Asymmetric Allostery in Estrogen Receptor-α Homodimers Drives Responses to the Ensemble of Estrogens in the Hormonal Milieu.

The estrogen receptor-α (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations -receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining binding of the same ligand in crystal structures of ER in the agonist versus antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist versus antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric versus dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing new modes for ligand-dependent regulation of ER activity. Significance: The estrogen receptor-α (ER) regulates transcription in response to a hormonal milieu that includes low levels of estradiol, a variety of environmental estrogens, as well as ER antagonists such as breast cancer anti-hormonal therapies. While ER has been studied as a homodimer, the variety of ligand and receptor concentrations in different tissues means that the receptor can be occupied with two different ligands, with only one ligand in the dimer, or as a monomer. Here, we use X-ray crystallography and molecular dynamics simulations to reveal a new mode for ligand regulation of ER activity whereby sequence-identical homodimers can act as functional or conformational heterodimers having unique signaling characteristics, with ligand-selective allostery operating across the dimer interface integrating two different signaling outcomes.

CD8+ T cells are necessary for improved sepsis survival induced by CD28 agonism in immunologically experienced mice.

Introduction: A hallmark of T cell dysregulation during sepsis is the downregulation of costimulatory molecules. CD28 is one of T cell costimulatory molecules significantly altered on memory T cells during sepsis. We recently showed that treatment with a αCD28 agonist in septic immunologically experienced mice led to improved survival. Therefore, here we aimed to identify the cell subset(s) necessary for the survival benefit observed in the context of CD28 agonism, and to further investigate the mechanism by which CD28 agonism improves sepsis survival in immunologically experienced mice. Methods: Mice received specific pathogen inoculation to generate memory T cell populations similar in frequency to that of adult humans. Once these infections were cleared and the T cell response had transitioned to the memory phase, animals were rendered septic via cecal ligation and puncture in the presence or absence of an agonistic anti-CD28 mAb. Results: Results demonstrated that CD8+ T cells, and not bulk CD4+ T cells or CD25+ regulatory T cells, were necessary for the survival benefit observed in CD28 agonist-treated septic immunologically experienced mice. Upon examination of these CD8+ T cells, we found that CD28 agonism in septic immunologically experienced mice was associated with an increase in Foxp3+ CD8+ T cells as compared to vehicle-treated controls. When CD8+ T cells were depleted in septic immunologically experienced mice in the setting of CD28 agonism, a significant increase in levels of inflammatory cytokines in the blood was observed. Discussion: Taken together, these results indicate that CD28 agonism in immunologically experienced mice effectively suppresses inflammation via a CD8+-dependent mechanism to decrease mortality during sepsis.

Stage-Stratified Incidence Rates of Colorectal Adenocarcinoma Among Patients Aged 46 to 49 in the United States.

This cross-sectional study uses Surveillance, Epidemiology, and End Results registry data to analyze colorectal adenocarcinoma staging incidence of patients aged 46 to 49 years from 2000 to 2020.

Venovenous Extracorporeal Membrane Oxygenation Candidacy Decision-Making: Lessons and Hypotheses From a Single-Center Observational Analysis.

BACKGROUND: Use of venovenous extracorporeal membrane oxygenation (ECMO) is increasing, but candidacy selection processes are variable and subject to bias. RESEARCH QUESTION: What are the reasons behind venovenous ECMO candidacy decisions, and are decisions made consistently across patients? STUDY DESIGN AND METHODS: Prospective observational study of all patients, admitted or outside hospital referrals, considered for venovenous ECMO at a tertiary referral center. Relevant clinical data and reasons for candidacy determination were cross-referenced with other noncandidates and candidates and were assessed qualitatively. RESULTS: Eighty-one consultations resulted in 44 noncandidates (54%), 29 candidates (36%; nine of whom subsequently underwent cannulation), and eight deferred decisions (10%). Fifteen unique contraindications were identified, variably present across all patients. Five contraindications were invoked as the sole reason to deny ECMO to a patient. In patients with three or more contraindications, additional contraindications were cited even if the severity was relatively minor. All but four contraindications invoked to deny ECMO to a patient were nonprohibitive for at least one other candidate. Contraindications documented in noncandidates were present but not mentioned in 21 other noncandidates (47%). Twenty-six candidates (90%) had at least one contraindication that was prohibitive in a noncandidate, including a contraindication that was the sole reason to deny ECMO. Contraindications were proposed as informing three prognostic domains, through which patterns of inconsistency could be understood better: (1) irreversible underlying pulmonary process, (2) unsurvivable critical illness, and (3) clinical condition too compromised for meaningful recovery. INTERPRETATION: ECMO candidacy decisions are inconsistent. We identified four patterns of inconsistency in our center and propose a three-domain model for understanding and categorizing contraindications, yielding five lessons that may improve candidacy decision processes until further research can guide practice more definitively.

Haplotype phasing of CYP2D6: an allelic ratio method using Agena MassARRAY data.

Pharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment. CYP2D6 is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced from CYP2D6 genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application to CYP2D6 has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of the CYP2D6 gene. We report application of a new protocol for CYP2D6 haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of the CYP2D6 gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conduct CYP2D6 haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies of CYP2D6 but for which the exact number of CYP2D6 genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. Finally, we demonstrate that our method is applicable to CYP2D6 hybrid tandem configurations.

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken. METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates. RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain. CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Severe Acute Respiratory Syndrome Coronavirus 2 Did Not Substantially Impact Injury Patterns or Performance of Players in the National Basketball Association From 2016 to 2021.

Purpose: To perform a descriptive epidemiologic analysis of National Basketball Association (NBA) injuries from 2016 to 2021, to evaluate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019, or COVID-19) on injury patterns and performance statistics, and to determine the effect of infection with SARS-CoV-2 on individual performance statistics. Methods: Injury epidemiology in the NBA from the 2016 to 2021 seasons was collected using a comprehensive online search. Injuries and time missed were categorized by injury location and type. Player positions and timing of injury were recorded. Performance statistics were collected including traditional game statistics and Second Spectrum (speed, distance) statistics. Comparisons were made over seasons and comparing the pre-COVID-19 pandemic seasons to the pandemic era seasons. Players diagnosed with COVID-19 were analyzed for changes in performance in the short or long term. Results: Of the 3,040 injuries captured, 1,880 (61.84%) were in the lower extremity. Guards (77.44%) and forwards (75.88%) had a greater proportion of soft-tissue injuries (P < .001) than centers. Guards had the highest proportion of groin (3.27%, P = .001) and hamstring (6.21%, P < .001) injuries. Despite minor differences on a per-season basis, there were no differences in injury patterns identified between pre-COVID-19 and COVID-19 eras. Of players diagnosed with COVID-19 during the NBA Bubble, there were no detriments in short- or long-term performance identified, including traditional game statistics and speed and distance traveled. Conclusions: In the NBA seasons from 2016 to 2021, most injuries were to the lower extremity. The SARS-CoV-2 pandemic did not substantially impact injury patterns in the NBA, including locations of injury and type of injury (bony or soft tissue). Furthermore, infection with SARS-CoV-2 does not appear to have a significant impact on performance in basketball-specific or speed and distance measures. Level of Evidence: Level IV, prognostic case series.

Speech Features as Predictors of Momentary Depression Severity in Patients With Depressive Disorder Undergoing Sleep Deprivation Therapy: Ambulatory Assessment Pilot Study.

BACKGROUND: The use of mobile devices to continuously monitor objectively extracted parameters of depressive symptomatology is seen as an important step in the understanding and prevention of upcoming depressive episodes. Speech features such as pitch variability, speech pauses, and speech rate are promising indicators, but empirical evidence is limited, given the variability of study designs. OBJECTIVE: Previous research studies have found different speech patterns when comparing single speech recordings between patients and healthy controls, but only a few studies have used repeated assessments to compare depressive and nondepressive episodes within the same patient. To our knowledge, no study has used a series of measurements within patients with depression (eg, intensive longitudinal data) to model the dynamic ebb and flow of subjectively reported depression and concomitant speech samples. However, such data are indispensable for detecting and ultimately preventing upcoming episodes. METHODS: In this study, we captured voice samples and momentary affect ratings over the course of 3 weeks in a sample of patients (N=30) with an acute depressive episode receiving stationary care. Patients underwent sleep deprivation therapy, a chronotherapeutic intervention that can rapidly improve depression symptomatology. We hypothesized that within-person variability in depressive and affective momentary states would be reflected in the following 3 speech features: pitch variability, speech pauses, and speech rate. We parametrized them using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) from open-source Speech and Music Interpretation by Large-Space Extraction (openSMILE; audEERING GmbH) and extracted them from a transcript. We analyzed the speech features along with self-reported momentary affect ratings, using multilevel linear regression analysis. We analyzed an average of 32 (SD 19.83) assessments per patient. RESULTS: Analyses revealed that pitch variability, speech pauses, and speech rate were associated with depression severity, positive affect, valence, and energetic arousal; furthermore, speech pauses and speech rate were associated with negative affect, and speech pauses were additionally associated with calmness. Specifically, pitch variability was negatively associated with improved momentary states (ie, lower pitch variability was linked to lower depression severity as well as higher positive affect, valence, and energetic arousal). Speech pauses were negatively associated with improved momentary states, whereas speech rate was positively associated with improved momentary states. CONCLUSIONS: Pitch variability, speech pauses, and speech rate are promising features for the development of clinical prediction technologies to improve patient care as well as timely diagnosis and monitoring of treatment response. Our research is a step forward on the path to developing an automated depression monitoring system, facilitating individually tailored treatments and increased patient empowerment.

Use of Social Media in Orthopaedic Surgery Training and Practice: A Systematic Review.

Background: Social media use has grown across healthcare delivery and practice, with dramatic changes occurring in response to the coronavirus (COVID-19) pandemic. The purpose of this study was to conduct a comprehensive systematic review to determine the current landscape of social media use by (1) orthopaedic surgery residencies/fellowship training programs and (2) individual orthopaedic surgeons and the change in use over time. Methods: We searched 3 electronic databases (PubMed, MEDLINE, and Embase) from their inception to April 2022 for all studies that analyzed the use of social media in orthopaedic surgery. Two reviewers independently determined study eligibility, rated study quality, and extracted data. Methodology was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Twenty-eight studies were included, of which 11 analyzed social media use by orthopaedic surgery residency and fellowship training programs and 17 examined its use by individual orthopaedic surgeons. Among residency and fellowship programs, Instagram was identified as the most common platform used, with 42% to 88% of programs reporting program-specific Instagram accounts, followed by Twitter/X (20%-52%) and Facebook (10%-38%). Social media was most commonly used by programs for recruitment and information dissemination to prospective residency applicants (82% and 73% of included studies, respectively). After the start of the COVID-19 pandemic, there was a 620% and 177% increase in the number of training programs with Instagram and Twitter/X accounts, respectively. Individual use of social media ranged from 1.7% to 76% (Twitter/X), 10% to 73% (Facebook), 0% to 61% (Instagram), 22% to 61% (LinkedIn), and 6.5% to 56% (YouTube). Conclusions: Instagram, Twitter/X, and Facebook are the premier platforms that patients, residency applicants, and institutions frequent. With the continued growth of social media use anticipated, it will be critical for institutions and individuals to create and abide by guidelines outlining respectful and professional integration of social media into practice. Level of Evidence: Level IV.

Suture-Augmented Anterior Cruciate Ligament Repair for Proximal Avulsion or High-Grade Partial Tears Shows Similar Side-to-Side Difference and No Clinical Differences at Two Years Versus Conventional Anterior Cruciate Ligament Reconstruction for Mid-Substance Tears or Poor Anterior Cruciate Ligament Tissue Quality.

PURPOSE: To compare objective and subjective clinical outcomes between suture-augmented anterior cruciate ligament (ACL) repair (SAACLR) and conventional ACL reconstruction (CACLR) with minimum 2-year follow-up. METHODS: In this nonrandomized, prospective study, 30 patients underwent SAACLR for proximal ACL avulsion or high-grade partial ACL tear (Sherman grade 1 or 2) and 30 patients underwent CACLR for proximal one-third/distal two-thirds junction tears and mid-substance tears (Sherman grade 3 or 4) tear types by 1 surgeon between 2018 and 2020. Failure was defined as ACL reinjury. Outcome measures were KT-1000 for side-to-side knee laxity evaluation, Visual Analog Scale for pain, International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Severity Score (KOOS), Tegner Activity Scale, Western Ontario and McMaster Universities Osteoarthritis Index, Lysholm Knee Scoring Scale, and Single Assessment Numeric Evaluation. Minimal clinically important difference (MCID) was calculated for IKDC and KOOS subscores. RESULTS: Three failures (10%) occurred in the SAACLR group, with no failures in the CACLR group (P = .24). A total of 23 (85%) SAACLR patients and 27 (90%) CACLR patients had patient-reported outcomes and physical examination at minimum 2 years. Two-year KT-1000 testing with 20 lbs showed less than 1 mm side-to-side difference between the groups. No significant differences in the percentage of patients meeting the MCID were found between the SAACLR and CACLR groups at 2 years: IKDC, 10.81 (82%) versus 10.54 (93%) (P = .48); KOOS Pain, 11.55 (73%) versus 10.58 (78%) (P = .94); KOOS Symptoms, 8.15 (77%) versus 10.32 (74%) (P = 1.0); KOOS Activities of Daily Living, 12.19 (59%) versus 12.28 (70%) (P = .60); 18.99 (71%) versus 16.77 (86%) (P = .42). Significantly higher IKDC scores were observed with SAACLR versus CACLR at 3 months (P = .01) and 6 months (P = .02), and significantly higher Lysholm scale, Tegner Activity Scale, and all KOOS subscale scores were observed at 6 months. CONCLUSIONS: At 2 years after surgery, KT-1000 testing showed less than 1 mm side-to-side difference and no differences were observed between the groups in the percentage of patients who met or exceeded the MCID. Significantly higher early patient-reported outcome scores were found with SAACLR versus CACLR. The rerupture rate between the groups was not significantly different. LEVEL OF EVIDENCE: Level II, Prospective cohort study.

Impulsivity, decision-making, and risk behavior in bipolar disorder and major depression from bipolar multiplex families.

OBJECTIVES: Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision-making, and risk-taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision-making, and risk-taking behavior in BD and MDD patients from bipolar multiplex families. METHODS: Eighty-two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision-making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. RESULTS: Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision-making was associated with both mood disorders (BD and MDD). In risk-taking behavior, no significant impairment was found in any group. LIMITATIONS: As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. CONCLUSIONS: Our findings show that alterations of cognitive domains-while present in both disorders-are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

Fatal ampicillin-sulbactam anaphylaxis in a 34-year-old male.

A 34-year-old man receiving his first dose of ampicillin-sulbactam for osteomyelitis in a hospital setting experienced fatal drug-induced anaphylaxis.

Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats.

BACKGROUND: Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. METHODS: Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. RESULTS: Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). CONCLUSIONS: Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.

Various factors can influence the development of alcohol addiction, but studying these factors in humans over the long-term is challenging and costly. With modern sensing technologies, rodents can be monitored throughout the lifespan, providing detailed information obtained under controlled conditions. Previous research suggests sex- and age-dependent differences in addiction processes, with female rats consuming more alcohol and age at first drink resulting in heavier later consumption, but a better characterization of these is needed. Using a rodent model of addiction and relapse, collecting high-resolution longitudinal drinking data in a computerized system over ~ 11 months, we studied differences in the development of addiction and compulsive-like drinking in male vs female as well as adult vs adolescent rats. Female rats drank more alcohol than male rats during the whole experiment, drinking much more weaker alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats in an aversive taste challenge, displaying more compulsive-like drinking. Increased consumption in females compared to males was driven by larger amounts consumed per approach. Little effect of age of onset of drinking was observed. Our results suggest sex-specific differences in the development of drinking patterns and solution preference, not only in terms of total amount consumed. These findings highlight the importance of awareness of sex-specific factors when developing models of addiction, as well as eventual treatment strategies and interventions.

Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort.

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7-10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020-October 2020; November 2020-February 2021). Associations of the children's and mothers' well-being with maternal perceived stress, of the children's well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children's but not the mothers' emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children's emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.

TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer.

Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.