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Purpose - The purpose of this paper is to explore whether attention, emotion, and cognitive regulation (CR) may be strategies to advance one’s ethnic identity. Design/methodology/approach - The paper is presented in three parts. The first section discusses integrative inquiry (INIQ) (Bresciani Ludvik et al., 2016), a mindfulness methodology and mindful inquiry training program, as a potential pathway to help mitigate stress and enhance healthy development and well-being strategies that combat stressors related to ethnic and racial identity; and increase opportunities for positive ethnic identity development. INIQ was designed to influence areas of the brain associated with attention regulation, emotion regulation, and CR in order to decrease stress and anxiety, and heighten executive functions of undergraduate and graduate students. The second section discusses an exploratory study to see whether INIQ resulted in higher mean scores for participants on their ethnic identity, as assessed by the multigroup ethnic identity measure (Phinney, 1992). Findings - The results indicated that there was a significant increase in pre-test and post-test scores for mindfulness (p=0.001) as well as the dependent measure for learning exploration (p=0.028) among 30 undergraduate, master’s- and doctoral-seeking students. There was also a non-significant increase for clear understanding (p=0.15) and overall ethnic identity achievement (p=0.387); and non-significant decrease for ethnic belonging (p=0.424). Originality/value - These findings suggest that INIQ may increase students’ ethnic learning exploration, which is an important process in ethnic identity development (Phinney and Ong, 2007). This study also suggests that INIQ increases mindfulness in participants. The authors conclude with a discussion and recommendations to future INIQ and other diversity centered student support practitioners interested in influencing positive ethnic identity formation.

This study investigated microaggressions Black children experienced in early childhood education during the pandemic. Using racial microaggressions as a framework, we sought to gain insights into these experiences through counter-narratives from parents of Black children. Parents provided unique insights into their children's experiences, giving voice to their daily realities in early learning contexts. This article focuses on how Black children are treated with second-class student status. Black children being positioned with second-class status was the most predominant theme from this work during the pandemic. This is noteworthy, as few studies have considered how the pandemic uniquely shaped Black children's educational realities.

Telehealth presents both the potential to improve access to care and to widen the digital divide contributing to health care disparities and obliging health care systems to standardize approaches to measure and display telehealth disparities. Based on a literature review and the operational experience of clinicians, informaticists, and researchers in the Supporting Pediatric Research on Outcomes and Utilization of Telehealth (SPROUT)–Clinical and Translational Science Awards (CTSA) Network, we outline a strategic framework for health systems to develop and optimally use a telehealth equity dashboard through a 3-phased approach of (1) defining data sources and key equity-related metrics of interest; (2) designing a dynamic and user-friendly dashboard; and (3) deploying the dashboard to maximize engagement among clinical staff, investigators, and administrators.

Introduction Undergraduate medical education and graduate medical education lack formal curricula on providing care for lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) youth. The onset of the COVID-19 pandemic has led to further challenges in delivering engaging, patient-centered education on LGBTQ+ health. Methods We developed a 90-minute case-based LGBTQ+ health curriculum delivered twice: to fourth-year medical students (in person only) and to pediatric residents (in-person and virtual options). Learners worked in small groups to engage in self-directed learning to review cases with associated questions, followed by a faculty-facilitated discussion and didactic component. Additionally, residents received a 45-minute patient-and-caregiver panel to explore lived experiences within the trans and nonbinary community. Retrospective pre-post surveys assessing knowledge, comfort, and perceived clinical impact were analyzed via paired t tests and descriptive statistics. Results Sixty-two learners completed our evaluation, including 19 residents and 43 medical students. After the curriculum, we noted significant improvement in learners’ perceived knowledge and comfort in all surveyed competencies; >90% of learners noted the curriculum was well organized and engaging, with the patient–caregiver panel marked as a highlight. Discussion A multimodal curriculum using case-based, problem-based learning and a patient–caregiver panel can be a promising method of providing interactive and up-to-date education on LGBTQ+ health care. This model can also be used to provide education on other medical education topics that are constantly evolving and lack national standardization.

Urothelial carcinoma is a common malignancy that carries a poor prognosis when the disease includes muscle invasion. Metastatic urothelial carcinoma is almost uniformly fatal. The evidence behind treatment options in the neoadjuvant, adjuvant and metastatic settings are discussed in this manuscript, with a focused review of standard and investigational cytotoxic, targeted, and immunotherapy approaches. We have focused especially on neoadjuvant cisplatin-based therapy (supported by level one evidence) and on novel immunotherapy agents such as checkpoint inhibitors, which have shown great promise in early clinical studies.

Autophagy is important for many physiological processes; and disordered autophagy can contribute to the pathogenesis of a broad range of systemic disorders. C. elegans is a useful model organism for studying the genetics of autophagy, however, current methods for studying autophagy are labor-intensive and not readily amenable to high-throughput procedures. Here we describe a fluorescent reporter, GFP::LGG-1::mKate2, which is useful for monitoring autophagic flux in live animals. In the intestine, the fusion protein is processed by endogenous ATG-4 to generate GFP::LGG-1 and mKate2 proteins. We provide data indicating that the GFP:mKate ratio is a suitable readout for measuring cellular autophagic flux. Using this reporter, we measured autophagic flux in L1 larvae to day 7 adult animals. We show that basal autophagic flux is relatively low during larval development but increases markedly in reproductive adults before decreasing with age. Furthermore, we show that wild-type, eat-2, and daf-2 mutant animals have distinct autophagic flux profiles through post-embryonic development. Finally, we demonstrate the utility of this reporter by performing a high-content small molecule screen to identify compounds that alter autophagic flux in C. elegans.

This article describes the content validation of the Transitioning Learners to Calculus in Community Colleges Institutional Self-Assessment Tool. The instrument comprises five content areas, each with an associated set of items representing practices to promote the success of underrepresented racially minoritized (URM) students as they transition into and through mathematics courses required for degrees in science, technology, engineering, and mathematics (STEM). Five subject matter experts participated in the content validation. Scale-level index scores for each content area were above .85, and 18 of 22 items met the content validity index threshold of 1.0. The instrument has demonstrated strong content validity and is recommended for mathematics programs in community colleges to self-assess the degree to which they have implemented these practices and to identify next steps to enhance their support of URM students in mathematics courses required for STEM degrees.

We introduce the disclosure-outcomes management model. The model views disclosure in intelligence interviews as a behaviour interviewees use to profitably navigate self-interest dilemmas. We theorized that interviewees compare the potential outcomes of disclosing to their self-interests. They evaluate the extent to which disclosure will facilitate or impede those self-interests: an interviewee’s self-interest dilemma elicits cooperation with respect to some information but not other information. A Preliminary Study (N = 300) supported the model’s predictions. We proposed a Replication Study (N = 369) to examine the model further. Participants assumed the role of an intelligence source undergoing an interview. They decided what information to disclose, contending the typical dilemma in an intelligence interview wherein disclosure could jeopardize or advance their self-interests. The results from the Preliminary and Replication studies were broadly in line with our proposition: perceived benefits positively influenced the likelihood of disclosing. However, a negative interaction between costs and benefits observed in the Preliminary Study did not replicate. That finding may be due to power constraints, not evidence against the existence of an interaction effect. Our proposal that—generally speaking—interviewees are likelier to disclose information units that seem less versus more risky requires further examination. Individual-level sensitivity to benefits, costs and their co-occurrence varied substantially in our studies. We discuss avenues for future research.

Background Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.Patients and methods Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed.Results 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing.Conclusions This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

Background Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis.Methods An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript.Results The panel determined unique clinical trial designs tailored to different stages of cancer development—from premalignant to unresectable/metastatic—that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments.Conclusions The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.

This study determined which molar base retentive designs produced the greatest shear bond strength (SBS) to human molars when using different adhesives.

The purpose of this study was to examine determinants of faculty-student engagement for Southeast Asian men in community colleges. Using data derived from the Community College Survey of Men (CCSM), this study investigated faculty-student engagement for 140 Southeast Asian men attending community colleges in the United States. Five groupings of predictor variables were examined: background/defining, campus ethos, environmental, academic, and non-cognitive factors. Backwards multiple linear regression was employed to identify variables with significant contributions to the model. The final model converged on the eighth iteration and significantly predicted the outcome, accounting for 38% of the variance in faculty-student engagement. Findings indicated that faculty validation, stressful life events, action control, and use of academic advising and career counseling services were significant predictors of faculty-student engagement. Implications for community college practice and research are discussed.

Background Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.Methods CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments.Results CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab.Conclusions Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer.Trial registration numbers NCT02110082; NCT02253992.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.

This essay articulates the benefits of teacher diversity by illustrating six themes: a) leading for social justice through local and global civic engagement; b) developing an inclusive school culture; c) culturally relevant pedagogy; d) cultural translators and transformers; e) role models; and (f) benefits accrued by White students. The authors draw from evidence in supporting arguments surrounding the benefits accrued when teacher diversity reflects the demographics of students served and the role educational leaders can play in advancing efforts to recruit and retain a diverse faculty pool. They challenge readers to consider the benefits accrued when deliberate efforts to increase teacher diversity are made in light of advancing student academic success.

Abstract The Great Debate session at the 2022 Melanoma Bridge congress (December 1–3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.

Summary: The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutrophil localization and clustering early in infection. Hla forms a narrow, ion-selective pore, suggesting that Hla may dysregulate calcium or other ions to impair neutrophil function. We found that sub-lytic Hla did not permit calcium influx but caused rapid membrane depolarization. Depolarization decreases the electrogenic driving force for calcium, and concordantly, Hla suppressed calcium signaling in vitro and in vivo and calcium-dependent leukotriene B4 (LTB4) production, a key mediator of neutrophil clustering. Thus, Hla disrupts the early patterning of the neutrophil response to infection, in part through direct impairment of neutrophil calcium signaling. This early mis-localization of neutrophils may contribute to establishment of infection.

As devices become ever smaller and more efficient, the crystallochemically controlled synthesis of high‐performance materials that comprise their core has attracted enormous attention. Integration of complex functional materials into the next generation of electronic devices will require exquisite control of anisotropic form, either as nanotubes, nanotapes, or nanowires, yet the easy preparation of abundant quantities of them remains stubbornly challenging. Herein, a template‐free, flux‐mediated growth of vast quantities of three compositions of phase‐pure, high‐temperature superconductor nanowires, including for the first time, nanowires of the technologically important quinternary superconductor Bi2Sr2CaCu2O8+x (B2212) is demonstrated. The results of this work may provide an opportunity to investigate the physics and chemistry of highly anisotropic superconductor nanowires and enable their incorporation into nanoelectronics and energy generation systems.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

This study examined the influence of multiple types of insecurity on student GPAs. Data demonstrated that students who did not experience one of the four insecurities had significantly higher GPAs that those facing housing, transportation, and employment barriers; food insecurity or combination; or all four insecurities.

Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b+ myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT.

The study explored the experiences and perceptions of Black girls as conveyed through the narratives of their parents. In particular, this study focused on racial microaggressions in early childhood education (preschool through third grade). The study employed narratives written by 44 parents of Black children. Ultimately, their narratives demonstrated that Black hair was viewed as a marker of second-class citizenship and as an indicator of defilement. The individuals communicating these microaggressions ranged from educators to other children in the classroom. Negative messages about Black hair are particularly concerning in early childhood education, especially given the important role early learning has on children's formative development. Implications for early childhood educators are extended.

BackgroundProinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics.MethodsLevels of TLS-kines in patients’ sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed.ResultsSerum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL13 and CXCL10 tumor transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high APRIL/CXCL10/CXCL13 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types.ConclusionSerum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.

BACKGROUND We previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODS Patients received SBRT to 2–4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTS In the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90–5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSION SBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATION Clinicaltrials.gov NCT02608385FUNDING Merck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.

This study explored how members of an illicit network navigate investigative interviews probing their crimes. We examined how perceived disclosure outcomes, namely, the projected costs and benefits, affect what members choose to reveal. We recruited N = 22 groups, maximum of six participants per group. Each group assumed the role of an illicit network and planned for possible interviews with investigators probing into the legitimacy of a business the network owns. All participants underwent an interview after the group planning stage. The results indicated that network members navigate the dilemma interviews bring by disclosing information they perceive would likely yield beneficial (or desirable) rather than costly (or undesirable) outcomes. Additionally, much of the participants' sensitivity to potential costs and benefits was explained by the group of which they are a part: different networks likely respond to costs and benefits in unique ways. This work contributes to understanding how illicit networks manage information disclosure in investigative interviews.

Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants that is associated with an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. We describe an in vitro model of the human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology. This model utilizes intestinal enteroids grown from surgically harvested intestinal tissue from premature infants and cocultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology by adding infant-derived microbiota. This model, named NEC-on-a-Chip, simulates the predominant features of NEC, including significant upregulation of proinflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation, and disrupted epithelial barrier integrity. NEC-on-a-Chip provides an improved preclinical model of NEC that facilitates comprehensive analysis of the pathophysiology of NEC using precious clinical samples. This model is an advance toward a personalized medicine approach to test new therapeutics for this devastating disease.

Cancer immunotherapy with immune-checkpoint blockade has improved the outcomes of patients with various malignancies, yet a majority do not benefit or develop resistance. To address this unmet need, efforts across the field are targeting additional coinhibitory receptors, costimulatory proteins, and intracellular mediators that could prevent or bypass anti-PD1 resistance mechanisms. The CD28 costimulatory pathway is necessary for antigen-specific T cell activation, though prior CD28 agonists did not translate successfully to clinic due to toxicity. Casitas B lymphoma-b (Cbl-b) is a downstream, master regulator of both CD28 and CTLA-4 signaling. This E3 ubiquitin ligase regulates both innate and adaptive immune cells, ultimately promoting an immunosuppressive tumor microenvironment (TME) in the absence of CD28 costimulation. Recent advances in pharmaceutical screening and computational biology have enabled the development of novel platforms to target this once ‘undruggable’ protein. These platforms include DNA encoded library screening, allosteric drug targeting, small-interfering RNA inhibition, CRISPR genome editing, and adoptive cell therapy. Both genetic knock-out models and Cbl-b inhibitors have been shown to reverse immunosuppression in the TME, stimulate cytotoxic T cell activity, and promote tumor regression, findings augmented with PD1 blockade in experimental models. In translating Cbl-b inhibitors to clinic, we propose specific gene expression profiles that may identify patient populations most likely to benefit. Overall, novel Cbl-b inhibitors provide antigen-specific immune stimulation and are a promising therapeutic tool in the field of immuno-oncology.

Increased execution of replication studies contributes to the effort to restore credibility of empirical research. However, a second generation of problems arises: the number of potential replication targets is at a serious mismatch with available resources. Given limited resources, replication target selection should be well-justified, systematic and transparently communicated. At present the discussion on what to consider when selecting a replication target is limited to theoretical discussion, self-reported justifications and a few formalized suggestions. In this Registered Report, we proposed a study involving the scientific community to create a list of considerations for consultation when selecting a replication target in psychology. We employed a modified Delphi approach. First, we constructed a preliminary list of considerations. Second, we surveyed psychologists who previously selected a replication target with regards to their considerations. Third, we incorporated the results into the preliminary list of considerations and sent the updated list to a group of individuals knowledgeable about concerns regarding replication target selection. Over the course of several rounds, we established consensus regarding what to consider when selecting a replication target. The resulting checklist can be used for transparently communicating the rationale for selecting studies for replication.

It is difficult to assess the effectiveness of community college initiatives serving men of color when there is a lack of understanding of the nature of the programming taking place. The purpose of this study was to understand the funding streams, interventions, and objectives of programs serving men of color in the community college. This study was motivated by the belief that understanding common interventions, outcomes, and goals illuminates practitioners' perspectives of the personal and institutional barriers facing men of color and the strategies that should be employed to address these barriers. The researchers believe that the information presented in this analysis of minority male initiatives will serve as a reference for understanding common approaches taken in the field for serving men of color in community colleges.

Chronic traumatic encephalopathy (CTE) has emerged in the public consciousness as a major public health challenge for athletics in all levels of competition. Football receives the greatest level of attention given its visibility in American culture. For many community colleges, football plays a central role is promoting institutional objectives and enhancing the student collegiate experience. In this paper, the authors discuss the ethical implications of continuing football in context of the increasing research linking football and CTE, which include the ethics of justice, critique, care, and profession. The authors stress the need for community colleges to determine the future of football at their institutions by critically examining how and if this sport meets their goals, needs, and ethical obligations.