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BackgroundIn May 2024, the FDA approved tarlatamab, a Delta-like ligand (DLL3)/CD3-targeted bispecific T-cell engager, for patients with extensive-stage small cell lung cancer (SCLC) with disease progression following platinum-based chemotherapy and at least one other prior line of therapy. We aim to examine the cellular immune cell profile changes seen in patients receiving this therapy in standard-of-care (SOC) practice.MethodsPatients who received tarlatamab at Mayo Clinic Rochester consented to research blood. Immune phenotyping was performed on whole blood by flow cytometry and analyzed by Kaluza. Data analysis was performed with Excel and PRISM.ResultsThirteen patients with a median age 64 years (range 41-80) who were treated and evaluable for clinical response were included, 53% were women. All had a history of tobacco use.Nine (69%) patients had progressive disease (PD) after a median of 2 cycles, whereas 4 patients had partial response (PR) or stable disease (SD) after at least 2 cycles and remain on therapy (no-PD). Compared to the no-PD group, those whose disease PD early had higher levels of exhausted CD8 T cells at baseline (PD1+TIGIT+CD57+, PD vs no-PD, cells/µL: 17.4±5.6, 7.6±2.6, p=0.006). Interestingly, a CD8 TIGIT+PD1negCD57neg population was also identified which was higher at baseline (PD vs no-PD, cells/µL: 21.5±16.9, 12.2±5.33, p=0.039) and decreased significantly for the PD group from baseline to day 7 (21.5±16.9 to 9.30±10, p=0.039; figure 1A). This population was found to have a different functional profile than the exhausted phenotype in other solid tumors and its role in small cell lung cancer has not been defined. At day 7, compared to the no-PD group, the PD group also had a high level of B-cells (PD vs no-PD, cells/µL: 10.3±15, 4.07±1.83, p=0.027), classical monocytes (PD vs no-PD, cells/µL: 365±279, 226±121, p=0.035), and immunosuppressive monocytes (CD14+HLA-DRneg monocytes, cells/µL: 119±93, 33±42, p=0.05). In addition, the no-PD group had a statistically significant decrease from baseline to day 7 in intermediate monocytes (32.5±7.9 to 17±2.6, p=0.049; figure 1B).ConclusionsIn this study investigating the SOC outcomes of tarlatamab, early PD was associated with higher presence of exhausted CD8 T cells, B cells, and immunosuppressive monocytes. Analysis of additional patients will be shared at SITC meeting.Abstract 844 Figure 1ACD8 T cell phenotype associated with clinical response[Image Omitted. See PDF.]Abstract 844 Figure 1BMonocyte phenotype associated with clinical response[Image Omitted. See PDF.]

Background Diabetes mellitus is a chronic disease that impacts an increasing percentage of people each year. Among its comorbidities, diabetics are two to four times more likely to develop cardiovascular diseases. While HbA1c remains the primary diagnostic for diabetics, its ability to predict long-term, health outcomes across diverse demographics, ethnic groups, and at a personalized level are limited. The purpose of this study was to provide a model for precision medicine through the implementation of machine-learning algorithms using multiple cardiac biomarkers as a means for predicting diabetes mellitus development. Methods Right atrial appendages from 50 patients, 30 non-diabetic and 20 type 2 diabetic, were procured from the WVU Ruby Memorial Hospital. Machine-learning was applied to physiological, biochemical, and sequencing data for each patient. Supervised learning implementing SHapley Additive exPlanations (SHAP) allowed binary (no diabetes or type 2 diabetes) and multiple classification (no diabetes, prediabetes, and type 2 diabetes) of the patient cohort with and without the inclusion of HbA1c levels. Findings were validated through Logistic Regression (LR), Linear Discriminant Analysis (LDA), Gaussian Naïve Bayes (NB), Support Vector Machine (SVM), and Classification and Regression Tree (CART) models with tenfold cross validation. Results Total nuclear methylation and hydroxymethylation were highly correlated to diabetic status, with nuclear methylation and mitochondrial electron transport chain (ETC) activities achieving superior testing accuracies in the predictive model (~ 84% testing, binary). Mitochondrial DNA SNPs found in the D-Loop region (SNP-73G, -16126C, and -16362C) were highly associated with diabetes mellitus. The CpG island of transcription factor A, mitochondrial (TFAM) revealed CpG24 (chr10:58385262, P  = 0.003) and CpG29 (chr10:58385324, P  = 0.001) as markers correlating with diabetic progression. When combining the most predictive factors from each set, total nuclear methylation and CpG24 methylation were the best diagnostic measures in both binary and multiple classification sets. Conclusions Using machine-learning, we were able to identify novel as well as the most relevant biomarkers associated with type 2 diabetes mellitus by integrating physiological, biochemical, and sequencing datasets. Ultimately, this approach may be used as a guideline for future investigations into disease pathogenesis and novel biomarker discovery.

Background Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process. Methods We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5 h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and pharmacological manipulations of VCP. Results VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on seeding in HEK293T tau biosensor cells and human neurons: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors only functioned when administered within 8 h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding. Conclusions Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification.

HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. [CR.sup.hi] cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.

Assimilation wetlands are natural, non-constructed, wetlands that are used for the removal of nutrients from treated municipal wastewater. This passive process is comparatively less expensive than other conventional forms of tertiary treatment of wastewater, making it desirable for municipalities. Assimilation wetlands are monitored for a number of environmental parameters, yet limited research has been conducted to understand the ecological impact of this water treatment process. Studies from a variety of systems throughout the United States provide conflicting evidence of the responses of wetland ecosystems to increased inundation and nutrient enrichment. Through an extensive review of existing literature, we summarize the impacts of increasing nutrient loading and inundation on receiving wetlands. Importantly, we address current research gaps and identify directions for future scientific study on this topic. Comprehensive ecosystem monitoring conducted at larger spatial and temporal scales, as well as controlled experimentation, are needed to fully understand ecosystem responses to long-term use of wetlands to remediate wastewater nutrients. Our intent is neither to promote nor detract from this process, but rather to bring attention to potential drivers of environmental change and inform those who manage these systems.

Study Objectives: Hospital readmissions are an important metric of quality and safety. This study seeks to characterize the relationship between readmissions and obstructive sleep apnea (OSA). A better understanding of this relationship could be utilized to develop preventative measures and reduce readmission rates. Methods: A retrospective review of patients discharged over a 24-month period to a Department of Defense hospital was conducted. Medical records review provided demographic data, presence of OSA and comorbid diseases, and whether readmission occurred within 30 days of discharge. Statistical analysis assessed risk factors for readmission, and multivariate analysis was performed. Next, 125 readmitted patients with OSA were randomly selected for detailed chart review and compared to a matched cohort that was not readmitted. Results: Of 22,261 unique patients discharged, 1,899 (8.5%) were readmitted. Patients with OSA had a readmission rate of 11.4% versus 7.6% for patients without OSA ( P < .00001). Multivariable analysis revealed an odds ratio of 1.46 for readmission in patients with OSA ( P < .0001). For the detailed chart review of 250 patients, length of hospital stay differed for the readmitted and non-readmitted groups (5.1 versus 3.6 days; P = .007). Apnea-hypopnea index (24.1 versus 27.2 events/h; P = .48) was similar between the groups. Also, inpatient (27.2% versus 26.4%) and outpatient (38.4% versus 37.6%) positive airway pressure (PAP) treatment rates were not different. Conclusions: This study found OSA to be an independent risk factor for readmission within 30 days of discharge. PAP therapy appears to be underutilized in patients with known OSA. Additional studies are needed to define the relationship between OSA, PAP adherence, and hospital readmission. Citation: Scalzitti NJ, O'Connor PD, Nielsen SW, Aden JK, Brock MS, Taylor DM, Mysliwiec V, Dion GR. Obstructive sleep apnea is an independent risk factor for hospital readmission. J Clin Sleep Med. 2018;14(5):753–758.

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1β and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.

Gross primary production and ecosystem respiration together define ecosystem metabolism and help indicate the importance of internal and external carbon sources. Spatial variability of these processes is poorly characterized in rivers. We measured metabolism in the Kansas River: (1) at 10 locations over 100 s of km in tributaries within the watershed and (2) over 20 km with detailed sampling in the main stem. Whole-river metabolism at the larger scale was decoupled from light, algal growth, and nutrient limitation, and was positively related to nutrients. Smaller-scale main stem sampling revealed almost as much variance over a few kilometers as the larger scale sampling. Local processes seemed to dominate dissolved oxygen dynamics, since diurnal dissolved oxygen patterns were better correlated with absolute time than data corrected for travel times. A single-station method compared against two-station metabolism methods indicated that local hotspots of metabolism occur at scales less than 1 km and that single-station estimates average out this variance. The main stem data provide support to the idea that functional processing zones control characteristics used to estimate system metabolism, but the nutrient effect at the whole watershed level indicates that transport from upstream can also be important.

Coronavirus disease 2019 (COVID-19) was first detected in the United States in January 2020 (1), and by mid-July, approximately 3.4 million cases had been reported in the United States (2). Information about symptoms among U.S. COVID-19 patients is limited, especially among nonhospitalized patients. To better understand symptom profiles of patients with laboratory-confirmed COVID-19 in the United States, CDC used an optional questionnaire to collect detailed information on a convenience sample of COVID-19 patients from participating states. Symptom data were analyzed by age group, sex, hospitalization status, and symptom onset date relative to expansion of testing guidelines on March 8, 2020 (3). Among 164 symptomatic patients with known onset during January 14-April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Among 57 hospitalized adult patients (aged ≥18 years), 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Gastrointestinal (GI) symptoms and other symptoms, such as chills, myalgia, headache, and fatigue, also were commonly reported, especially after expansion of testing guidelines. To aid prompt recognition of COVID-19, clinicians and public health professionals should be aware that COVID-19 can cause a wide variety of symptoms.