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In a pair of artificial language experiments, we investigated the learnability and emergence of different dependency structures: branching, center-embedding, and crossed. In natural languages, branching is the most common dependency structure; center-embedding occurs but is often disfavored, and crossed dependencies are very rare. Experiment 1 addressed learnability, testing comprehension, and production on small artificial languages exemplifying each dependency type in noun phrases. As expected, branching dependency grammars were the easiest to learn, but crossed grammars were not different from center-embedding. Experiment 2 employed iterated learning to examine the emergence and stabilization of consistent grammar using the same type of stimuli as Experiment 1. The initial participant in each chain of transmission was trained on phrases generated by a random grammar, with the language produced by that participant passed to the next participant through an iterated learning process. Branching dependency grammar appeared in most chains within a few generations and remained stable once it appeared, although one chain stabilized on output consistent with a crossed grammar; no chains converged on center-embedding grammars. These findings, along with some previous results, call into question the assumption that crossed dependencies are more cognitively complex than center-embedding, while confirming the role of learnability in the typology of dependency structures.

The nursing faculty shortage challenges nursing educators, administrators, and staff to find innovative ways to understand and address faculty retention.The purpose of this study was to examine nurse educators' perceptions of workplace collegiality and the possible correlation to role satisfaction and role persistence.Participants (n = 177) were recruited nationally from a Commission on Collegiate Nursing Education accredited schools listing. Three survey instruments were utilized: Survey of Collegial Communication, Job Satisfaction Survey, and Michigan Organizational Assessment Questionnaire.The study found a positive relationship between collegiality and job satisfaction in academia. The Pearson correlation results indicated there was a significant negative correlation between the intent to remain and collegiality.The findings suggest nursing educators perceive collegiality as an important component of job satisfaction and intent to remain.

This article examines hormone concentrations and body temperature (

Americans, over several decades, have consistently identified themselves as being religious and/or spiritual. Even though religious devotion has been recognized as a relevant diversity facet, therapeutic applications have been problematic. In the career development literature, numerous studies examined the influence of religion/spirituality (R/S) and generally categorized them in three ways. These include R/S as religious calling, as an integral feature of career interests and values, and as a supportive role. Yet, notable gaps exist among the articles. Researchers tended to operationalize R/S in a unidimensional manner, as a stand-alone construct instead of comprising multiple features. Investigations of religious calling in vocational matters were not recent. Further, few authors considered the influence of quest religious orientation on career development. In the present study, the relationships between seven career development and thirteen R/S variables using a sample of religious undergraduates (n = 290) enrolled in a career exploration course at a Christian university in the Midwest region of the United States were investigated. Findings from hierarchical regression analyses of vocational identity, career commitment, and career indecision checking for gender effects revealed three consistent salient predictors – religious calling, life-satisfaction, and quest religiosity. Implications of the results and possible therapeutic applications for career counselors are proposed.

Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. Still, inferring biological processes requires additional post hoc statistics and annotation for interpretation of features learned from software packages developed for NMF implementation. Here, we aim to introduce a suite of computational tools that implement NMF and provide methods for accurate, clear biological interpretation and analysis. A generalized discussion of NMF covering its benefits, limitations, and open questions in the field is followed by three vignettes for the Bayesian NMF algorithm CoGAPS (Coordinated Gene Activity across Pattern Subsets). Each vignette will demonstrate NMF analysis to quantify cell state transitions in public domain single-cell RNA-sequencing (scRNA-seq) data of malignant epithelial cells in 25 pancreatic ductal adenocarcinoma (PDAC) tumors and 11 control samples. The first uses PyCoGAPS, our new Python interface for CoGAPS that we developed to enhance runtime of Bayesian NMF for large datasets. The second vignette steps through the same analysis using our R CoGAPS interface, and the third introduces two new cloud-based, plug-and-play options for running CoGAPS using GenePattern Notebook and Docker. By providing Python support, cloud-based computing options, and relevant example workflows, we facilitate user-friendly interpretation and implementation of NMF for single-cell analyses.

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

This review of the literature was conducted to define avoidant restrictive food intake disorder (ARFID) and provide the current evidence-based treatment modalities and implications for Nurse Practitioners. A specific case is used to illustrate the daily struggles of a pediatric patient with ARFID that include bullying, self-doubt, and anxiety related to eating. There is a need for increased awareness of the disorder to increase identification of the disorder, enhance the research on treatment modalities for the disorder, and most importantly, to increase the quality of life for those with the disorder and their family members.

Introduction: High demand for speech-language pathology means children sometimes wait over 12 months for services, missing out on timely support. Waiting can be a time of stress, concern, and powerlessness for caregivers. Provision of information via a website may support families and encourage active waiting. Objective: The aim of this study was to compare children’s speech, intelligibility, language, and literacy outcomes, and caregivers’ satisfaction and empowerment in active versus passive waiting conditions. Methods: Ninety-seven preschool-aged children referred to a community health speech-language pathology service in Australia were screened for eligibility. Eligible children (n =42) with speech/language difficulties were randomly allocated to: (a) active waiting (provision of a purpose-built website; n = 20), or (b) passive waiting (control group; n = 22). Pre- and post-assessments (after 6 months on a waiting list) were completed with children and caregivers by a speech-language pathologist blinded to group allocations. Results: Intention to treat (n =36) and per-protocol analyses (n =30) were conducted to measure group differences in child and caregiver outcomes at post-assessment using one-way ANCOVA, controlling for baseline scores. There were no statistically significant differences between groups for children’s speech, intelligibility, language, and literacy, or caregivers’ empowerment and satisfaction. Children in both groups made minimal gains over 6 months. Conclusions: Provision of an active waiting website did not lead to statistically significant change in child or caregiver outcomes, and children in both groups made little progress over a 6-month period. Early speech-language pathology intervention delivered with appropriate dosage is needed to optimise children’s outcomes. Until timely and effective speech-language pathology intervention can be provided for all who need it, provision of early assessments may be beneficial. There remains a need for effective ways to support children and families on waiting lists.

Previous work suggests that Dihydroorotate dehydrogenase (DHODH) inhibition via teriflunomide (TERI) may provide protection in multiple disease models. To date, little is known about the effect of TERI on the heart. This study was performed to assess the potential effects of TERI on cardiac ischemia reperfusion injury.Male and female rat hearts were subjected to global ischemia (25 min) and reperfusion (120 min) on a Langendorff apparatus. Hearts were given either DMSO (VEH) or teriflunomide (TERI) for 5 min prior to induction of ischemia and during the reperfusion period. Left ventricular pressure, ECG, coronary flow, and infarct size were determined using established methods. Mitochondrial respiration was assessed via respirometry.Perfusion of hearts with TERI led to no acute effects in any values measured across 500 pM-50 nM doses. However, following ischemia-reperfusion injury, we found that 50 nM TERI-treated hearts had an increase in myocardial infarction (p 0.001). In 50 nM TERI-treated hearts, we also observed a marked increase in the severity of contracture (p 0.001) at an earlier time-point (p = 0.004), as well as reductions in coronary flow (p = 0.037), left ventricular pressure development (p = 0.025), and the rate-pressure product (p = 0.008). No differences in mitochondrial respiration were observed with 50 nM TERI treatment (p = 0.24-0.87).This study suggests that treatment with TERI leads to more negative outcomes following cardiac ischemia reperfusion, and administration of TERI to at-risk populations should receive special considerations.

Electronic medical records have made great advances in the provision of quality health care but have increased physician workload and often limit face-to-face time with patients. These effects are particularly felt in the academic dermatology clinic, a critical time of practice development. Time constraints from implementation of electronic medical records have resulted in low patient volume and reduced educational opportunities. A review of the literature suggests that utilizing scribes as physician aides in the academic dermatology setting may increase patient access, clinic volume, educational experience, and hospital revenue.

Background: Oncogenic mutations in KRAS are expressed in up to 90% of pancreatic ductal adenocarcinomas (PDAC). Vaccination against mutant KRAS (mKRAS) is thus a promising approach as an off-the-shelf immunotherapeutic treatment for PDAC. We developed a mKRAS peptide vaccine targeting 6 common KRAS mutations (G12V, G12A, G12C, G12R, G12D, or G13D (NCT04117087). We evaluated the mKRAS specific T cell response induced by vaccination in combination with immune checkpoint inhibitors (ICIs) in patients with resected PDAC. Materials and Methods: This is an ongoing pilot study of a pooled mKRAS long peptide vaccine in combination with ICIs in patients with resected PDAC and mutations in one of 6 KRAS mutations in our vaccine. Patients with no evidence of disease on imaging within 6 months of completion of adjuvant chemotherapy were vaccinated with the mKRAS vaccine (0.3mg/peptide and 0.5mg poly-ICLC (Hiltonol: Oncovir)) weekly for 4 doses followed by booster vaccines every 8 weeks. Patients also received ipilimumab (1mg/kg, every 6 weeks for 2 doses) and nivolumab (3mg/kg, every 3 weeks in the priming phase) followed by nivolumab (480mg, flat dose in boost phase). To evaluate the expansion of mKRAS-specific T cells in the periphery, pre- and post-vaccination peripheral blood mononuclear cells (PBMCs) were restimulated with control or individual mKRAS peptides and assessed for IFNγ release by ELISPOT. To further phenotype the responding CD4 and CD8 T cell compartments, peptide-restimulated PBMCs were evaluated for T cell activation, proliferation, memory and exhaustion marker expression by CyTOF. Paired single-cell RNA and TCR sequencing are being performed to isolate mKRAS-specific TCRs and their corresponding transcriptional profiles. These TCRs are being functionally validated in vitro using CRISPR-Cas12a-based genome knock-in of human T cells. Results: At the time of data cut off (1/12/2023) 8/11 patients enrolled had a positive mKRAS-specific T cell response in post-vaccine sample timepoints defined by a >5 fold increase in IFNγ producing T cells after peptide restimulation. CyTOF analysis of peptide-restimulated PBMCs demonstrated expansion of polyfunctional (IFNγ+IL2+TNFα+) mKRAS-specific CD4 and CD8 T cells with both central and effector memory phenotypes after vaccination. mKRAS-specific CD4 T cells were induced at a greater proportion. Our single-cell analysis has identified and validated a novel CD4+ TCR that recognizes KRAS G12V in the context of HLA-DRB1*07:01. Conclusions: This study thus far indicates the induction of de novo, high quality mKRAS-specific T cells in the periphery post-vaccine. Ongoing studies will define TCR diversity and clonality of mKRAS-specific T cells to each mKRAS epitope. Overall, our data will be used to identify peripheral T cell-based biomarkers that may be able to predict response to mKRAS-targeted immunotherapy. Citation Format: Amanda L. Huff, Saurav D. Haldar, Emily Davis-Marcisak, Thatcher Heumann, Gabriella Longway, Alexei Hernandez, Maximillian F. Konig, Brian Mog, Ludmila Danilova, Luciane Kagohara, Julie M. Nauroth, Amy M. Thomas, Elana J. Fertig, Won Jin Ho, Elizabeth M. Jaffee, Nilo Azad, Neeha Zaidi. A pooled mutant KRAS peptide vaccine activates polyfunctional T cell responses in patients with resected pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB197.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a low tumor mutational burden and therefore few neoantigen targets that can be recognized by cytotoxic T cells. Most PDACs are thus insensitive to either single or dual immune checkpoint inhibitor (ICI) therapy. Personalized neoantigen vaccines can expand the number and repertoire of anti-tumor T cells that infiltrate the tumor and mediate cytotoxicity. To model a personalized neoantigen vaccine treatment strategy in PDAC, we previously developed PancVAX, a peptide-based vaccine targeting 12 neoantigens expressed in the murine pancreatic cell line Panc02 (Kinkead et al, JCI Insight 2018). Although we observed increased T cell infiltration present in the tumor post-vaccination, these cells expressed high levels of exhaustion markers. We therefore hypothesized that sequential administration of anti-CTLA-4 and anti-PD-1 would enhance the pool of T cells primed by the neoantigen vaccine and maintain activation of antigen-experienced T cells, respectively, to yield optimal and durable neoantigen-specific anti-tumor immunity in PDAC. To address this, mice bearing subcutaneous Panc02 tumors were vaccinated with two rounds of the PancVAX neoantigen vaccine followed by anti-CTLA-4 and anti-PD-1 3 days later. Anti-PD-1 maintenance was given twice weekly beginning at the first vaccine dose. Twelve days after the last peptide vaccine dose, tumors were harvested and dissociated into single-cell suspensions for paired single-cell RNA-sequencing and TCR-sequencing. Mice that were untreated or given ICIs without PancVAX had the highest proportions of CD8+ T cells expressing exhaustion markers. PancVAX-treated mice had more intratumoral cycling CD8 T cells and effector CD8+ T cells with high cytotoxic gene expression. Among mice treated with PancVAX, tumors from mice treated with PancVAX + anti-PD1 or PancVAX + anti-PD1 + anti-CTLA-4 had the highest proportions of effector CD8+ T cells. Ongoing analyses include differential gene expression and pathway analysis between treatment conditions in the T cell compartment in mice treated with combination ICI and PancVAX. Additionally, we will assess changes in T cell clonality and diversity within the tumors when mice are treated with single or combination therapy. These results will define a transcriptional signature associated with the generation of a productive anti-tumor immune response when neoantigen vaccines and ICI are used in combination. This work demonstrates how the addition of ICIs to personalized neo-epitope vaccines for PDAC can further enhance the quality of vaccine-induced T cell effector function in an otherwise immunologically cold tumor type and supports their inclusion in neoantigen vaccination strategies for patients with PDAC. Citation Format: Jacob T. Mitchell, Amanda Huff, Emily Davis-Marcisak, Fangluo Chen, Todd D. Armstrong, Luciane T. Kagohara, James Leatherman, Rulin Wang, Srinivasan Yegnasubramanian, Elizabeth M. Jaffee, Elana J. Fertig, Neeha Zaidi. Combination PancVAX neo-epitope vaccine with anti-CTLA-4 and anti-PD-1 antibodies enhances infiltration of cytotoxic T cells and mitigates T cell exhaustion in a murine model of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5076.

Earp, Lewis, and Hart (2021) write about the racism entrenched in policies criminalizing drug use and possession and describe the disparate impact that these policies have on certain racialized com...

Much of our understanding of GH’s action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.

Objective:Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion.Setting:From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP.Participants:All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible.Results:No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens.Conclusions:Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.

Multiple source apportionment approaches were employed to investigate PAH sources which contribute to small craft harbor (SCH) sediments in Nova Scotia (NS), Canada. A total of 580 sediment samples were analyzed using PAH diagnostic ratios, Unmix Optimum receptor modeling, and by assessment of the composition of the PAH profile. PAH diagnostic ratios suggest PAHs are primarily of pyrogenic (thermal) origin, while UnmixO modeling identifies four individual sources which best describe surficial sediments and suggests contributions from both pyrogenic and petrogenic origins. These include coal combustion, automobile exhaust, and biomass incineration. PAH profile assessment determined an overwhelming contribution of high molecular weight PAHs, which exhibited a strong correlation with total PAH concentrations.

Ecological risk assessment of metals (As, Cd, Cr, Cu, Hg, Ni, Pb and Zn) in surface sediments from 31 small craft harbours (SCHs) in Nova Scotia, Canada was conducted using multiple risk assessment approaches. Approaches used were contamination factor, pollution load index, geoaccumulation index, potential ecological risk factor for individual metals, comprehensive potential ecological risk index, mean probable effect level quotient and mean effects range median quotient. Results indicated most SCHs exhibited low ecological risk from sediment metal concentrations, except for two harbours. Metal contamination was highest in Canso Harbour, followed by Clarks Harbour. SCH sediments were only slightly contaminated with low probability of pollution according to mean probable effect level and mean effects range median quotients. However, pollution load and geoaccumulation indexes indicated Cd and Hg had the highest metal contamination across SCH sediments. Cadmium and Hg had the highest potential ecological risk, respectively compared to other metals.

The looming climate and energy crises, exacerbated by increased waste generation, are driving research and development of sustainable resource management systems. Research suggests that organic materials, such as food waste, grass, and manure, have potential for biotransformation into a range of products, including: high-value volatile fatty acids (VFAs); various carboxylic acids; bioenergy; and bioplastics. Valorizing these organic residues would additionally reduce the increasing burden on waste management systems. Here, we review the valorization potential of various sustainably sourced feedstocks, particularly food wastes and agricultural and animal residues. Such feedstocks are often micro-organism-rich and well-suited to mixed culture fermentations. Additionally, we touch on the technologies, mainly biological systems including anaerobic digestion, that are being developed for this purpose. In particular, we provide a synthesis of VFA recovery techniques, which remain a significant technological barrier. Furthermore, we highlight a range of challenges and opportunities which will continue to drive research and discovery within the field. Analysis of the literature reveals growing interest in the development of a circular bioeconomy, built upon a biorefinery framework, which utilizes biogenic VFAs for chemical, material, and energy applications.

Pancreatic cancer is responsible for more than 48,000 deaths and 60,000 new cancer cases every year in the United States while the overall 5-year survival rate is only 10%. These numbers point towards an urgent need for new therapeutic approaches wherein therapy resistance poses a tremendous challenge. We and others have identified the role of growth hormone (GH) and its cognate receptor (GHR), overexpressed in pancreatic ductal adenocarcinoma patients (PDAC; >90% of pancreatic cancer cases), in driving therapy resistance by directly upregulating multidrug efflux, phenotype switch via epithelial-to-mesenchymal transition (EMT) and inhibition of apoptosis. Our laboratory had pioneered the discovery of pharmacologic GHR antagonists including the only approved and prescribed GHR antagonist, pegvisomant, and a new antagonist candidate named compound-G. Here, we used in vitro, in vivo and in silico analyses to assess the feasibility and efficacy of a treatment regimen including GHR antagonist and chemotherapy to manage PDAC. Both pegvisomant and compound-G exhibit significant suppression of cancer cellular viability, invasive potential, drug efflux rate and apoptosis in PDAC cell cultures. In male and female Nude mice with human PDAC xenografts, GHR inhibition by either pegvisomant or compound-G markedly re-sensitized the tumors towards both low and high doses of gemcitabine treatment. Compound G plus high doses of gemcitabine lead to almost complete tumor clearance in 40% of the mice. Also, tissue analyses reveal increased production of GH in tumors treated with chemotherapy. In the GHR antagonist treated tumors, significantly lower expression of ABC transporter (Abcb1, Abcg5, Abcc2, Abcg2), EMT mediator (Cdh2, Zeb1, Snai2, Epas1) and apoptosis marker (Bcl2) genes compared to control were observed - accounting for the observed sensitization to gemcitabine. In the human PDAC patient datasets, increased expression of GHR correlates strongly with increased expression of multidrug efflux transporters, anti-apoptotic markers, and EMT transcription factors. Therefore, we provide robust pre-clinical validation for a treatment regimen combining GHR antagonist and chemotherapy leading to highly efficacious tumor clearance. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute. Citation Format: Reetobrata Basu, Prateek Kulkarni, Emily Davis, Silvana Duran, John J. Kopchick. Combination of growth hormone receptor antagonist and gemcitabine leads to highly efficacious tumor clearance in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2620.

Knockdown of the growth hormone receptor (GHR) in melanoma cells downregulates ATP-binding cassette (ABC) transporters and sensitizes them to multiple drug treatments in vitro. The goal for this study is to understand whether a GHR antagonist (GHA) could suppress different types of cancers by sensitizing tumors to drug treatments in vivo through the downregulation of ABC transporters. Sera from GHA transgenic mice inhibited the proliferation of mouse melanoma cells (B16F10) in culture and suppressed expression of multiple ABC transporters. When B16-F10 cells were intradermally inoculated into GHA mice, tumor size was markedly reduced, as was STAT5 activation and ABCG1, ABCG2 levels. We then tested the effect of the GHA on the efficacy of cisplatin in vivo. GHA sensitized melanomas to cisplatin, leading to the smallest tumors among all groups. GHKO mice showed the same effect. We further extended this investigation to hepatocellular carcinoma (HCC). GHA mice were subcutaneously inoculated with mouse HCC (Hepa1 6 cells) and subsequently treated with sorafenib. The HCC tumors in GHA mice were markedly sensitive to sorafenib treatment compared to the same in wild-type mice. RNA analysis showed that when HCC was exposed to the combined treatment, relatively decreased ABC transporters expression was found. Immunohistochemical staining showed that phosphorylation of STAT5 and ABCB1 were downregulated in HCC tissues, suggesting that GHA in vivo downregulates ABC transporters in HCC, and therefore sensitizes them to sorafenib. Clinical data derived from HCC patients using the TCGA database showed that multiple ABC transporters in both types of cancer correlate with GHR levels; that is, when GHR levels are relatively high, patient survival is significantly decreased. Additionally, higher ABCC1 levels also lead to significantly decreased survival rate in HCC patients. Collectively, the results indicate that a GHA is effective in sensitizing both melanoma and HCC to available treatments in vivo and may be used as a therapeutic strategy for higher efficacy of tumor clearance. Citation Format: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick. Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2621.

Growth hormone (GH) has been reported to drive leukemia cell proliferation as early as 1977, while downstream effectors of the GH signaling pathway (i.e., insulin-like growth factor 1; IGF1) have more recently been widely implicated in the aggressive pathology and robust therapy resistance phenotypes of acute myeloid leukemia (AML). It is also known that patients with acromegaly (high levels of circulating GH and IGF1) develop AML at a significantly higher rate than the general population, while individuals with GH resistance remain completely resistant to all types of cancer. Despite all of the aforementioned evidence pointing to a critical role of GH in AML progression and prognosis, a detailed transcriptomic analysis of human patients is lacking. We aim to address this gap by thorough in silico studies aimed at revealing the nature and extent to which the GH axis can be suitable targeted in AML. Here, we present a summary of our analyses of clinical and transcriptomic data from 200 human patients with AML from The Cancer Genome Atlas database, using multiple bioinformatics software programs in the public domain. Our study revealed that GH receptor (GHR) is expressed more highly in AML than in normal myeloid cells, and a robust correlation exists between GH responsiveness and patient survival. A sex-specific profiling of the patient transcriptomic data identified critical pathways related to therapy resistance, extracellular matrix remodeling, metastasis, and immune evasion to be upregulated differentially in male and female AML patients with relatively elevated GHR expression compared to patients with relatively lower GHR expression. Furthermore, we identified microRNAs which are differentially expressed in AML patients with higher than median GHR expression. We validated these miRNAs to be effective indicators of disease progression and prognosis and can be valuable markers in liquid biopsy approaches. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Edison Biotechnology Institute. Citation Format: Emily Davis, Reetobrata Basu, John J. Kopchick. Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2695.

Additional file 2 : Table S2. Primers used for breakpoint junction analyses: Primers used to define breakpoint junctions in families 1-4. Table S3. Missense variants identified in ATAD3A: Bioinformatic predictions of missense variants identified in this study. Figure S1. Homozygous variant in Family 8: Visualization of exome sequencing reads showing the homozygous variant c.980G>C, p.(Arg327Pro). Figure S2. Segregation analysis in Family 7: Data showing that the c.150C>G variant is de novo, whereas the c.1703_1705del variant is maternally inherited. Figure S3. Compound heterozygous deletion affecting ATAD3A in Family 1: Visualization of exome sequencing read alignments indicating two overlapping deletions inherited in trans. Figure S4. Breakpoint junction sequencing of paternally inherited ATAD3B/ATAD3A deletion in Family 1: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S5. Read depth analysis of exome sequencing data in Family 2: The compound heterozygous deletion can be appreciated. Figure S6. Breakpoint junction sequencing of first ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S7. Breakpoint junction sequencing of second inherited ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S8. Confirmatory array data from Family 3: The heterozygous deletion can be appreciated in the proband and mother’s samples, but not in the father’s sample. Figure S9. Breakpoint junction sequencing of maternally inherited ATAD3B/ATAD3A deletion in Family 3: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S10. Breakpoint junction sequencing of paternally inherited 2-exon deletion in ATAD3A (Family 4): Delineation of the breakpoint junction by Sanger sequencing spanning the deletion, and evolutionary conservation of the skipped exons. Figure S11. Schematic diagram of all CNVs identified in this study: Diagram of the six CNVs studied; five of six were resolved at the breakpoint junction level. Figure S12. dAtad3a is expressed ubiquitously in embryos: Confocal micrographs of an embryo expressing GFP protein under the control of dAtad3a-T2A-Gal4 showed that dAtad3a is expressed ubiquitously. Figure S13. R176W and L83V did not affect mitochondria content and morphology in larvae muscles: Mitochondria content and morphology of dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V are comparable to those in wildtype controls. Figure S14. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial content in embryos: Mitochondrial content in dAtad3a null mutant embryo and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P is higher than those in wild type control embryos. Figure S15. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial numbers and size in embryos: In embryo VNC, dAtad3a null mutant and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P exhibited an increase in the mitochondrial size and numbers compared to those in wild type controls. Figure S16. R176W causes small mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W exhibited smaller size of mitochondria compared to those expressing dAtad3aWT, or dAtad3aL83V. Figure S17. R176W and L83V cause various defects in mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V exhibited small, and membrane-defective mitochondria compared to those expressing dAtad3aL83V.

Naturalistic stimuli (e.g., movies) provide the opportunity to study lifelike experiences in the lab. While young adults respond to these stimuli in a highly synchronized manner (as indexed by intersubject correlations [ISC] in their neural activity), older adults respond more idiosyncratically. Here, we examine whether eye movement synchrony (eye-ISC) also declines with age during movie-watching and whether it relates to memory for the movie. Our results show no age-related decline in eye-ISC, suggesting that age differences in neural ISC are not caused by differences in viewing patterns. Both age groups recalled the same number of episodic details from the movie, however, older adults recalled more semantic and false information. In both age groups, more recall of false information related to lower eye-ISC. Finally, older adults showed better cued-recall than younger adults across event boundaries, suggesting that older adults may form broader associations across events when encoding everyday experiences.

The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain1-4. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature5. Here we use a model of efficient coding6 to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.

Using an ensemble of atoms in an optical cavity, we engineer a family of nonlocal Heisenberg Hamiltonians with continuously tunable anisotropy of the spin-spin couplings. We thus gain access to a rich phase diagram, including a paramagnetic-to-ferromagnetic Ising phase transition that manifests as a diverging magnetic susceptibility at the critical point. The susceptibility displays a symmetry between Ising interactions and $XY$ (spin-exchange) interactions of the opposite sign, which is indicative of the spatially extended atomic system behaving as a single collective spin. Images of the magnetization dynamics show that spin-exchange interactions protect the coherence of the collective spin, even against inhomogeneous fields that completely dephase the noninteracting and Ising systems. Our results underscore prospects for harnessing spin-exchange interactions to enhance the robustness of spin squeezing protocols.

Nonlocal light-mediated interactions between cold atoms coupled to the mode of an optical cavity present unique prospects for simulating the quantum dynamics of strongly-interacting many-body systems. In a recent publication, we introduced a tunable, nonlocal sparse spin network that can be engineered in near-term single-mode cavity QED platforms.1 In this companion paper, we study this spin network in detail and pedagogically review its basic dynamical properties, providing theoretical details and calculations that expand on the statements made in our original publication. We show that the network exhibits two distinct notions of emergent geometry - linear and treelike - that can be accessed using a single tunable parameter. In either of these two extreme limits, we find a succinct description of the resulting dynamics in terms of two distinct metrics on the network, encoding a notion of either linear or treelike distance between spins. We also show that the network can be mapped in these two extreme limits onto exactly solvable models: a linear Heisenberg spin chain in one limit, and a Dyson hierarchical model in the other. These observations highlight the essential role played by the geometry of the interaction structure in determining a system's dynamics, and raise prospects for novel studies of nonlocal and highly chaotic quantum dynamics in near-term experiments.

Complementary food hygiene is important to reduce infant exposures to enteric pathogens; however, interventions to improve food hygiene in low- and middle-income countries often ignore the larger context in which childcare occurs. In this study, we explore on observational and qualitative information regarding childcare in an informal community in Kenya. Our findings demonstrate that behaviors associated with food contamination, such as hand feeding and storing food for extended periods, are determined largely by the larger social and economic realities of primary caretakers. Data also show how caregiving within an informal settlement is highly dynamic and involves multiple individuals and locations throughout the day. Findings from this study will help inform the development and implementation of food hygiene interventions in informal urban communities.

Polycyclic aromatic hydrocarbons (PAHs) have been widely studied in sediments due to their ubiquity and persistence in aquatic environments and potential for impairment to biota. Small craft harbour (SCH) sediments in Nova Scotia (NS), Canada, have yet to be studied comprehensively. SCHs are essential to the fishing industry, which is important for the Canadian economy. This spatiotemporal characterization study evaluated thirty-one SCHs across NS between 2001 and 2017 by analyzing sediment reports (secondary data). Sediment PAH concentrations varied widely across all SCHs. Few SCHs exhibited sediment PAH concentrations likely to impair biota based on comparison to sediment quality guidelines. Sediments in the Gulf region of NS were least impacted by PAHs, while the Southwest region was most impacted. Distribution of individual PAHs in sediments follows global trends, with high molecular weight PAHs dominating samples.

Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression. 21 of 29 variants associated with full expressivity of the CF phenotype generated 25% WT-CFTR function; two were higher than 75% WT-CFTR. As expected, 14 of 19 variants associated with partial expressivity of CF had >25% WT-CFTR function; however, four had minimal to no effect on CFTR function (>75% WT-CFTR). Thus, 6 of 48 (13%) missense variants believed to be disease causing did not alter CFTR function. Functional studies substantially refined pathogenicity assignment with expert annotation and criteria from the American College of Medical Genetics and Genomics and Association for Molecular Pathology. However, four algorithms (CADD, REVEL, SIFT, and PolyPhen-2) could not differentiate between variants that caused severe, moderate, or minimal reduction in function. In the setting of variable expressivity, these results indicate that functional assays are essential for accurate interpretation of missense variants and that current prediction tools should be used with caution.

Nursing education is continuously evolving to meet Nursing and Midwifery Council (NMC) requirements for registered nurses. NMC standards state that all registered nurses are responsible for the student learning experience. However, newly qualified nurses can feel underprepared to support pre-registration student learning in the clinical area as the university setting does not facilitate formal peer support. This article will discuss the implementation of a peer facilitation scheme for pre-registration nursing students undertaking the BSc (Hons) and PGDip programmes in a higher education institution in London. The scheme trained second-year nursing students to be peer facilitators for first-year clinical skills sessions. This article will also consider the benefits of the scheme for both first and second-year student nurses.

We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.

Purpose: To compare children’s speech, language and early literacy outcomes, and caregivers' empowerment and satisfaction following provision of 12 sessions of direct intervention (therapy), or face-to-face advice or a purpose-built website (device) while waiting for therapy. Method: A four-stage randomised controlled trial was undertaken involving three- to six-year-old children referred to speech-language pathology waiting lists at two Australian community health centres over eight months (n = 222). Stage 1 (screening): 149 were eligible to participate. Stage 2 (pre-assessment): 117 were assessed. Stage 3 (intervention): 110 were randomised to advice (33), device (39) or therapy (38). Stage 4 (post-assessment): 101 were re-assessed by a speech-language pathologist blinded to the intervention condition. Result: After controlling for baseline levels, children’s speech (percentage of consonants correct) was significantly higher in the therapy group compared to the advice and device conditions. Caregivers' satisfaction was also significantly higher in the therapy condition compared to the device condition. There were no significant differences between the three conditions for children’s intelligibility, language and early literacy or caregivers' empowerment. Conclusion: Therapy resulted in significantly higher speech outcomes than the advice and device conditions and was associated with significantly greater caregiver satisfaction. Provision of a website containing evidence-based material or a single session of advice may be a viable alternative while children wait for therapy targeting intelligibility, language and early literacy, and to empower caregivers.

Numerous conceptually important quantum algorithms rely on a black-box device known as an oracle, which is typically difficult to construct without knowing the answer to the problem that the algorithm is intended to solve. A notable example is Grover's search algorithm. Here we propose a Grover search for solutions to a class of NP-complete decision problems known as subset sum problems, including the special case of number partitioning. Each problem instance is encoded in the couplings of a set of qubits to a central spin or boson, which enables a realization of the oracle without knowledge of the solution. The algorithm provides a quantum speedup across a known phase transition in the computational complexity of the partition problem, and we identify signatures of the phase transition in the simulated performance. Whereas the naive implementation of our algorithm requires a spectral resolution that scales exponentially with system size for NP-complete problems, we also present a recursive algorithm that enables scalability. We propose and analyze implementation schemes with cold atoms, including Rydberg-atom and cavity-QED platforms., Comment: 23 pages, 13 figures, typos corrected, edits for clarity

Organic sediment contaminants [polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs), and polycyclic aromatic hydrocarbons (PAHs)] were assessed using secondary monitoring data from a former tidal estuary (Boat Harbour) impacted by historical industrial effluents. Spatiotemporal characterization of PCDD/Fs and PAHs in sediments was conducted to inform a sediment remediation program designed to return this contaminated aquatic site back to a tidal lagoon. Spatiotemporal variations of sediment PCDD/F and PAH concentrations across Boat Harbour and off-site reference locations were assessed using secondary monitoring data collected between 1992 and 2015. Sediment PCDD/F toxic equivalency (TEQ) and PAH concentrations were compared to sediment quality guidelines. Sediment PCDD/F concentrations exceeded the highest effect thresholds posing severe ecological health risks. High sediment PCDD/F concentrations have persisted in Boat Harbour despite implementation of Pulp and Paper Mill Effluent Chlorinated Dioxins and Furans Regulations in 1992. PAH concentrations varied greatly. Five individual PAH compounds frequently exceeded severe effect thresholds, in contrast to total PAHs, which were below severe effect thresholds. Forensic analysis using PAH diagnostic ratios suggests pyrogenic PAHs derived from wood processes or coal combustion were likely sources. Twenty-five years of monitoring data revealed large data gaps in our understanding of sediment characteristics in Boat Harbour. Gaps included spatial (vertical and horizontal) and temporal variations, presenting challenges for remediation to accurately delineate sediment contaminants. Deeper horizons were poorly characterized compared to shallow sediments (0–15 cm). Historical secondary monitoring data showed that spatial coverage across Boat Harbour was inadequate. Due to severe ecological health risks associated with high sediment PCDD/F concentrations, remediation of the entire sediment inventory is recommended. Detailed vertical and horizontal sampling within Boat Harbour, establishment of local baseline concentrations, and additional sampling in down-gradient-receiving environments for a suite of contaminants are required to better characterize sediments prior to remediation.

Data from cell culture, mice, and human epidemiological studies have identified and validated growth hormone receptor (GHR) expression and growth hormone (GH) action as an oncogenic factor in cancer. Recent studies by us and others have revealed a unique aspect of GH mediated endocrine regulation of pharmacological therapy resistance in human melanoma and breast cancer. GH overexpression was found to not only promote tumor proliferation, migration, and invasion but also associated with refractoriness towards radiation and chemotherapy. However, the underlying mechanisms of the observed GH effects were unknown. To understand the molecular details of therapy resistance of the GH-GHR axis in cancer, we have used four different GHR-positive human cancers of pancreas, kidney, lung, and melanoma. We have identified multi-modal therapy resistance pathways regulated by GH action in these tumors, which was absent in GHR-negative cell lines. Here we report our latest findings explaining the method of action of GH driven cancer therapy resistance and the associated mediators. Expression of GHR and an autocrine / paracrine GH production, elicited specifically by onset of therapy (chemo, targeted, radiation) upregulates (i) ATP-binding cassette containing multidrug efflux pumps, (ii) phenotype switch via epithelial-to-mesenchymal transition, (iii) extracellular matrix rearrangement to promote tumor invasion, and (iv) cytokine mediated immunoediting. Attenuation of the GHR activity using GHR-antagonists or CRISPR-Cas9 mediated GHR knockout severely sensitized the cells towards therapy. In vivo studies using syngeneic mouse models and a thorough analyses of the TCGA data provide robust confirmation to our in vitro findings. Based on the above and ongoing studies in different mouse models of GH action, we speculate that targeting GHR as an adjuvant in cancer therapeutics might synergize therapeutic applications and lead towards a significantly improved prognosis for GHR-positive cancers.

Dynamic spatial light modulators (SLMs) are capable of precisely modulating a beam of light by tuning the phase or intensity of an array of pixels in parallel. They can be utilized in applications ranging from image projection to beam front aberration and microscopic particle manipulation with optical tweezers. However, conventional dynamic SLMs are typically incompatible with high-power sources, as they contain easily damaged optically absorbing components. To address this, we present an SLM that utilizes a viscous film with a local thickness controlled via thermocapillary dewetting. The film is reflowable and can cycle through different patterns, representing, to the best of our knowledge, the first steps towards a dynamic optical device based on the thermocapillary dewetting mechanism.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH, high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO, high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

We report direct observations of photon-mediated spin-exchange interactions in an atomic ensemble. Interactions extending over a distance of 500 microns are generated within a cloud of cold rubidium atoms coupled to a single mode of light in an optical resonator. We characterize the system via quench dynamics and imaging of the local magnetization, verifying the coherence of the interactions and demonstrating optical control of their strength and sign. Furthermore, by initializing the spin-1 system in the mF = 0 Zeeman state, we observe correlated pair creation in the mF = +/- 1 states, a process analogous to spontaneous parametric down-conversion and to spin mixing in Bose-Einstein condensates. Our work opens new opportunities in quantum simulation with long-range interactions and in entanglement-enhanced metrology.

Spatiotemporal (2001–2017) characterization of sediment metal concentrations were assessed in 31 small craft harbours (SCHs) in Nova Scotia, Canada by analyzing secondary data from government sediment assessment reports. Surficial sediment samples (n = 576) were collected prior to routine maintenance or constriction dredging activities. Sediment metal concentration ranges were 0.5–62 (As), 0.05–3.8 (Cd), 1–305 (Cr), 0.5–220 (Cu), 0.003–1.85 (Hg), 0.73–583 (Pb) and 5–2300 (Zn) mg/kg (dw), respectively. Most sediment metal concentrations (>56% of samples) were below low effect level and >96% were below high effect level sediment quality guidelines, suggesting limited ecological impairment to marine biota. Despite wide temporal coverage (16 years), large variation in sediment concentrations across SCHs were likely due to regular dredging activities preventing long-term accumulation of contaminants. Spatial distribution and enrichment factor results revealed that Canso was most impacted by metals, followed by Clarks Harbour.

Background: Immune checkpoint inhibitors (ICIs) provide benefit for immunogenic cancers that naturally attract T cell infiltration, but have limited benefit for patients with tumors that lack natural T cells in the tumor microenvironment (TME) including many breast cancers. Suboptimal and inconsistent immune responsiveness in many cancers is likely the result of a lack of tumor antigen expression and/or recognition together with multiple suppressive signals within the TME that provide a formidable barrier to T cell infiltration. Emerging data suggest that these factors can be overcome by combining epigenetic modulation that reprograms myeloid-derived suppressor cells (MDSCs) and upregulate T cell-attracting signals within the TME, with ICIs. Our paralleled preclinical and clinical trial investigates the mechanisms and efficacy of the epigenetic modulator, entinostat (ENT) to reprogram the immune suppressive cells within the TME. Methods: We conducted a multicenter phase 1 clinical trial (NCT02453620) of entinostat combined with nivolumab +/- ipilimumab in patients with advanced cancers including hormone-receptor positive or triple-negative breast cancer (TNBC). Mandatory tumor samples are being obtained pre-treatment, post-treatment with 2 weeks of entinostat, and 8 weeks post combination therapy with ICIs. We used immunohistochemical (IHC) for CD8 and FoxP3 to determine a ratio representative of immune infiltration in response to therapy. Preclinical studies utilize mouse models of breast cancer (NeuN and 4T1) and mirror the treatment scheme used in the clinical trial. We employed multiparameter flow cytometry, single cell RNA sequencing, bulk RNA sequencing of tumor specimens and patient samples to specifically interrogate the role of ENT in modulating STAT3 as a master regulator of downstream inflammatory pathways. Results: With regard to the clinical trial, out of 35 patients enrolled, 11 were diagnosed with breast cancer. We observed 4 partial responses, 2 responses in patients with breast cancer, with an ORR of 12%. We have almost completed accrual of our expansion cohort of 15 patients with advanced HER2 negative breast cancer. The primary outcomes of the clinical trial will be reported elsewhere, here we are focusing on important correlative findings which suggest a combination of ENT with ICIs alters CD8/FoxP3 ratios in certain patients. Bulk-RNA sequencing or patient samples is underway. Preliminary data from animal models obtained using scRNA-seq has begun to elucidate altered MDSC signaling pathways, and to identify gene expression changes in immune, stromal, and tumor cells following treatment with ENT. These data are also expected to identify new targets for ICI sensitization. Conclusions: Preliminary results with IHC staining suggests increased immune infiltration with combination therapy. Sequencing analysis will likely provide deeper insight into mechanisms driving response. The mechanisms of response to ICIs in patients with breast cancer have yet to be elucidated. These studies will provide the necessary scientific evidence to uncover mechanisms behind the transformation of the immunosuppressive TME and provide new targets that could improve clinical response to ICIs to maximize patient survival. The core biological themes explored will likely have a broad impact in the field of breast cancer and affect the paradigm of therapies available to patients in the clinic. These findings will help determine how treatment with ICIs will be successful to obtain durable responses for breast cancer patients. Citation Format: Evanthia T Roussos Torres, Luciane Tsukamoto Kagohara, Emily Davis, Christine Rafie, Brian Christmas, Qingfeng Zhu, Chenguang Wang, David Lim, Robert Anders, Elana Fertig, Vincent Chung, Patricia Lorusso, Adam Brufsky, Elizabeth M Jaffee, Vered Stearns, Roisin Connolly. Reprogramming the suppressive tumor microenvironment of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-06.