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It is well known by now that John McGahern was a scrupulous reviser of his own work, even if this insight into his compositional methods has not been accompanied by a substantial body of research on the archive and the revisions themselves. This essay aims to address this anomaly by focusing on the genetic evolution of McGahern's short story ‘Doorways’. Specifically, it will concentrate on the earliest handwritten drafts when the work is at its most provisional. The consensus view of McGahern's writing practices is of an artist committed to ideals of Flaubertian perfectionism, but implicit in this view is a bias towards the more granular work of late-stage refinement. The approach this essay takes shows McGahern at his most distant from the Flaubertian perfectionist that he is best known as, thus opening up new ways to reconsider how those works achieve their distinctive appearance of refined delicacy and simplicity.

This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.

Hydration plays an important role in performance, injury prevention, and recovery for athletes engaged in competitive sports. Therefore, it is important that strength and conditioning coaches understand an athlete’s hydration needs to prevent illness and enhance performance. The purpose of this study was to identify hydration knowledge, attitudes, and behaviors of collegiate track and field throwers, as well as identify barriers to hydration and sources of nutritional information. The Rehydration and Refueling in Collegiate Track and Field Throwers Survey was sent to 271 track and field thrower coaches with a request to forward the email to current track and field throwers. Pearson correlation coefficients were calculated regarding knowledge, attitude, and behavior scores among the participants in this sample. Differences among response patterns were assessed via Chi-square analysis. Alpha level was set at p = .05. Results demonstrated that 97.3% (n = 287) of respondents knew that dehydration would decrease performance, but 50.5% (n = 149) erroneously believed thirst was the best indicator of dehydration. Chi-square analysis demonstrated a significant difference in reported values between participants who intended to eat a performance-enhancing diet and those who consumed less fluid than recomended values (207 – 295 m)l in the 2-3 hours prior to competition (χ2 = 10.87, p < .05). Pearson correlation coefficients demonstrated a large association between knowledge and behavior (r = .70, p < .05), a medium association between knowledge and attitude (r = .41, p < .05), and a small association between attitude and behavior (r = .21, p < .05). This suggests that strength and conditioning coaches and health staff need to educate and monitor hydration behaviors among collegiate track and field throwers to optimize performance.

Researchers suggest that sport participation among athletes with disabilities promotes healthier lifestyles, increases self-esteem, and enhances peer acceptance. Ideally, coaches should be confident in teaching skills, tactics, and sportsmanship, while exhibiting appropriate leadership behaviors in order to positively impact the psychosocial development of any athlete. Thus, the present research examined sources of coaching efficacy that predict leadership behaviors in coaches who work with athletes who have physical disabilities. Seventy international Paralympic coaches of female and male sport teams completed a modified version of the Coaching Success Questionnaire-2, the Coaching Efficacy Scale and the Leadership Scale for Sports. Regression models indicated that total coaching efficacy was a significant predictor of instructional and positive feedback leadership behaviors, with prior success also being a significant predictor of instructional behavior.

During a shot put, there are different finite variables that can be controlled by the thrower, including release angle, release height, release direction, and release velocity. Previous studies have determined thresholds of release velocity necessary for achieving certain distances, and this case study sought to expand upon that concept. Conclusions from key biomechanical data can make a significant difference in the performance of athletes in the shot put if properly understood by coaches. By utilizing this scientific approach to the shot put event, the throws coach will be able to determine more accurate adjustments and devise training stimuli to better accommodate the athlete. In this case study, researchers and the coach attempted to bridge the gap in the approach to teaching and coaching the glide shot put by using a physics-based equation regarding projectile motion in tandem with biomechanical analyses. The use of immediate feedback via video analysis was an essential part the coaching and teaching system. The athlete’s release angles decreased, and her maximum release velocities increased from 12.5 m/s in 2015 to 13.1 m/s in 2016. This USATF coaching education shot put project is an example in which the cooperation between sport science and coaching helped to produce an Olympic berth (19.24 m) by Felisha Johnson in the women’s shot put in 2016.

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R2-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2–82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.

Coaches are trusted to create effective training plans based on the abilities of their athletes. However, there can exist a discrepancy between the coaches’ intended training intensity and the intensity perceived by their athletes. Thus, the purpose of this study was to evaluate athletes’ perceptions of training intensity and how they compared to their coach’s intended training intensity. Six female collegiate track and field athletes who ran >800 meter events were recruited for this study (Mean [SD]: 21.3 [1.2] years). Training duration, rate of perceived exertion (RPE), average heart rate for each training session and hours slept nightly were recorded for the next 14 weeks. Easy training days showed a discernible difference with actual session RPE rating higher than the target value (mean [SD] perception 3.25 [.847], target 1.51 [.692], p

Introduction The newly diagnosed pancreatic ductal adenocarcinoma (PDAC) population has a high unmet need for effective treatments, with median survival of < 1 year. The phase 3 APACT (Adjuvant Pancreatic Adenocarcinoma Clinical Trial) evaluated the use of adjuvant nab-paclitaxel plus gemcitabine vs. gemcitabine in 866 patients with surgically resected PDAC. We explored the tumor microenvironment (TME) of >500 baseline resected APACT tumors to identify TME features that are associated with adverse outcomes. Methods Biopsy analyses included RNA-seq, DNA-seq, and multiplexed immunohistochemistry (mIHC). We quantified, for 533 patient biopsies, via mIHC the spatial arrangement of 7 immune cell types and 2 checkpoint markers relative to tumor and nontumor regions, and pairwise colocalization relative to each other. We identified combinations of biomarkers that correlate significantly with molecular signatures, predefined patient subsets, and overall survival (OS). Hazard ratios (HR) and p-values were computed via a Cox proportional hazards regression model which included resection and lymph node status as covariates. Significantly differentially-expressed transcripts were associated with biomarkers derived from the mIHC via unpaired t-test. Results Higher densities of CD8+ T cells within tumor regions correlated with longer OS (hazard ratio HR=0.76; p=0.03), and higher overall densities of CD163+ macrophages correlated with shorter OS (HR=1.44; p=0.006). We furthermore identified a patient subset (n=72) with a combination of higher CD8+ T cell and lower CD163+ macrophage densities that had a strikingly significant decreased HR of 0.46 (p=0.009). Moreover, patients with a high degree of spatial colocalization between CD8+ T cells and dual-positive CMAF+CD163+ M2-like macrophages observed a significant increased HR of 1.51 (p=0.0006), a biomarker only surpassed by nodal status in significance of correlation with OS (HR=1.9; p=0.00015). While this cellular colocalization was computed to be independent of cell densities, we found that the association of this colocalized pair of cell types with shorter OS was most significant for patients with lower overall CD8+ T cell densities (HR=1.84; p=0.0004). We further identified differentially regulated transcripts associated with this interaction and found specific putative ligand-receptor pairs that were also associated with lower OS. Conclusion A combination of greater infiltration of CD8+ cytotoxic T cells and lower infiltration of macrophages is associated with longer OS in the APACT trial. Moreover, the spatial colocalization between CD8+ T cells and CMAF+ M2 macrophages is associated with shorter OS. These findings were observed across both treatment arms of the study. Future investigation of this apparent interaction, and associated differentially expressed transcripts, may inform management of patients with pancreatic adenocarcinoma and increase effectiveness of PDAC therapies. Citation Format: David J. Reiss, Andrew Browne, Brian Fox, Alexander V. Ratushnyy, Maria Wang, Andrew V. Biankin, Thomas Lila. Spatial arrangements of immune cells of the pancreatic ductal adenocarcinoma tumor microenvironment correlated with outcomes in the phase 3 APACT trial [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C085.

The ability to predict individual differences in motor learning has significant implications from both theoretical and applied perspectives. However, there is high variability in the methodological and analytical strategies employed as evidence for such predictions. Here, we critically examine the evidence for predictions of individual differences in motor learning by reviewing the literature from a 20-year period (2000-2020). Specifically, we examined four factors: (i) the predictor and predicted variables used, (ii) the strength of the prediction and associated sample size, (iii) the timescale over which the prediction was made, and (iv) the type of motor task used. Overall, the results highlight several issues that raise concerns about the quality of the evidence for such predictions. First, there was a large variation in both predictor and predicted variables, suggesting the presence of a large number of researcher degrees of freedom. Second, sample sizes tended to be small and the strength of the correlation showed an inverse relation with sample size. Third, the timescale of most predictions was very short, mostly constrained to a single day. Last, most studies were largely restricted to two experimental paradigms - adaptation and sequence learning. Based on these issues, we highlight recommendations for future studies to improve the quality of evidence for predicting individual differences in motor learning.

Background The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Methods and findings Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5–29, 49–69 versus 70–82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI –1 to 31, 92–120 versus 113–129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6–36, 49–73 versus 74–90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. Conclusions In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies., Author summary Why was this study done? The cells around a tumor, also known as the tumor microenvironment (TME), can help a tumor grow by suppressing the immune system or fight a tumor by mounting an immune response. Most studies of multiple myeloma (MM) have focused on the tumor itself, rather than the bone marrow (BM) TME in which the tumor is growing. We hypothesized that the MM TME held clues that could help us better treat patients. What did the researchers do and find? We used a gene-expression–based computational technique to determine which cell types were present in patient BM. Patients with BM lacking a family of innate immune cells called granulocytes presented with worse outcomes compared to other patients. As MM progresses from a predisease to a cancerous state, the percentage of granulocytes decreases; the patients with the fewest granulocytes had more serious diseases. What do these findings mean? If granulocytes help myeloma patients respond to therapy, then addressing the decline in granulocytes may improve MM treatment. Patients with MM and few granulocytes in their BM should be watched for worse outcomes.

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R

The purpose of this study was to test the perceived effects of psychological skills training (PST) on anxiety and anaerobic performance in college-aged students. Fifty-five college students (44 females, 11 males) volunteered to complete an online survey instrument. Participants were recruited via convenience sampling methods to answer questions built through a Qualtrics online survey. The questionnaire was split into two sections. The first section asked participants to identify psychological skills, their familiarity with them, and their frequency of use. The second section consisted of categorizing each skill so participants could mark the extent to which it influences their training goal. Data analysis showed males were more familiar with five out of six psychological skills when compared to females. This is result is likely due to males showing higher stress levels during training and performance compared to females. The findings of this study confirm the importance of mental health education and PST in college students.

This paper describes several aspects of the physical layer and over the air interface of Loon. Loon utilizes stratospheric balloon-based high-altitude platforms (HAPs) that use Long-Term Evolution (LTE) to connect people with standard User Equipment (UEs) to the Internet. In particular, topics covered include the Loon prototype eNodeB (eNB) antenna pattern, the observed channel, UE battery life, and coexistence with terrestrial networks using the same spectrum. While channel models from a HAP to the ground have been well studied in the past, the use of polarization diversity to establish Multi-Input Multi-Output (MIMO) communication to real UEs below 1 GHz has not. In addition, a theoretical analysis of terrestrial coexistence and an analysis of the estimated impact on UE battery life when communicating with HAPs are presented. Finally, results from several measurement campaigns and from experiments with polarization diversity are presented as a spot check of theory.

Summary Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease affecting over 100 000 people in Europe with an increasing incidence. Available treatments offer only slowing of disease progression and are poorly tolerated by patients leading to cessation of therapy. Lung transplant remains the only cure. Therefore, alternative treatments are urgently required. The pathology of IPF is complex and poorly understood and thus creates a major obstacle to the discovery of novel treatments. Additionally, preclinical assessment of new treatments currently relies upon animal models where disparities with human lung biology often hamper drug development. At a cellular level, IPF is characterized by persistent and abnormal deposition of extracellular matrix by fibroblasts and alveolar epithelial cell injury which is seen as a key event in initiation of disease progression. In-depth investigation of the role of alveolar epithelial cells in health and disease has been impeded due to difficulties in primary cell isolation and culture ex vivo. Novel strategies employing patient-derived induced pluripotent stem cells engineered to produce type 2 alveolar epithelial cells (iAEC2) cultured as three-dimensional organoids have the potential to overcome these hurdles and inform new effective precision treatments for IPF leading to improved survival and quality of life for patients worldwide.

Background and Objectives: National Collegiate Athletic Association (NCAA) soccer coaches implement numerous warm-up and flexibility strategies to prepare athletes for training and competition. The F&eacute, d&eacute, ration Internationale de Football Association (FIFA) developed the 11+ injury prevention program to reduce non-contact injuries. This study aimed to analyze the level of familiarity with and implementation of the evidence-based FIFA 11+ amongst NCAA Division I (DI) and Division III (DIII) men&rsquo, s and women&rsquo, s soccer coaches. Materials and Methods: NCAA soccer coaches in the United States received an Institutional Review Board&mdash, approved survey hyperlink. A total of 240 coaches completed the survey. The respondents represented 47.5% men&rsquo, s and 52.5% women&rsquo, s teams distributed within DI and DIII programs. Descriptive statistics are reported as frequency counts and mean &plusmn, standard deviation where applicable. Pearson&rsquo, s chi-square tests were performed to assess potential differences with a significance level set at &alpha, &lt, 0.05. Results: The results indicated that approximately 62% of the respondents reported being familiar with the FIFA 11+ program. Of those coaches familiar with the program, 15.0% reported full implementation, 57.5% reported partial implementation, and 27.5% reported no implementation. Chi-square analyses revealed significant differences in FIFA 11+ implementation based upon division level (&chi, 2 = 4.56, p = 0.033) and coaching certification levels (&chi, 2 = 13.11, p = 0.011). Conclusions: This study indicates that there is a gap between FIFA 11+ knowledge and actual implementation. To reduce the risk of non-contact injury, there is a need to educate coaches and athletic trainers on the purpose of the FIFA 11+ program and how to perform the exercises correctly.

Introduction: Mutations in TP53 occur in 10% of patients (pts) with AML and HR-MDS and have been associated with worse outcomes and an immunosuppressive phenotype. To define the immune and epigenetic landscape in TP53-M advanced myeloid neoplasms (MN), we compared data from 61 pts with HR-MDS or AML with TP53 mutations (TP53-M) to 143 TP53 wildtype (TP53-WT) pts who were followed prospectively with serial samples in a well-annotated clinical trial in which all pts received hypomethylating agent (HMA)-based therapy. Methods: The FUSION trial (NCT02775903) was a large, randomized phase 2 study comparing azacitidine (AZA) monotherapy with AZA + anti-PD-L1 antibody durvalumab in 2 separate cohorts of previously untreated unfit AML and HR-MDS pts (Zeidan A et al, ASH 2019). Responses were classified by IWG 2003 and 2006 criteria for AML and MDS, respectively. Survival was estimated using Kaplan-Meier techniques. Samples from peripheral blood (PB) and bone marrow (BM) were obtained at baseline and serially on trial. A 38-targeted mutation analysis was performed at Munich Leukemia Laboratory. Only level 1 pathogenic TP53 mutations with variant allele frequency (VAF) ≥2% were included. DNA methylation was assessed using Illumina's Infinium Human Methylation EPIC methylation array. Immunophenotyping and immune checkpoint expression was performed using flow cytometry. Gene expression profiles were studied by RNA-sequencing. Results: Of 129 AML and 84 HR-MDS pts enrolled in FUSION trial, 37 had TP53-M AML, 88 TP53-WT AML, 24 TP53-M HR-MDS, and 55 TP53-WT HR-MDS pts. The average VAF for TP53 mutations were 37%, and 90% had ≥10% VAF. TP53-M AML pts were more likely to have poor-risk cytogenetics, therapy-related disease, and lower BM blast percentage compared to TP53-WT AML pts. TP53-M HR-MDS were more likely to have secondary MDS, very poor risk cytogenetics by IPSS-R, and very high risk IPSS-R score. There were no statistically significant differences in overall response rate (ORR) between TP53-M and TP53-WT pts (AML cohort: ORR: 35.1% [95% CI: 21%-53%] vs. 34.1% [CI: 26%-45%]; HR-MDS cohort: ORR: 41.7% [CI: 23%-63%] vs. 60% [CI: 46%-73%]). Median OS was 8.1 [95% CI: 5.4 - 13] months (mos) among TP53-M AML pts and 16.6 [95% CI: 13 - 21] mos for TP53-WT AML pts [Figure 1A]. Median OS was 9.8 [95% CI: 9.3 - 20+] mos for TP53-M HR-MDS pts and 23.5 [95% CI: 12 - 25+] mos for TP53-WT HR-MDS pts [Figure 1B]. Global DNA methylation was independent of TP53 mutation status in both AML (global methylation score x10^5: TP53-M: 4.9 [SD: 0.23] vs TP53-WT: 4.8 [SD: 0.33]; p=0.35) and HR-MDS pts (global methylation score: TP53-M: 4.8 [SD: 0.20] vs TP53-WT: 4.7 [SD: 0.25]; p=0.24) at baseline. DNA methylation changes after one cycle of AZA treatment were similar in both cohorts (AML: TP53-M:4.4 [SD: 0.38] vs TP53-WT: 4.5 [SD: 0.41, p=0.33]; HR-MDS: TP53-M: 4.3 [SD: 0.35] vs TP53-WT: 4.3 [SD: 0.36]; p=0.52). In RNA sequencing (Figure 2), TP53-M pts had higher expression of T-cell genes (e.g. IL7R) in both AML and HR-MDS compared to TP53-WT pts. Compared to TP53-WT pts, IFN alpha signature genes were reduced only in TP53-M AML pts but were increased in TP53-M HR-MDS pts. PD-L1 (CD274) expression was correlated with the T-cell gene signature and had a higher expression in TP53-M samples. TP53-M pts showed lower expression of tumor associated genes (e.g. CD34) consistent with the tumor cell percentages seen by BM flow cytometry. However, in gene set enrichment analysis, MYC target genes, MTORC1, and E2F were enriched in TP53-M samples consistent with the higher expression of proliferation genes (e.g., MKI67). In the bone marrow flow cytometry of AML pts, more T-cells were seen in TP53-M pts (Figure 3A), and PDL1 positive tumor cells were trending higher in TP53-M pts while the total abundance of tumor cells was slighter higher in TP53-WT (Figure 3B). Discussion: We confirm here that achieving a response to AZA therapy in AML or HR-MDS pts is not impacted by presence of TP53 mutations, however as expected median OS was substantially shorter among TP53-M pts for both AML and HR-MDS. In analyzing the epigenetic landscape, there were no differences in baseline global DNA methylation by TP53 status. RNA sequencing showed enrichment of T-cell genes and PD-L1, and an increase in gene expression of proliferation genes in TP53-M pts. Taken together, these findings support the presence of immunosuppressive microenvironment among TP53-M pts with advanced MN. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Jasper: Consultancy; Epizyme: Consultancy; Acceleron: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; BioCryst: Other: Clinical Trial Committees; Astex: Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; ADC Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Agios: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; Ionis: Consultancy; Astellas: Consultancy. Hasle: Bristol Myers Squibb: Current Employment. Thompson: Bristol Myers Squibb: Current Employment. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boss: Bristol Myers Squibb: Current Employment. Fox: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Introduction: The transmembrane protein CD47 is ubiquitously expressed on normal cells and often overexpressed on cancer cells, including NHL. Binding of CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an anti-phagocytic signal enabling tumor cells to escape the innate immune response. Macrophage antitumor activity can be restored by simultaneously blocking the CD47-SIRPα signaling axis and inducing a pro-phagocytic signal with the use of tumor-opsonizing antibodies. Targeting SIRPα on monocytes and macrophages rather than the ubiquitously expressed CD47 may overcome some toxicities associated with anti-CD47 therapies. Here, we report the discovery and characterization of a fully human anti-SIRPα antibody and its preclinical activity in combination with the opsonizing antibody rituximab in CD20+ diffuse large B-cell lymphoma (DLBCL) cell lines. Methods: A total of ~ 10 10 fully human immunoglobulin G antibodies were screened for binding to the extracellular domain of recombinant human SIRPα using a yeast display platform. Surface plasmon resonance was used to determine CC-95251 binding coverage across SIRPα haplotypes. The ability of CC-95251 to block CD47-SIRPα interaction was measured using Octet ® and Biacore™ assays. We determined the crystal structure of SIRPα in complex with the CC-95251 Fab to characterize its epitope and to define the structural basis for CD47-SIRPα interaction blockade. To identify tumor types likely susceptible to CD47-SIRPα axis disruption, expression levels of CD47-SIRPα and CD163 were assessed in bulk tumor samples using The Cancer Genome Atlas (TCGA) data. The antitumor effects of CC-95251 in combination with rituximab were examined by measuring the percentage of phagocytic macrophages in co-culture experiments of differentiated macrophages and CD20+ DLBCL cell lines (OCI-Ly3, RIVA, Pfeiffer, and Karpas 422). To confirm CC-95251 binding to monocytes, immunophenotyping of peripheral blood mononuclear cells from healthy donors and cynomolgus monkeys was performed using multiparameter flow cytometry. Lastly, pharmacokinetics and hematologic effects were analyzed in cynomolgus monkeys after treatment with 10, 30, or 100 mg/kg CC-95251. Results: Initial screening by yeast display yielded ~ 350 candidates. The top 24 clones were characterized fully and CC-95251 was selected as the lead monoclonal antibody exhibiting high binding affinity across the 6 most prevalent SIRPα human haplotypes. CC-95251 potently blocked CD47-SIRPα binding in a dose-dependent manner, with a concentration of 100 nM inhibiting CD47 binding almost completely. Co-crystallization modeling showed that CC-95251 engages SIRPα in a region overlapping the CD47 binding site, demonstrating a mechanism for CD47-SIRPα blockade. DLBCL was identified as a suitable tumor type for CC-95251 treatment based on CD47-SIRPα expression and macrophage infiltration. Co-culture experiments of donor macrophages and several DLBCL cell lines showed that CC-95251 monotherapy had weak-to-moderate antitumor activity. However, when combined with rituximab, the levels of phagocytic macrophages were markedly increased in a CC-95251 dose-dependent manner, suggesting that inhibition of the CD47-SIRPα anti-phagocytic axis with CC-95251 and activation of pro-phagocytic signaling with rituximab provide an enhanced antitumor effect in DLBCL cell lines. CC-95251 predominantly bound to cells of myeloid origin, including monocytes and, to a lesser extent, myeloid dendritic cells, whereas no binding to natural killer cells was observed. Toxicology studies in cynomolgus monkeys showed safe intravenous delivery of CC-95251 at therapeutic doses, with no evidence of white blood cell, monocyte, lymphocyte, or red blood cell depletion. Conclusions: CC-95251 is a novel, high-affinity, fully human monoclonal anti-SIRPα antibody that blocks the binding of CD47 to SIRPα. When combined with the therapeutic opsonizing antibody rituximab, CC-95251 enhances macrophage phagocytic activity against DLBCL cell lines in co-culture models. These results support the clinical evaluation of CC-95251 + rituximab for relapsed or refractory NHL. A phase 1 dose-escalation and -expansion study of CC-95251 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403). Disclosures Chan: Bristol Myers Squibb: Current Employment. Trout: Bristol Myers Squibb: Ended employment in the past 24 months. Mikolon: Bristol Myers Squibb: Current Employment. Adams: Bristol Myers Squibb: Current Employment. Guzman: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Fenalti: Bristol Myers Squibb: Current Employment. Mavrommatis: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abbasian: Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Dearth: Bristol Myers Squibb: Current Employment. Fox: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sivakumar: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hariharan: Bristol Myers Squibb: Current Employment.

Tumor cells engage in bidirectional interactions with stroma and immune cells to promote disease progression and immune evasion. Stroma-specific gene signatures have been associated with outcome in diffuse large B-cell lymphoma (DLBCL), but their immunobiology has been understudied. To characterize the stromal landscape in lymphoma, we performed high-dimensional imaging mass cytometry analysis of the major stroma subsets and revealed a marked expansion and remodeling of the immuno-specialized fibroblastic reticular cells (FRCs) in human DLBCL biopsies (n=53). The FRC network was similarly remodeled in tumors from the IμBcl6 transgenic model of lymphoma, and aberrant fibroblasts were in close proximity to cancer cells. Modelling the interactions between murine and patient FRCs and tumor cells, using 2D and 3D cultures, showed that lymphoma drives the acquisition of an inflammatory-like, pro-tumoral (upregulation of fibroblast activating protein-α, FAP) phenotype and associated functional capabilities. Comparative bulk transcriptomic analysis revealed that lymphoma-FRCs undergo transcriptional reprogramming and activate gene pathways associated with inflammatory responses. Moreover, single-cell RNA-seq revealed an expansion of activated FRC clusters expressing B cell supporting genes, while T cell-associated FRCs were contracted. Altered chemokine signaling pathways in DLBCL-FRCs were functionally linked to reduced attraction of T cells and impeded migration along the lymphoma-reticular network. Moreover, lymphoma-FRCs upregulated expression of inhibitory PD-1 ligands that reduced the anti-tumor cytolytic activity of CD8+ T cells, a T cell bispecific antibody (CD20-TCB, glofitamab) and anti-CD19 CAR T cells in our coculture models. To overcome the immunosuppressive activity of DLBCL-FRCs, we investigated the use of CD20-TCB in combination with stroma-targeting immunocytokine fusion protein drug (FAP-IL2v, RG7461) or costimulatory fusion protein (FAP-4-1BBL, RG7827). Functional cytotoxicity assays using human and murine primary DLBCL patient samples revealed that both stroma-targeting drugs paired effectively with the CD20-TCB to enhance the cytotoxic activity of autologous CD8+ T cells. In addition, the ability of immune-/stroma- targeted combination immunotherapy to trigger anti-tumor activity and CD8+ T cell retention within the FRC-TME was demonstrated using 3D precision-cut lymph node slice-based organotypic cultures of DLBCL and other B cell malignancies. In conclusion our data reveal that lymphoma cells actively reprogram FRCs that acquire altered immunoregulatory function which prevents effective T cell motility and suppresses the anti-tumor function of cytolytic T cells. Importantly, we demonstrate that combination immunotherapy incorporating fibroblast-targeting fusion proteins could effectively recover anti-tumor T cell activity. Citation Format: Benedetta Apollonio, Nedyalko Petrov, Filomena Spada, Peter Jarvis, Domenico Cozzetto, Shichina Kannambath, David Kuo, Mansoor Saqui, Rose-Marie Amini, Gunilla Enblad, Graham Charlotte, Reuben Benjamin, Anna Vardi, Elisabeth Phillips, Jon Salisbury, Eric N. Olson, Brian Fox, Patrick Hagner, Anita Gandhi, Ruth F. Jarrett, Sylvia Herter, Marina Bacac, Christina Klaus, Christian Klein, Alexander Deutsch, Alan G. Ramsay. Stroma-immune landscape in lymphoma: new mechanisms of immunosuppression and therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3165.

Background and aim Institute of Obstetricians and Gynaecologists (RCPI) guideline for preterm prelabour rupture of the membranes (PPROM) recommends the administration of antenatal corticosteroids for women who are 24 to 36 weeks pregnant with anticipated preterm labour. It reduces the risks of respiratory distress syndrome, intraventricular haemorrhage and necrotizing enterocolitis. Recommended steroid is 12 mg of intramuscular Betamethasone given 24 hours apart and at least 24 hours before delivery. This study determined the level of adherence to the guidelines. Methodology Mothers who presented in preterm prelabour rupture of membranes between 1/1/2015 and 31/12/2018 were incorporated into this study. Mothers were evaluated for maternal age, parity, body mass index, ethnicity and demographic distribution. Babies were evaluated for gender, gestational age, weight, corticosteroid type and time of administration prior to delivery, number of doses, type of respiratory support, comorbidities and length of hospital stay. Data was recorded on a collection sheet. Results 103 mothers with PPROM were eligible to receive antenatal steroids, of whom 44(43%) received recommended treatment and 59(57%) received incomplete or no treatment. Out of infants who received complete course of antenatal steroids, 7(16%) required surfactant and intubation, 3 (7%) required CPAP and surfactant, 16(36.4%) required only CPAP, 1 (2%) required high flow oxygen and 17(38.6%) did not need any respiratory support. Of the 59 infants who had an incomplete course or no steroids, 12(20%) required surfactant and intubation, 4(6.8%) required surfactant and CPAP, 20(34%) required CPAP, 1 (2%) required low flow oxygen and 22(37.2%) did not require any support. Of those who received complete treatment, 26 were early preterm (28- Conclusion It was found that adherence to guideline is satisfactory. Imminent preterm delivery prevented 100% adherence to the protocol. This is a risk reduction strategy and parents should be made aware of the possible outcomes.

Failure to clear antigens causes CD8+ T cells to become increasingly hypo-functional, a state known as exhaustion. We combined manually extracted information from published literature with gene expression data from diverse model systems to infer a set of molecular regulatory interactions that underpin exhaustion. Topological analysis and simulation modeling of the network suggests CD8+ T cells undergo 2 major transitions in state following stimulation. The time cells spend in the earlier pro-memory/proliferative (PP) state is a fixed and inherent property of the network structure. Transition to the second state is necessary for exhaustion. Combining insights from network topology analysis and simulation modeling, we predict the extent to which each node in our network drives cells towards an exhausted state. We demonstrate the utility of our approach by experimentally testing the prediction that drug-induced interference with EZH2 function increases the proportion of pro-memory/proliferative cells in the early days post-activation.

James Joyce’s America is the first study to address comprehensively and integrally the nature of Joyce’s relationship with the United States. It challenges the most prevalent view of Joyce as merely indifferent or hostile towards America, arguing that his works show an increasing level of engagement with American history, culture, and politics that culminates in the abundance of allusions to the United States in Finnegans Wake, the very title of which (from an Irish-American song) signals the importance of America to that work. The focus throughout remains consistently on Joyce’s concept of America within the framework of an Irish history to which his works obsessively return. That is, Joyce’s thematic preoccupation with Ireland and its history corresponds to a formal concentration in this study on America’s relation to that specifically post-Famine history. Within that context, it explores first Joyce’s relation to Irish America and how post-Famine Irish history as Joyce saw it transformed the country from a nation of invasions and settlements to one spreading out across the globe, ultimately connecting Joyce’s response to this historical phenomenon to the diffusive styles of Finnegans Wake. This then leads into discussions on American popular and literary cultures in terms of how they appear in relation to or as a function of the British-Irish colonial context in the post-Famine era, before concluding with a consideration of how Joyce incorporated aspects of his American reception into the Wake.

Building on the final chapter’s analysis of Joyce’s reception, the conclusion to this study addresses a subject that has been largely implicit throughout: the predominance of American scholarship in Joyce studies. It also addresses the question of why it has taken so long for an ‘industry’ dominated by Americans to produce a study of America’s role in Joyce’s thinking. At the same time, this conclusion also takes the opportunity to state in a more concise and synoptic manner than has previously been possible precisely what Joyce thought of America. The book’s final gesture is to point beyond itself to work remaining to be done on the broad and many-sided subject of Joyce and America.

Chapter 2 examines allusions to American popular culture in Joyce’s work. A potentially voluminous subject given the sheer range of references, the chapter narrows it down to areas which show a continued engagement across Joyce’s works. One of the most significant examples of this is blackface minstrelsy. Indeed, Joyce, it would appear, is particularly drawn to a specific kind of American popular culture, one with a strong sense of a connection with a history of colonialism, empire, and race. Within this framework, Joyce appropriates and renegotiates Irish relations to not only blackface minstrels, but also the Mutt and Jeff comic strip, Hollywood movies, Broadway musicals, cowboys and Indians, jazz, flappers, speakeasies, and myriad other markers of American popular culture.

Chapter 3 focuses on Joyce’s allusions to American literature. It will look to historicize precisely Joyce’s use of American literature within contemporary perceptions of that writing and the canon; clarifying those perceptions is the aim of the first part of this chapter. Walt Whitman was, the following section argues, an important but ultimately compromised model of a decolonized, national poet for the young Joyce. My argument in the next section, focusing on Bret Harte, emphasizes the point that Harte’s reputation in Ireland in the early twentieth century when Joyce wrote Dubliners was significantly more literary than it is today and that Joyce, like Yeats, was drawn to what appeared as a decolonized literary culture with obvious appeal for Irish writers. Finally, Washington Irving provides another focus for a discussion of allusions to writing marked by colonial histories and revolutions.

Chapter 4 looks at how Joyce incorporated his American reception into Finnegans Wake, with an emphasis on how the Wake represents Joyce’s attitude towards the sudden imperative between the wars to respond to his reception in America. This includes not only the banning, burning, piracy, and trials of his works in Prohibition America, but also a transatlantic print culture which saw his works as they were serialized being published almost exclusively in American-run Little Magazines aimed at American audiences. Moreover, this chapter argues that while the ‘Americanization of Joyce Studies’ didn’t fully take hold until after the Second World War, Joyce was aware of and responded to incipient moves in that direction

The introduction outlines the case that Joyce was far more attentive to the history, culture, and politics of the United States than the critical consensus has previously allowed for. It does so by delineating the specific historical factors that made America significant for Irish writers, including Joyce; by summarizing the textual and manuscript evidence for the significance of America in Joyce’s works; by arguing that those works display an increasing level of engagement with the US roughly in line with key points of transition in Irish and American histories; and by signalling that the focus on the interrelation of those histories provides an explanatory category for a synoptic reading of Joyce’s work as a whole. Finally, in presenting an overview of the chapters to follow, it builds on this historically focused rationale to discuss briefly in broader terms the necessary frames and limits of a study on Joyce and America.