Photochemical Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Evaluation in Ex Vivo Human Tissue.

PURPOSE: Experimental investigation in human eyelids to confirm that exposing excised tarsal plates to ultraviolet-A radiation can induce a stiffening effect through the riboflavin-photosensitized crosslinking of tarsal collagen. METHODS: Thirteen tarsal plates excised from nonfrozen human cadavers were irradiated with ultraviolet-A rays (365 nm wavelength) at an irradiance of 75 mW/cm2 for 3 minutes, equivalent to a radiation fluence of 13.5 J/cm2, in the presence of a riboflavin derivative as a photosensitizer. The tensile stress (strength) and Young's modulus (stiffness) of both nonirradiated and irradiated specimens were measured with the BioTester 5000 in the uniaxial mode at a strain of 10% and analyzed statistically. Individual specimens excised from 2 cadavers were also examined by routine histopathologic protocols to assess the effect of radiation on the Meibomian glands and collagen organization. RESULTS: The irradiation enhanced both stiffness and strength of the human tarsal specimens, the difference between the test samples and controls being statistically significant (p < 0.0002 for n = 13). Histology indicated no damage to tarsal connective tissue or to Meibomian glands, and revealed a more compact packing of the collagen network located around the glands, which may be beneficial. The existence of collagen compaction was also supported by the reduction of samples' thickness after irradiation (p = 0.0645). CONCLUSIONS: The irradiation of tarsal tissue with ultraviolet-A light of tarsus appears to be a safe and effective method for reducing eyelid laxity in human patients.

Repeatability and reproducibility of the Forskolin-induced swelling (FIS) assay on intestinal organoids from people with Cystic Fibrosis.

BACKGROUND: The forskolin-induced swelling (FIS) assay measures CFTR function on patient-derived intestinal organoids (PDIOs) and may guide treatment selection for individuals with Cystic Fibrosis (CF). The aim of this study is to demonstrate the repeatability and reproducibility of the FIS assay following a detailed Standard Operating Procedure (SOP), thus advancing the validation of the assay for precision medicine (theranostic) applications. METHODS: Over a 2-year period, FIS responses to CFTR modulators were measured in four European labs. PDIOs from six subjects with CF carrying different CFTR genotypes were used to assess the repeatability and reproducibility across the dynamic range of the assay. RESULTS: Technical, intra-assay repeatability was high (Lin's concordance correlation coefficient (CCC) 0.95-0.98). Experimental, within-subject repeatability was also high within each lab (CCCs all >0.9). Longer-term repeatability (>1 year) showed more variability (CCCs from 0.67 to 0.95). The reproducibility between labs was also high (CCC ranging from 0.92 to 0.97). Exploratory analysis also found that between-lab percentage of agreement of dichotomized CFTR modulator outcomes for predefined FIS thresholds ranged between 78 and 100 %. CONCLUSIONS: The observed repeatability and reproducibility of the FIS assay within and across different labs is high and support the use of FIS as biomarker of CFTR function in the presence or absence of CFTR modulators.

Expert consensus report on lipid mediators: Role in resolution of inflammation and muscle preservation.

This meeting report presents a consensus on the biological aspects of lipid emulsions in parenteral nutrition, emphasizing the unanimous support for the integration of lipid emulsions, particularly those containing fish oil, owing to their many potential benefits beyond caloric provision. Lipid emulsions have evolved from simple energy sources to complex formulations designed to improve safety profiles and offer therapeutic benefits. The consensus highlights the critical role of omega-3 polyunsaturated fatty acids (PUFAs), notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil and other marine oils, for their anti-inflammatory properties, muscle mass preservation, and as precursors to the specialized pro-resolving mediators (SPMs). SPMs play a significant role in immune modulation, tissue repair, and the active resolution of inflammation without impairing host defense mechanisms. The panel's agreement underscores the importance of incorporating fish oil within clinical practices to facilitate recovery in conditions like surgery, critical illness, or immobility, while cautioning against therapies that might disrupt natural inflammation resolution processes. This consensus not only reaffirms the role of specific lipid components in enhancing patient outcomes, but also suggests a shift towards nutrition-based therapeutic strategies in clinical settings, advocating for the proactive evidence-based use of lipid emulsions enriched with omega-3 PUFAs. Furthermore, we should seek to apply our knowledge concerning DHA, EPA, and their SPM derivatives, to produce more informative randomized controlled trial protocols, thus allowing more authoritative clinical recommendations.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathological factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer(BC) chemotherapy response remains poorly understood. This study examines the variance in the gut microbiome(GM) of BC patients compared to healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease. Our study reveals distinct clustering, effectively separating the BC and healthy cohorts. However, no significant differences were observed between chemotherapy responders and non-responders within community subgroups. Machine Learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs AUC 0.50), although no single microbial species emerged as a fully reliable biomarker. The evaluation of short-chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, p = 0.017) and Clostridia (rs = 0.52, p = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, p=0.02) and Enterobacteriaceae (rs = 0.52, p < 0.03) correlated with increased fecal propionic acid. In conclusion, our study constitutes the first large-scale, multi-center assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa.

Development and validation of a generic methyltransferase enzymatic assay based on an SAH riboswitch.

Methylation of proteins and nucleic acids plays a fundamental role in epigenetic regulation, and discovery of methyltransferase (MT) inhibitors is an area of intense activity. Because of the diversity of MTs and their products, assay methods that detect S-adenosylhomocysteine (SAH) - the invariant product of S-adenosylmethionine (SAM)-dependent methylation reactions - offer some advantages over methods that detect specific methylation events. However, direct, homogenous detection of SAH requires a reagent capable of discriminating between SAH and SAM, which differ by a single methyl group. Moreover, MTs are slow enzymes and many have submicromolar affinities for SAM; these properties translate to a need for detection of SAH at low nanomolar concentrations in the presence of excess SAH. To meet these needs, we leveraged the exquisite molecular recognition properties of a naturally occurring SAH-sensing RNA aptamer, or riboswitch. By splitting the riboswitch into two fragments, such that SAH binding induces assembly of a trimeric complex, we engineered sensors that transduce binding of SAH into positive fluorescence polarization (FP) and time resolved Förster resonance energy transfer (TR-FRET) signals. The split riboswitch configuration, called the AptaFluor™ SAH Methyltransferase Assay, allows robust detection of SAH (Z' > 0.7) at concentrations below 10 nM, with overnight signal stability in the presence of typical MT assay components. The AptaFluor assay tolerates diverse MT substrates, including histones, nucleosomes, DNA and RNA, and we demonstrated its utility as a robust, enzymatic assay method for several methyltransferases with SAM Km values < 1µM. The assay was validated for HTS by performing a pilot screen of 1,280 compounds against the SARS-CoV-2 RNA capping enzyme, nsp14. By enabling direct, homogenous detection of SAH at low nanomolar concentrations, the AptaFluor assay provides a universal platform for screening and profiling MTs at physiologically relevant SAM concentrations.

TAF2, within the TFIID complex, regulates the expression of a subset of protein-coding genes.

TFIID, one of the general transcription factor (GTF), regulates transcriptional initiation of protein-coding genes through direct binding to promoter elements and subsequent recruitment of other GTFs and RNA polymerase II. Although generally required for most protein-coding genes, accumulated studies have also demonstrated promoter-specific functions for several TFIID subunits in gene activation. Here, we report that TBP-associated factor 2 (TAF2) specifically regulates TFIID binding to a small subset of protein-coding genes and is essential for cell growth of multiple cancer lines. Co-immunoprecipitation assays revealed that TAF2 may be sub-stoichiometrically associated with the TFIID complex, thus indicating a minor fraction of TAF2-containing TFIID in cells. Consistently, integrated genome-wide profiles show that TAF2 binds to and regulates only a small subset of protein-coding genes. Furthermore, through the use of an inducible TAF2 degradation system, our results reveal a reduction of TBP/TFIID binding to several ribosomal genes upon selective ablation of TAF2. In addition, depletion of TAF2, as well as the TAF2-regulated ribosomal protein genes RPL30 and RPL39, decreases ribosome assembly and global protein translation. Collectively, this study suggests that TAF2 within the TFIID complex is of functional importance for TBP/TFIID binding to and expression of a small subset of protein-coding genes, thus establishing a previously unappreciated promoter-selective function for TAF2.

Centralized intestinal organoid generation is a feasible and safe approach for personalized medicine as demonstrated in the HIT-CF Europe Organoid Study.

BACKGROUND: Patient-derived intestinal organoids (PDIOs) show great potential as in vitro drug testing platform for personalised medicine in Cystic Fibrosis and oncology. PDIOs can be generated by culturing adult stem cells obtained through rectal forceps biopsy or suction biopsy, but the safety of these procedures and the success rates of generating organoids after shipment to a centralized lab using these procedures has not been studied in this context. We here report the safety and success rates of both biopsy procedures and the subsequent generation of PDIOs in the international multicentre HIT-CF Organoid Study. METHODS: 502 biopsy procedures were conducted, on 489 adult people with Cystic Fibrosis from 33 different hospitals across 12 countries. Depending on the preference of the hospital, either rectal forceps biopsies or suction biopsies were obtained and internationally shipped to a central laboratory for organoid generation. RESULTS: No adverse events were reported for 280 forceps biopsy procedures, while 222 rectal suction biopsy procedures resulted in 2 adverse events, namely continued bleeding and a probably nonrelated gastroenteritis. The success rate of organoid generation from all biopsies was 95%, and the main reason for failure was insufficient sample viability (3.2%). CONCLUSION: Our results indicate that both rectal suction biopsy and forceps biopsy procedures are safe procedures. The high success rates of PDIO generation from the obtained tissue samples demonstrate the feasibility of the organoid technology for personalised in vitro testing in an international setting.

Fluid distribution during surgery in the flat recumbent, Trendelenburg, and the reverse Trendelenburg body positions.

BACKGROUND: The distribution and elimination of infused crystalloid fluid is known to be affected by general anesthesia, but it is unclear whether changes differ depending on whether the patient is operated in the flat recumbent position, the Trendelenburg ("legs up") position, or the reverse Trendelenburg ("head up") position. METHODS: Retrospective data on hemodilution and urine output obtained during and after infusion of 1-2 L of Ringer's solution over 30-60 min were collected from 61 patients undergoing surgery under general anesthesia and 106 volunteers matched with respect to the infusion volume and infusion time. Parameters describing fluid distribution in the anesthetized and awake subjects were compared by population volume kinetic analysis. RESULTS: General anesthesia decreased the rate constant for urine output by 79% (flat recumbent), 91% (legs up) and 91% (head up), suggesting that laparoscopic surgery per se intensified the already strong anesthesia-induced fluid retention. General anesthesia also decreased the rate constant governing the return of the distributed fluid to the plasma by 32%, 15%, and 70%, respectively. These results agree with laboratory data showing a depressive effect of anesthetic drugs on lymphatic pumping, and further suggest that the "legs up" position facilitates lymphatic flow, whereas the "head up" position slows this flow. Both Trendelenburg positions increased swelling of the "third fluid space". CONCLUSIONS: General anesthesia caused retention of infused fluid with preferential distribution to the extravascular space. Both Trendelenburg positions had a modifying influence on the kinetic adaptations that agreed with the gravitational forces inflicted by tilting to body.

Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression.

With our current appreciation of the complexity of eukaryotic transcription, whose dysregulation drives diseases including cancer, it is becoming apparent that identification of key events coordinating multiple aspects of transcriptional regulation is of special importance. To elucidate how assembly of RNA polymerase II (Pol II) with Mediator complex preinitiation complexes (PICs) and formation of transcription-permissive 3D chromatin organization are coordinated, we studied MED1, a representative subunit of the Mediator complex that acts to establish functional preinitiation complexes (PICs) that forms biomolecular condensates through an intrinsically disordered region (IDR) to facilitate transcription, and is implicated in the function of estrogen receptor α (hereafter ER) in ER-positive breast cancer (ER+ BC) cells. We found that MED1 is acetylated at 6 lysines in its IDR and, further, that MCF7 ER+ BC cells in which endogenous MED1 is replaced by an ectopic 6KR (non-acetylatable) mutant (6KR cells) exhibit enhanced cell growth and elevated expression of MED1-dependent genes. These results indicate an enhanced function of 6KR MED1 that may be attributed to two mechanisms: (1) reorganized PIC assembly, as indicated by increased MED1 and Pol II, decreased MED17, and equivalent ERα occupancies on chromatin, particularly at active enhancers and promoters; (2) sub-TAD chromatin unfolding, as revealed by HiCAR (Hi-C on accessible regulatory DNA) analyses. Furthermore, in vitro assays demonstrate distinct physio-chemical properties of liquid-liquid phase separation (LLPS) for 6KR versus 6KQ MED1 IDRs, and for non-acetylated versus CBP-acetylated WT MED1 IDR fragments. Related, Pol II CTD heptads are sequestered in 6KR and control WT MED1 IDR condensates, but not 6KQ and CBP-acetylated WT MED1 IDR condensates. These findings, in conjunction with recent reports of PIC structures, indicate that MED1 coordinates reorganization of the PIC machinery and the rewiring of regional chromatin organization through acetylation of its IDR. This study leads to an understanding of how the transition in phase behavior of a transcription cofactor acts as a mechanistic hub integrating linear and spatial chromatin functions to support gene expression, and have potential therapeutic implications for diseases involving MED1/Mediator-mediated transcription control.

What Does the Military Health System Need to Support Future Combat Operations? Lessons from Aeromedical Evacuations from 2008 to 2020.

INTRODUCTION: Aeromedical evacuations from the past few decades have yielded massive amounts of data that may inform the Military Health System (MHS) on patient needs, specifically for understanding the inpatient and outpatient needs of evacuees. In this study, we evaluate inpatient and outpatient trends based on aeromedical evacuation data from recent conflicts. We anticipate that evacuations requiring MHS inpatient beds are primarily trauma-related and necessitate an increased need for inpatient trauma care. MATERIALS AND METHODS: We conducted a descriptive analysis of aeromedical evacuations using the U.S. Transportation Command Regulating and Command & Control Evacuation System database. We queried the database for aeromedical evacuations originating from the U.S. EUCOM and ending in the CONUS, from January 1, 2008 to June 4, 2020. With the resultant data, evacuee demographics were characterized by gender, age, active duty (AD) versus non-AD, and branch of service. Following this, the proportion of battle injury to disease and non-battle injury was categorized by both patient age ranges and year. Additionally, evacuations were stratified by their ICD codes, as well as the primary specialty responsible for care. Lastly, evacuations were categorized by inpatient and outpatient care status. RESULTS: The final dataset yielded 32,485 unique patients. The majority of evacuees were male (86.9%) with a mean age of 29.0 ± 9.6 years. Evacuees were primarily AD Military (96.7%), with the majority of those personnel being in the Army (70.2%). The total number of evacuations steadily increased from 2008 (n = 3,703) until a peak in 2010 (n = 4,929), which was also the peak year for battle injury (n = 1,472). Battle injury was also most prevalent in the 21 to 24 age group (24.7%) and declined in older age groups. Regarding diagnoses, the leading categories were injury/poisoning (33.1%), psychiatric (28.1%), and musculoskeletal (12.1%). As for specialty care of evacuees, psychiatry received the largest share of total evacuations (28.1%), followed by orthopedic surgery (22.7%) and general surgery (8.6%). Looking at proportions of inpatient and outpatient care, the majority of evacuees required outpatient care (65.6%) with a sizable minority requiring inpatient care (34.4%). Inpatient evacuations peaked in 2010 (n = 2,013), accounting for 40.8% of all evacuations that year. Orthopedic surgery had the largest share of inpatient evacuations (27.3%), followed by psychiatry (21.5%) and general surgery (18.2%). As for outpatient care, the specialties with the largest proportion of outpatient evacuations were psychiatry (33.6%), orthopedic surgery (20.3%), and neurology (9.8%). CONCLUSIONS: The results of this study reveal what the MHS can expect in future conflicts. Most evacuations are for psychiatric-/injury-/musculoskeletal-related diagnoses, typically requiring care by psychiatrists, orthopedic surgeons, or general surgeons. Outpatient care is important, though it is critical to bolster inpatient care requirements as future conflicts may bring extensive numbers of inpatient casualties. The MHS should program and plan resources accordingly, planning for the care of surgical/injured and psychiatric patients.

Impact of Depression and Anxiety on Patient Reported Outcomes Measures after Lumbar Fusion.

BACKGROUND: Depression and anxiety are common in patients undergoing spinal surgery and might negatively impact outcomes. This study investigates the possible effect of these diagnoses on patient reported outcomes following lumbar fusion. METHODS: Retrospective review of a registry containing prospectively collected data of lumbar fusion procedures at a single institution was performed from May 23, 2012 to June 15, 2022. Patients with a minimum of two year follow-up were included. Demographic information, diagnoses, medications, patient-reported outcomes measures (PROMs), and complications data at preoperative, three months, six months, 1 year, and two years postoperative were collected. Statistical analysis was performed using Student's t-tests, χ2, binomial correlation, odds ratios, logistic regression, and mean clinically important difference. RESULTS: A total of 156 patients were included (60 males, 96 females) with mean age 62.6 ± 11.1 years at surgery. Thirty-nine (25%) had depression and/or anxiety (DA). Baseline Oswestry Disability Index (ODI) and EuroQol Group 5D questionnaire (EQ5D) scores were significantly worse in the DA cohort compared to controls (ODI 51.1 ± 18.3 vs. 42.9 ± 15.8; P = 0.010, EQ5D 0.46 ± 0.21 vs. 0.57 ± 0.21; P = 0.005). Both cohorts experienced similar relative improvement at two years (delta ODI -18.2 ± 27.9 vs. -17.8 ± 22.1; P = 0.924, EQ5D 6.8 ± 33.8 vs. 8.1 ± 32.9; P = 0.830). Absolute outcome scores were worse in the DA cohort at all intervals. DA were not independently predictive of changes in PROMs (delta ODI mean difference 4.49, r2 = 0.36, P = 0.924). CONCLUSIONS: The present study showed similar improvement in PROMs following lumbar fusion for patients with anxiety and depression compared to healthy controls. These data suggest these patients are no less likely to benefit from appropriately planned lumbar fusion.

Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Vestibular Schwannoma International Study of Active Surveillance Versus Stereotactic Radiosurgery: The VISAS Study.

PURPOSE: The present study assesses the safety and efficacy of stereotactic radiosurgery (SRS) versus observation for Koos grade 1 and 2 vestibular schwannoma (VS), benign tumors affecting hearing and neurological function. METHODS AND MATERIALS: This multicenter study analyzed data from Koos grade 1 and 2 VS patients managed with SRS (SRS group) or observation (observation group). Propensity score matching balanced patient demographics, tumor volume, and audiometry. Outcomes measured were tumor control, serviceable hearing preservation, and neurological outcomes. RESULTS: In 125 matched patients in each group with a 36-month median follow-up (P = .49), SRS yielded superior 5- and 10-year tumor control rates (99% CI, 97.1%-100%, and 91.9% CI, 79.4%-100%) versus observation (45.8% CI, 36.8%-57.2%, and 22% CI, 13.2%-36.7%; P < .001). Serviceable hearing preservation rates at 5 and 9 years were comparable (SRS 60.4% CI, 49.9%-73%, vs observation 51.4% CI, 41.3%-63.9%, and SRS 27% CI, 14.5%-50.5%, vs observation 30% CI, 17.2%-52.2%; P = .53). SRS were associated with lower odds of tinnitus (OR = 0.39, P = .01), vestibular dysfunction (OR = 0.11, P = .004), and any cranial nerve palsy (OR = 0.36, P = .003), with no change in cranial nerves 5 or 7 (P > .05). Composite endpoints of tumor progression and/or any of the previous outcomes showed significant lower odds associated with SRS compared with observation alone (P < .001). CONCLUSIONS: SRS management in matched cohorts of Koos grade 1 and 2 VS patients demonstrated superior tumor control, comparable hearing preservation rates, and significantly lower odds of experiencing neurological deficits. These findings delineate the safety and efficacy of SRS in the management of this patient population.

Colorectal Disease and the Gut Microbiome: What a Surgeon Needs to Know.

The gut microbiome is defined as the microorganisms that reside within the gastrointestinal tract and produce a variety of metabolites that impact human health. These microbes play an intricate role in human health, and an imbalance in the gut microbiome, termed gut dysbiosis, has been implicated in the development of varying diseases. The purpose of this review is to highlight what is known about the microbiome and its impact on colorectal cancer, inflammatory bowel disease, constipation, Clostridioides difficile infection, the impact of bowel prep, and anastomotic leaks.

NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors.

The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary fibrous tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to soft tissue sarcomas. SFTs can arise throughout the body and are usually managed surgically. However, 30-40% of SFTs will relapse local-regionally or metastasize. There are no systemic therapies with durable activity for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the NAB2 and STAT6 loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2's co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.