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Holly A Maulhardt,1 Alyson M Marin,1 Gere S diZerega1,2 1US Biotest, Inc, San Luis Obispo, CA, USA; 2Nanology, LLC, Fort Worth, TX, USACorrespondence: Gere S diZerega, US Biotest, Inc, 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA, Tel +01 805 595 1300, Email Gere.diZerega@usbiotest.comAbstract: The effects of intratumoral (IT) large surface area microparticle paclitaxel (LSAM-PTX) alone and in combination with systemic administration of the programmed cell death protein antibody (anti-mPD-1) were evaluated in a syngeneic murine model of melanoma. Groups of mice with subcutaneously implanted Clone M3 (Cloudman S91) tumors were treated with single and combination therapies. Tumor volume (TV) measurements, body weights, and clinical observations were followed in-life. At end of study, tumor-site tissues were collected, measured, and processed for flow cytometry along with blood and lymph nodes. The combination of LSAM-PTX + anti-mPD-1 resulted in an antitumoral response, which produced a significant decrease in TV compared to control animals. TV decreases also occurred in the LSAM-PTX and anti-mPD-1 groups. Flow cytometry analysis found increases in granulocytes and M2 macrophages and decreases in dendritic cells (DC) and monocytic myeloid-derived suppressor cells (M-MDSC) in tumor-site tissues. Increases in granulocytes and decreases in CD4+ T cells, macrophages, and M1 macrophages were found in the blood of animals administered the combination treatment. Increases in natural killer (NK) cells were found in lymph node tissue in the combination treatment group. These findings suggest that IT LSAM-PTX may provide benefit in the local treatment of melanomas and may synergize with systemic anti-PD-1 therapy, leading to additional tumoricidal outcomes without added systemic toxicity.Keywords: clone M-3, nanopac, combinatorial immunotherapy, PD-1

Abstract Background Mantle cell lymphoma (MCL) is a type of B‐cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real‐world data are scarce. Methods In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). Results On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow‐up of 8.6 months, the mean duration of response (DOR), progression‐free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. Conclusions In summary, pirtobrutinib represented a safe and effective treatment option in a small real‐world population.

Abstract CD19‐directed chimeric antigen receptor (CAR)‐T cell therapy has become a standard treatment for relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL). While the benefits of CAR‐T cell treatment are clear in the general patient population, there remains a relative scarcity of real‐world evidence regarding its efficacy and toxicity in patients (pts) aged ≥70 years with DLBCL. We conducted a multicenter retrospective analysis including 172 r/r DLBCL pts with CAR‐T cell treatment, axicabtagene ciloleucel or tisagenlecleucel, between 2019 and 2023 at three tertiary centers. Pts were grouped by age at CAR‐T infusion (

ObjectiveThe Consortium for Clinical Characterization of COVID-19 by EHR (4CE) is an international collaboration addressing coronavirus disease 2019 (COVID-19) with federated analyses of electronic health record (EHR) data. We sought to develop and validate a computable phenotype for COVID-19 severity.Materials and methodsTwelve 4CE sites participated. First, we developed an EHR-based severity phenotype consisting of 6 code classes, and we validated it on patient hospitalization data from the 12 4CE clinical sites against the outcomes of intensive care unit (ICU) admission and/or death. We also piloted an alternative machine learning approach and compared selected predictors of severity with the 4CE phenotype at 1 site.ResultsThe full 4CE severity phenotype had pooled sensitivity of 0.73 and specificity 0.83 for the combined outcome of ICU admission and/or death. The sensitivity of individual code categories for acuity had high variability-up to 0.65 across sites. At one pilot site, the expert-derived phenotype had mean area under the curve of 0.903 (95% confidence interval, 0.886-0.921), compared with an area under the curve of 0.956 (95% confidence interval, 0.952-0.959) for the machine learning approach. Billing codes were poor proxies of ICU admission, with as low as 49% precision and recall compared with chart review.DiscussionWe developed a severity phenotype using 6 code classes that proved resilient to coding variability across international institutions. In contrast, machine learning approaches may overfit hospital-specific orders. Manual chart review revealed discrepancies even in the gold-standard outcomes, possibly owing to heterogeneous pandemic conditions.ConclusionsWe developed an EHR-based severity phenotype for COVID-19 in hospitalized patients and validated it at 12 international sites.

Across the lifespan, individuals frequently choose between exploiting known rewarding options or exploring unknown alternatives. A large body of work has suggested that children may explore more than adults. However, because novelty and reward uncertainty are often correlated, it is unclear how they differentially influence decision-making across development. Here, children, adolescents, and adults (ages 8–27 years, N = 122) completed an adapted version of a recently developed value-guided decision-making task that decouples novelty and uncertainty. In line with prior studies, we found that exploration decreased with increasing age. Critically, participants of all ages demonstrated a similar bias to select choice options with greater novelty, whereas aversion to reward uncertainty increased into adulthood. Computational modeling of participant choices revealed that whereas adolescents and adults demonstrated attenuated uncertainty aversion for more novel choice options, children’s choices were not influenced by reward uncertainty.

Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma‐promoting, alternatively activated M2‐like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor‐associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)‐conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B‐cell lymphoma (DLBCL) cells or, classically, by macrophage colony‐stimulating factor (M‐CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD‐L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M‐CSF stimulation in M2‐like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose‐dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL‐TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co‐cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma‐only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206‐positive cells, with high MRC1 expression being characteristic of HL‐stage IV. In summary, the lymphoma‐TAM interaction contributes to matrix‐remodeling and lymphoma cell dissemination.

Even after years of training and awareness building at the state and national level, industrial cross-cutting systems (motor-driven, steam, process heating) continue to offer significant opportunities for energy savings. The US Department of Energy estimates these remaining savings at more than 7 percent of all industrial energy use. This paper presents a different approach to promoting industrial system energy efficiency -- providing plant personnel with ready access to data upon which to base energy management decisions.In 2005, a Del Monte Foods fruit processing plant in Modesto, California worked with Lawrence Berkeley National Laboratory (LBNL) to specify and purchase permanent instrumentation for monitoring their compressed air system. This work, completed as part of a demonstration project under a State Technologies Advancement Collaborative (STAC) grant, was designed to demonstrate the effectiveness of enterprise energy management (EEM), which is predicated on the assumption that the energy efficiency of existing, cross-cutting industrial systems (motor-driven, steam) can be improved by providing management and operating personnel with real-time data on energy use. The initial STAC grant provided for the installation and some initial analyses, but did not address the larger issue of integrating these new data into an ongoing energy management program for the compressed air system.The California Energy Commission (CEC) decided to support further analysis to identify potential for air system optimization. Through the CEC's Energy in Agriculture Program, a compressed air system audit was performed by Tom Taranto to: Measure and document the system's baseline and CASE Index of present operation; Establish methods to sustain an ongoing CASE Index measure of performance; Use AIRMaster+ to analyze supply side performance as compared to the CASE Index; Identify demand side opportunities for efficiency and performance improvement; Assess supply / demand balance and energy reduction opportunities; Evaluate the present air compressor control strategy and potential improvement, and Collect data to benchmark parameters for compressed air systems at similar facilities.This paper addresses the benefits and limitations of both continuous and targeted measurement in benchmarking, optimizing, and sustaining an efficient compressed air system. Included are methods used in applying both of these measurements to a complex industrial system. Further, this paper will describe the results of these additional analyses and the plant response to them.

Our prior research has identified neural correlates of cognitive control in the anterior cingulate cortex (ACC), leading us to hypothesize that the ACC is necessary for increasing attention as rats flexibly learn new contingencies during a complex reward-guided decision-making task. Here, we tested this hypothesis by using optogenetics to transiently inhibit the ACC, while rats of either sex performed the same two-choice task. ACC inhibition had a profound impact on behavior that extended beyond deficits in attention during learning when expected outcomes were uncertain. We found that ACC inactivation slowed and reduced the number of trials rats initiated and impaired both their accuracy and their ability to complete sessions. Furthermore, drift-diffusion model analysis suggested that free-choice performance and evidence accumulation (i.e., reduced drift rates) were degraded during initial learning--leading to weaker associations that were more easily overridden in later trial blocks (i.e., stronger bias). Together, these results suggest that in addition to attention-related functions, the ACC contributes to the ability to initiate trials and generally stay on task. [ABSTRACT FROM AUTHOR]

Abstract Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53, APC, BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis.