STAT1-Deficient HPV E6/E7-Associated Cancers Maintain Host Immunocompetency against Therapeutic Intervention.

Human papillomavirus (HPV) remains a global health concern because it contributes to the initiation of various HPV-associated cancers such as anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancer. In HPV-associated cancers, oncogenesis begins with an HPV infection, which is linked to the activation of the Janus protein tyrosine kinase (JAK)/STAT signaling pathway. Various STAT signaling pathways, such as STAT3 activation, have been well documented for their tumorigenic role, yet the role of STAT1 in tumor formation remains unclear. In the current study, STAT1-/- mice were used to investigate the role of STAT1 in the tumorigenesis of a spontaneous HPV E6/E7-expressing oral tumor model. Subsequently, our candidate HPV DNA vaccine CRT/E7 was administered to determine whether the STAT1-/- host preserves a therapeutic-responsive tumor microenvironment. The results indicated that STAT1-/- induces robust tumorigenesis, yet a controlled tumor response was attained upon CRT/E7 vaccination. Characterizing this treatment effect, immunological analysis found a higher percentage of circulating CD4+ and CD8+ T cells and tumor-specific cytotoxic T cells. In addition, a reduction in exhaustive lymphocyte activity was observed. Further analysis of a whole-cell tumor challenge affirmed these findings, as spontaneous tumor growth was more rapid in STAT1-/- mice. In conclusion, STAT1 deletion accelerates tumorigenesis, but STAT1-/- mice maintains immunocompetency in CRT/E7 treatments.

Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine.

BACKGROUND: Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier. METHOD: Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7. RESULTS: Due to OMV's intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells. CONCLUSION: The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.

Industry Perceptions and Experiences with the Access Consortium New Active Substance Work-Sharing Initiative (NASWSI): Survey Results and Recommendations.

The Access Consortium New Active Substance Work-Sharing Initiative, or "Access" for simplicity, allows regulatory authorities (RAs) of the Access Consortium countries to jointly review applications for the registration of new active substances or for new indications. Using a survey developed by the pharmaceutical industry trade associations of the five Access Consortium countries-Australia, Canada, Singapore, Switzerland, and the United Kingdom (UK)-this study gathered insights into the perceptions and experiences of the Access pathway held by affiliates of pharmaceutical companies. Understanding industry perceptions of Access is important for the success of the initiative, as participation is voluntary. Findings indicate that affiliates who participated in Access had mostly positive experiences with this pathway; most affiliates were satisfied with their interactions with the Access RAs and appeared willing to continue to participate in the initiative. Affiliates' reasons for not having yet participated in Access included a lack of opportunity to do so and perceived barriers, such as the Access pathway being too complicated to manage. Recommendations to improve Access cover six key areas: ensure predictability, increase guidance and transparency, streamline processes, maintain flexibility, increase harmonization, and advance RA-industry cooperation. This study should facilitate informed discussions among relevant stakeholders on how to improve Access to maximize efficiencies, accelerate approvals, and improve patient access to innovative medicines.

A Learning Assessment to Increase Diversity in Academic Health Sciences.

Importance: Strategies and innovations to advance racial and ethnic equity in recruitment, promotion, and retention at academic health science institutions are needed. Objective: This learning assessment aims to isolate evidence-based strategies to advance racial equity in the academic health sciences, which have implications for policy and institution-level interventions. Evidence Review: This learning assessment used a mixed-methods approach, including a quantitative survey, qualitative in-depth interviews, and a scoping literature review. Survey respondents were recruited from outreach lists that included researchers working with racial and ethnic minoritized populations. In-depth interviews were conducted among 60 university administrators, faculty/staff, scholars, students, and individuals affiliated with governmental, nongovernmental, and identity-based professional associations. A search of the literature in PsycINFO, MEDLINE, ERIC, Education Source, Academic Search Ultimate, and CINAHL was conducted for the scoping review. The scoping review included 366 primary articles of studies evaluating strategies to advance racial and ethnic equity at academic health science institutions. Findings: The survey yielded analyzable results from 328 individuals, including faculty, students, administrators, or staff, and individuals not currently employed at or enrolled full time at a university or college. The interviews included 60 participants with a mean (SD) age of 49.3 (16.5) years, and 39 (65%) were female. The scoping review included 366 primary research articles that met inclusion criteria for analysis. Data were analyzed individually across the survey, interviews, and scoping review, and findings were triangulated. While each of the 3 assessments yielded unique findings, 13 common themes emerged across all project components. Results revealed strategies implemented and evaluated successfully, as well as challenges and barriers to advancing equity in the academic health sciences. Conclusions and Relevance: In this study, 13 meaningful strategies emerged across the survey, in-depth interviews, and scoping review. Through triangulation of findings, recommendations of actionable steps were made.

Salmonella immunotherapy engineered with highly efficient tumor antigen coating establishes antigen-specific CD8+ T cell immunity and increases in antitumor efficacy with type I interferon combination therapy.

Bacteria-based cancer therapy employs various strategies to combat tumors, one of which is delivering tumor-associated antigen (TAA) to generate specific immunity. Here, we utilized a poly-arginine extended HPV E7 antigen (9RE7) for attachment on Salmonella SL7207 outer membrane to synthesize the bacterial vaccine Salmonella-9RE7 (Sal-9RE7), which yielded a significant improvement in the amount of antigen presentation compared to the previous lysine-extended antigen coating strategy. In TC-1 tumor mouse models, Sal-9RE7 monotherapy decreased tumor growth by inducing E7 antigen-specific immunity. In addition, pairing Sal-9RE7 with adjuvant Albumin-IFNß (Alb-IFNß), a protein cytokine fusion, the combination significantly increased the antitumor efficacy and enhanced immunogenicity in the tumor microenvironment (TME). Our study made a significant contribution to personalized bacterial immunotherapy via TAA delivery and demonstrated the advantage of combination therapy.

FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors.

BACKGROUND: Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells. METHODS: Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells. RESULTS: CD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells. CONCLUSIONS: These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

Comprehensive Profiling of Secreted Factors in the Cerebrospinal Fluid of Moyamoya Disease Patients.

Moyamoya disease (MMD) is characterized by progressive occlusion of the intracranial internal carotid arteries, leading to ischemic and hemorrhagic events. Significant clinical differences exist between ischemic and hemorrhagic MMD. To understand the molecular profiles in the cerebrospinal fluid (CSF) of MMD patients, we investigated 62 secreted factors in both MMD subtypes (ischemic and hemorrhagic) and examined their relationship with preoperative perfusion status, the extent of postoperative angiographic revascularization, and functional outcomes. Intraoperative CSF was collected from 32 control and 71 MMD patients (37 ischemic and 34 hemorrhagic). Multiplex Luminex assay analysis showed that 41 molecules were significantly elevated in both MMD subtypes when compared to controls, including platelet-derived growth factor-BB (PDGF-BB), plasminogen activator inhibitor 1 (PAI-1), and intercellular adhesion molecule 1 (ICAM1) (p < 0.001). Many of these secreted proteins have not been previously reported in MMD, including interleukins (IL-2, IL-4, IL-5, IL-7, IL-8, IL-9, IL-17, IL-18, IL-22, and IL-23) and C-X-C motif chemokines (CXCL1 and CXCL9). Pathway analysis indicated that both MMD subtypes exhibited similar cellular/molecular functions and pathways, including cellular activation, migration, and inflammatory response. While neuroinflammation and dendritic cell pathways were activated in MMD patients, lipid signaling pathways involving nuclear receptors, peroxisome proliferator-activated receptor (PPAR), and liver X receptors (LXR)/retinoid X receptors (RXR) signaling were inhibited. IL-13 and IL-2 were negatively correlated with preoperative cerebral perfusion status, while 7 factors were positively correlated with the extent of postoperative revascularization. These elevated cytokines, chemokines, and growth factors in CSF may contribute to the pathogenesis of MMD and represent potential future therapeutic targets.

Referrals to Community and State Agencies to Address Social Determinants of Health for Improving Mental Health, Functioning, and Quality of Care Outcomes for Diverse Adults.

Objectives. To examine whether referral for social determinants of health (SDH) needs decreases psychological distress and posttraumatic stress disorder (PTSD) symptoms and improves level of functioning and quality of care among diverse adults. Methods. Data are from control participants (n = 503 adults) in a randomized controlled trial testing a mental health intervention in North Carolina and Massachusetts. We fitted multilevel mixed-effects models to repeated assessments (baseline, 3, 6, and 12 months) collected between September 2019 and January 2023. Results. After referral to services for trouble paying utility bills, participants reported lower PTSD symptoms. Participants reported better quality of care when receiving referrals to mental health care. After adjusting for income and employment status, we found that participants who were referred more often also had lower PTSD symptoms and better levels of functioning. Conclusions. Referrals for certain SDH needs might decrease PTSD symptoms and improve self-reported quality of care and functioning. However, referrals alone, without ensuring receipt of services, might be insufficient to affect other mental health outcomes. Research is needed on training and providing care managers time for offering interpersonal support, securing services, and understanding agencies' contexts for addressing high SDH needs. (Am J Public Health. 2024;114(S3):S278-S288. https://doi.org/10.2105/AJPH.2023.307442).

Immune responses, therapeutic anti-tumor effects, and tolerability upon therapeutic HPV16/18 E6/E7 DNA vaccination via needle-free biojector.

IMPORTANCE: Respectively, HPV16 and HPV18 cause 50% and 20% of cervical cancer cases globally. Viral proteins E6 and E7 are obligate drivers of oncogenic transformation. We recently developed a candidate therapeutic DNA vaccine, pBI-11, that targets HPV16 and HPV18 E6 and E7. Single-site intramuscular delivery of pBI-11 via a needle elicited therapeutic anti-tumor effects in mice and is now being tested in high-risk human papillomavirus+ head and neck cancer patients (NCT05799144). Needle-free biojectors such as the Tropis device show promise due to ease of administration, high patient acceptability, and the possibility of improved delivery. For example, vaccination of patients with the ZyCoV-D DNA vaccine using the Tropis device is effective against COVID19, well tolerated, and licensed. Here we show that split-dose, multi-site administration and intradermal delivery via the Tropis biojector increase the delivery of pBI-11 DNA vaccine, enhance HPV antigen-specific CD8+ T-cell responses, and improve anti-tumor therapeutic effects, suggesting its translational potential to treat HPV16/18 infection and disease.

Applying a Smartwatch to Predict Work-related Fatigue for Emergency Healthcare Professionals: Machine Learning Method.

INTRODUCTION: Healthcare professionals frequently experience work-related fatigue, which may jeopardize their health and put patient safety at risk. In this study, we applied a machine learning (ML) approach based on data collected from a smartwatch to construct prediction models of work-related fatigue for emergency clinicians. METHODS: We conducted this prospective study at the emergency department (ED) of a tertiary teaching hospital from March 10-June 20, 2021, where we recruited physicians, nurses, and nurse practitioners. All participants wore a commercially available smartwatch capable of measuring various physiological data during the experiment. Participants completed the Multidimensional Fatigue Inventory (MFI) web form before and after each of their work shifts. We calculated and labeled the before-and-after-shift score differences between each pair of scores. Using several tree-based algorithms, we constructed the prediction models based on features collected from the smartwatch. Records were split into training/validation and testing sets at a 70:30 ratio, and we evaluated the performances using the area under the curve (AUC) measure of receiver operating characteristic on the test set. RESULTS: In total, 110 participants were included in this study, contributing to a set of 1,542 effective records. Of these records, 85 (5.5%) were labeled as having work-related fatigue when setting the MFI difference between two standard deviations as the threshold. The mean age of the participants was 29.6. Most of the records were collected from nurses (87.7%) and females (77.5%). We selected a union of 31 features to construct the models. For total participants, CatBoost classifier achieved the best performances of AUC (0.838, 95% confidence interval [CI] 0.742-0.918) to identify work-related fatigue. By focusing on a subgroup of nurses <35 years in age, XGBoost classifier obtained excellent performance of AUC (0.928, 95% CI 0.839-0.991) on the test set. CONCLUSION: By using features derived from a smartwatch, we successfully built ML models capable of classifying the risk of work-related fatigue in the ED. By collecting more data to optimize the models, it should be possible to use smartwatch-based ML models in the future to predict work-related fatigue and adopt preventive measures for emergency clinicians.

Recent Advances on Social Determinants of Mental Health: Looking Fast Forward.

The fields of psychiatry and mental health are increasingly recognizing the importance of social determinants of health (SDOH) and their impact on mental health outcomes. In this overview, the authors discuss the recent research, from the past 5 years, on advances made in SDOH work. SDOH frameworks and theories have expanded to include more social conditions, from traumas associated with immigration to psychosocial and community strengths, that impact mental health and well-being. Research has consistently shown the pervasive deleterious impacts of inequitable social conditions (e.g., food insecurity, housing instability) on minoritized populations' physical and mental health. Social systems of oppression (e.g., racism, minoritization) have also been shown to confer higher risk for psychiatric and mental disorders. The COVID-19 pandemic illuminated the inequitable impact of the social determinants of health outcomes. More efforts have been made in recent years to intervene on the social determinants through interventions at the individual, community, and policy levels, which have shown promise in improving mental health outcomes in marginalized populations. However, major gaps remain. Attention should be paid to developing guiding frameworks that incorporate equity and antiracism when designing SDOH interventions and improving methodological approaches for evaluating these interventions. In addition, structural-level and policy-level SDOH efforts are critical for making long-lasting and impactful advances toward mental health equity.

Intersectional approaches are essential to identify the multiple sources of oppression.

Intersectional and multilevel approaches are required to tackle mental health disparities for marginalized populations. Intersectionality offers a guiding framework to study how social structures and systems work at multiple socioecological levels to influence the health and well-being of minoritized communities. This special section showcases research using intersectional approaches elucidating mental health and psychopathology outcomes among diverse populations. This commentary briefly summarizes five articles in this special section and discusses their contributions to health disparities research. These articles apply multilevel approaches to investigating how institutional and systemic marginalization impact mental health burden among understudied populations, including sexual and gender minority populations of color and Indigenous people. The studies also highlight future directions for research on the explanatory mechanisms of intersectionality that open the door to designing preventive interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of online care on functional and psychological outcomes in patients with psoriasis: A randomized controlled trial.

BACKGROUND: The impact of online care on patients' functional and psychological outcomes is critical to determine yet still unknown. OBJECTIVE: To evaluate how a novel online health model that facilitates physician-patient collaboration compares with in-person care for improving functional status and mental health of patients with psoriasis. METHODS: This 12-month randomized controlled equivalency trial randomly assigned patients with psoriasis 1:1 to receive online or in-person care. Functional impairment and depression were assessed at baseline and at 3-month intervals using the 5-level EuroQol-5 Dimensions index and Patient Health Questionnare-9. RESULTS: Overall, 296 patients were randomly assigned to the online or in-person groups. The between-group difference in overall improvement in the EuroQol Visual Analogue Scale was -0.002 (95% confidence interval, -2.749 to 2.745), falling within an equivalence margin of ±8. The between-group difference in overall improvement in the 5-level EuroQol-5 Dimensions index was 0 (95% confidence interval, -0.003 to 0.003), falling within an equivalence margin of ±0.1. The between-group difference in overall improvement in Patient Health Questionnare-9 score was -0.33 (95% CI, -1.20 to 0.55), falling within an equivalence margin of ±3. LIMITATIONS: Slightly different attrition rates between online and in-person arms (11% vs 9%), but no impact on outcomes. CONCLUSION: The online health model was equivalent to in-person care for reducing functional impairment and depressive symptoms in patients with psoriasis.

Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes.

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Brain-wide neural dynamics of poststroke recovery induced by optogenetic stimulation.

Poststroke optogenetic stimulations can promote functional recovery. However, the circuit mechanisms underlying recovery remain unclear. Elucidating key neural circuits involved in recovery will be invaluable for translating neuromodulation strategies after stroke. Here, we used optogenetic functional magnetic resonance imaging to map brain-wide neural circuit dynamics after stroke in mice treated with and without optogenetic excitatory neuronal stimulations in the ipsilesional primary motor cortex (iM1). We identified key sensorimotor circuits affected by stroke. iM1 stimulation treatment restored activation of the ipsilesional corticothalamic and corticocortical circuits, and the extent of activation was correlated with functional recovery. Furthermore, stimulated mice exhibited higher expression of axonal growth-associated protein 43 in the ipsilesional thalamus and showed increased Synaptophysin+/channelrhodopsin+ presynaptic axonal terminals in the corticothalamic circuit. Selective stimulation of the corticothalamic circuit was sufficient to improve functional recovery. Together, these findings suggest early involvement of corticothalamic circuit as an important mediator of poststroke recovery.

Why are the batteries in the microwave?: Use of semantic information under uncertainty in a search task.

A major problem in human cognition is to understand how newly acquired information and long-standing beliefs about the environment combine to make decisions and plan behaviors. Over-dependence on long-standing beliefs may be a significant source of suboptimal decision-making in unusual circumstances. While the contribution of long-standing beliefs about the environment to search in real-world scenes is well-studied, less is known about how new evidence informs search decisions, and it is unclear whether the two sources of information are used together optimally to guide search. The present study expanded on the literature on semantic guidance in visual search by modeling a Bayesian ideal observer's use of long-standing semantic beliefs and recent experience in an active search task. The ability to adjust expectations to the task environment was simulated using the Bayesian ideal observer, and subjects' performance was compared to ideal observers that depended on prior knowledge and recent experience to varying degrees. Target locations were either congruent with scene semantics, incongruent with what would be expected from scene semantics, or random. Half of the subjects were able to learn to search for the target in incongruent locations over repeated experimental sessions when it was optimal to do so. These results suggest that searchers can learn to prioritize recent experience over knowledge of scenes in a near-optimal fashion when it is beneficial to do so, as long as the evidence from recent experience was learnable.

A review and roadmap of the skin, lung and gut microbiota in systemic sclerosis.

As our understanding of the genetic underpinnings of SSc increases, questions regarding the environmental trigger(s) that induce and propagate SSc in the genetically predisposed individual emerge. The interplay between the environment, the immune system, and the microbial species that inhabit the patient's skin and gastrointestinal tract is a pathobiological frontier that is largely unexplored in SSc. The purpose of this review is to provide an overview of the methodologies, experimental study results and future roadmap for elucidating the relationship between the SSc host and his/her microbiome.

Contrasting lexical biases in bilingual English-Mandarin speech: Verb-biased mothers, but noun-biased toddlers.

Is noun dominance in early lexical acquisition a widespread or a language-specific phenomenon? Thirty Singaporean bilingual English-Mandarin learning toddlers and their mothers were observed in a mother-child play interaction. For both English and Mandarin, toddlers' speech and reported vocabulary contained more nouns than verbs across book reading and toy playing. In contrast, their mothers' speech contained more verbs than nouns in both English and Mandarin but differed depending on the context of the interaction. Although toddlers demonstrated a noun bias for both languages, the noun bias was more pronounced in English than in Mandarin. Together, these findings support early noun dominance as a widespread phenomenon in the lexical acquisition debate but also provide evidence that language specificity also plays a minor role in children's early lexical development.