness to act concerning their child's health, was measured using the standardized 13-item Parent Patient Activation Measure (P-PAM). Differences in parent activation by race/ethnicity were assessed using analysis of variance. Multivariate regression analyses were used to test associations between parent activation and child obesity risk behaviors. RESULTS: In pooled unadjusted analyses, Latinx parents had significantly lower activation compared to Black parents (P = .023), but these differences were no longer statistically significant after adjusting for other sociodemographic characteristics (P = .06). Higher activation was associated with slightly greater odds of consuming ≥ 5 daily servings of fruits and vegetables for System 2 only (odds ratio: 1.04, 95% confidence interval: 1.01, 1.07). Associations between parental activation and child screen time or physical activity were not significant. CONCLUSIONS: Findings highlight potential measurement limitations of the P-PAM including the inability of the measure to capture barriers to health system navigation and cultural and linguistic considerations. Further attention to the nuanced interplay between parental activation and contextual and sociodemographic risk factors (eg, food availability, immigrant status, economic opportunity, language proficiency) should be considered in the development of early childhood obesity interventions in primary care settings.

Sex-specific effects of psychedelics on prepulse inhibition of startle in 129S6/SvEv mice.

BACKGROUND: Prepulse inhibition (PPI) of startle is a sensorimotor gating phenomenon perturbed in a variety of neuropsychiatric conditions. Psychedelics disrupt PPI in rats and humans, but their effects and involvement of the serotonin 5-HT2A receptor (5-HT2AR) in mice remain unexplored. METHODS: We tested the effect of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.5 mg/kg, i.p.) on startle amplitude and %PPI in response to acoustic stimuli under up to four different experimental conditions that included changes in background and stimulus intensity, prepulse and pulse duration, and interstimulus interval in male and female 129S6/SvEv mice. We also evaluated the effect of the 5-HT2AR antagonist M100,907 (1 mg/kg, i.p.) on DOI-induced startle amplitude and %PPI, as well as the effect of the psychedelic LSD (0.24 mg/kg, i.p.) and the dopamine agonists apomorphine (5 mg/kg, s.c.) and SKF-82,958 (0.5 mg/kg, i.p.) in male 129S6/SvEv mice. RESULTS: DOI altered startle amplitude with either pulse alone or prepulse + pulse presentations in all PPI conditions, and increased %PPI in three out of four PPI conditions in male mice - an effect that was prevented by M100,907. In female mice, DOI increased %PPI without affecting startle amplitude. %PPI was positively correlated with startle amplitude in males while being negatively correlated in female mice. In male mice, LSD also increased %PPI, although it did not affect startle amplitude, whereas apomorphine and SKF-82,958 induced decreases in %PPI. CONCLUSION: Our findings highlight a distinct effect of the psychedelic DOI on PPI in 129S6/SvEv mice, suggesting 5-HT2AR-dependent PPI improvement in a paradigm-dependent and sex-dependent manner.

Satisfied as professionals, but also exhausted and worried!!: The role of job demands, resources and emotional experiences of Spanish nursing home workers during the COVID-19 pandemic.

Nursing home workers have been exposed to great physical and mental burdens during the COVID-19 pandemic. Although this has generated high levels of exhaustion, it may also have contributed to feelings of professional satisfaction. The objective of this study was to explore the levels of satisfaction among nursing home workers during the COVID-19 pandemic, as well as the role of job demands, resources and emotional experiences in explaining their levels of satisfaction. This cross-sectional study was conducted in Spain between March and May 2020. Three hundred and thirty-five nursing home workers participated. A quantitative analysis was conducted, as was a content analysis of the responses to an open-ended question about the respondents' perceptions of job demands and resources during the crisis. The results showed that workers had very high levels of satisfaction. Social pressure from work, contact with death and suffering, and emotional exhaustion were negatively associated with satisfaction. Moreover, under conditions of extensive contact with suffering people and great fear of contagion, social support at work was shown to promote professional satisfaction. In conclusion, nursing home workers in Spain experienced high rates of satisfaction during the COVID-19 crisis despite the high job demands, lack of job resources, fear of contagion and exhaustion. The main practical implication of this study is the importance of ensuring optimal working conditions in the nursing home sector in order to guarantee professional satisfaction, prevent burnout, reduce turnover and promote post-crisis resilience.

EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma.

PURPOSE: Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity. EXPERIMENTAL DESIGN: Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays. RESULTS: We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis. CONCLUSIONS: Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13. See related commentary by Weiss and Bailey, p. 4360.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice.

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR-/-) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR-/- littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR-/- animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.

Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.

Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME.