CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment.

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.

Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.

Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.

Effect of Ionic Strength and pH on the Sorption of Heavy Metals onto Polyaniline Copolymers in Aqueous Solutions.

Polyaniline (PANI) and two copolymers, poly(aniline-co-o-toluidine) (PoTOL-50) and poly(aniline-co-o-anisidine) (PoANI-50) were synthesized with equal input ratios (1:1) to enhance PANI as sensing material for the sensing of various heavy metal analytes in aqueous solutions. The polymers were evaluated for both their sensitivity and selectivity toward four heavy metals (Ba2+, Cd2+, Cu2+, and Ni2+) and two common matrix interferents (Ca2+ and Mg2+) at 10 and 40 ppm. The effect of pH and ionic strength of the aqueous solutions on the sensitivity and selectivity was also evaluated. All three polymers showed high sensitivity and selectivity to Ba2+. Varying the pH and ionic strength of solutions did not show significant differences in either the selectivity or the sensitivity of the polymers.

Understanding Effects of Alkyl Side-Chain Density on Polaron Formation Via Electrochemical Doping in Thiophene Polymers.

Polarons exist when charges are injected into organic semiconductors due to their strong coupling with the lattice phonons, significantly affecting electronic charge-transport properties. Understanding the formation and (de)localization of polarons is therefore critical for further developing organic semiconductors as a future electronics platform. However, there are very few studies reported in this area. In particular, there is no direct in situ monitoring of polaron formation and identification of its dependence on molecular structure and impact on electrical properties, limiting further advancement in organic electronics. Herein, how a minor modification of side-chain density in thiophene-based conjugated polymers affects the polaron formation via electrochemical doping, changing the polymers' electrical response to the surrounding dielectric environment for gas sensing, is demonstrated. It is found that the reduction in side-chain density results in a multistep polaron formation, leading to an initial formation of localized polarons in thiophene units without side chains. Reduced side-chain density also allows the formation of a high density of polarons with fewer polymer structural changes. More numerous but more localized polarons generate a stronger analyte response but without the selectivity between polar and non-polar solvents, which is different from the more delocalized polarons that show clear selectivity. The results provide important molecular understanding and design rules for the polaron formation and its impact on electrical properties.

Stem cells tightly regulate dead cell clearance to maintain tissue fitness.

Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by 'non-professional phagocytes', local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXRα, and tissue-specific retinoids for RARγ activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.

Rocks, lichens, and woody litter influenced the soil invertebrate density in upland tundra heath.

Soil invertebrates are an integral part of Arctic ecosystems through their roles in the breakdown of litter, soil formation, and nutrient cycling. However, studies examining soil invertebrates in the Arctic are limited and our understanding of the abiotic and biotic drivers of these invertebrate communities remains understudied. We examined differences in soil invertebrate taxa (mites, collembolans, enchytraeids) among several undisturbed upland tundra heath sites in Nunavut Canada and identified the drivers (vegetation and substrate cover, soil nutrients and pH) of the soil invertebrate community across these sites. Soil invertebrate densities were similar to that of other Arctic studies. While invertebrate communities were relatively consistent between our sites, cover of rocks, woody litter, and the lichen Alectoria nigricans had significant, positive influences on the density of all invertebrates studied. Mites and collembolans were more closely associated with cover of lichens, whereas enchytraeids were more closely associated with woody litter and rocks. Our results suggest that anthropogenic (e.g., resource exploration and extraction) and/or natural (e.g., climate change) disturbances that result in changes to the vegetation community and woody litter inputs will likely impact soil invertebrates and the ecosystem services they provide.

Agroecosystem edge effects on vegetation, soil properties, and the soil microbial community in the Canadian prairie.

Edge effects resulting from adjacent land uses are poorly understood in agroecosystems yet understanding above and belowground edge effects is crucial for maintaining ecosystem function. The aim of our study was to examine impacts of land management on aboveground and belowground edge effects, measured by changes in plant community, soil properties, and soil microbial communities across agroecosystem edges. We measured plant composition and biomass, soil properties (total carbon, total nitrogen, pH, nitrate, and ammonium), and soil fungal and bacterial community composition across perennial grassland-annual cropland edges. Edge effects due to land management were detected both aboveground and belowground. The plant community at the edge was distinct from the adjacent land uses, where annual, non-native, plant species were abundant. Soil total nitrogen and carbon significantly decreased across the edge (P < 0.001), with the highest values in the perennial grasslands. Both bacterial and fungal communities were different across the edge with clear changes in fungal communities driven directly and indirectly by land management. A higher abundance of pathogens in the more heavily managed land uses (i.e. crop and edge) was detected. Changes in plant community composition, along with soil carbon and nitrogen also influenced the soil fungal community across these agroecosystems edges. Characterizing edge effects in agroecosystem, especially those associated with soil microbial communities, is an important first step in ensuring soil health and resilience in these managed landscapes.

Statewide Variation in Cannabinoid Regulations.

As a growing number of states legalize the use of cannabinoids for medical and non-medical purposes, there continues to be large gaps in the understanding of appropriate dosing, impact on health, and the state's role in regulation of products. Here, we present a summary of 2022 cannabis regulations by state to evaluate for the presence of THC:CBD ratios, maximum THC concentration or content within products, specific caps for cannabis possession, and requirements for testing for cannabinoid content and/or contaminants such as pesticides and heavy metals. These results are presented in Map 1 and Table 1 and demonstrate substantial variation among product THC content, purchasing limits, and quality measurements across the country. Finally, we note there is currently no centralized data collection platform for this set of information between states as cannabis use evolves, creating poor transparency between consumers and state regulators.

Revealing the Meaning of Cannabis Use as an Occupation: A Scoping Review.

Background: Occupational science and occupational therapy typically perceive occupations as promoting health and well-being. However, this perspective overlooks the many occupations that are viewed as illegal, unhealthy, or risky, such as drug use. Due to its negative association with health, drug use is perceived as not holding significance or meaning in people's lives. Objective: This study explores how individuals perceive and describe the meaning of their cannabis use in the context of their lives, from an occupational perspective. Methods: A scoping review was conducted using Levac et al.' modifications to Arksey and O'Malley's framework. To examine the peer-reviewed literature, 7 databases were searched using terms related to cannabis and meaning. Descriptive statistics were used to describe the selected studies, and reflexive thematic analysis identified cross-study themes. Results: Fourteen studies were selected. Most studies have been published since 2008, with 5 published in the last 2 years. Four themes were identified across the studies: (a) preserving life; (b) navigating the routines of everyday life; (c) understanding the self, identity, and belonging; and (d) expanding the view of the world. Conclusions: Cannabis use was revealed in this study as a support for navigating occupational routines and enhancing occupational repertoires and engagement, feelings of belonging, and collective user identities. As such, substance abuse treatment practices, including those provided by occupational therapists, should recognize the potential significance of cannabis use within people's lives. Using a harm reduction approach, occupational therapists can acknowledge the ways in which clients use cannabis to manage their daily routines, while also focusing on supporting clients to reduce the ill-effects of cannabis. As individuals become more engaged in occupations that are significant in their lives, their need for and meaning of cannabis use may change leading to a possible reduction in its use and a shift in their identity construction.

More than just a substrate for mites: Moss-dominated biological soil crust protected population of the oribatid mite, Oppia nitens against cadmium toxicity in soil.

Metal-impacted sites often need aggressive ecorestoration strategies to restore a functional plant-soil system. The use of biological soil crusts for soil stabilization, moisture retention and C and N input in disturbed and contaminated soils is becoming a more common ecorestoration practice. Biological soil crusts comprise cyanobacteria, fungi, lichens, and bryophytes (mostly moss). Moss-dominated BSCs provide significant N mineralization rate in most terrestrial ecosystems. Oribatid mites or moss mites dominate moss-dominated BSCs and provide essential ecosystem services such as decomposition and nutrient cycling. We hypothesized that moss-dominated BSCs would create a high-quality habitat niche for O. nitens to resist Cd-induced toxicity. Adult mites were exposed to Cd for 28 days in soil with or without BSCs that were aged for eight months. Cadmium toxicity to mites in soil without BSCs was 1.7 and 5.4times greater than in soil with BSCs, respectively for the mites reproduction and instantaneous population growth rate (PGRi). The moss-dominated BSC did not reduce Cd bioavailability in the mites but increased the mite's resilience to Cd toxicity, likely mediated by the trophic transfer of calcium from the BSC to the mites. Our work identifies a second mechanistic avenue by which BSCs are useful for ecorestoration, i.e., the improvement of soil invertebrate physiology to resist metal stress.

Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.

AIM: Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. METHODS AND RESULTS: We carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization. CONCLUSION: We present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.

Ras drives malignancy through stem cell crosstalk with the microenvironment.

Squamous cell carcinomas are triggered by marked elevation of RAS-MAPK signalling and progression from benign papilloma to invasive malignancy1-4. At tumour-stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway5,6. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden7. Coupling our clonal skin HRASG12V mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFß signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)-AKT-mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.

Environmental Impact of Triclopyr on Habitat Quality in Boreal Rights-of-Way.

The indirect effects of herbicides on habitat quality in boreal ecoregions remain poorly understood. Herbicides are commonly applied on boreal rights-of-way to control vegetation below power lines, where they can indirectly enter the soil ecosystem after leaf abscission. Key soil processes such as litter decomposition and soil nutrient cycling can be influenced by altering litter chemistry and/or impacting decomposer species. Disruption of these soil processes could lead to changes in ecosystem health of boreal systems. The indirect impacts of triclopyr on habitat quality of treated boreal rights-of-way were examined through litter mass loss and quality (carbon-to-nitrogen ratios) and the response of boreal invertebrates (Folsomia candida and Oppia nitens) in microcosms and avoidance tests. Litter breakdown rates were not significantly different within a year of treatment. However, we did observe nitrogen profile differences between field-treated and untreated samples, which likely resulted from triclopyr-induced repression of natural leaf senescence processes. At field application rates, there were no differences in survival and reproduction rates of F. candida, which is key in litter breakdown. The triclopyr concentrations that caused 50% of tested F. candida and O. nitens to avoid treated litter were above field application rates. Therefore, field application rates of triclopyr are not expected to impair habitat quality and ecosystem services of boreal ecoregions based on the parameters we evaluated. Our study improves understanding of the effects of herbicide application on habitat quality and is critical for responsible herbicide use on boreal rights-of-way. Environ Toxicol Chem 2022;41:2955-2967. © 2022 SETAC.

Lymphatic Mapping and Sentinel Node Biopsy in High-Grade Uterine Cancers.

PURPOSE OF REVIEW: Sentinel lymph node (SLN) mapping has been adopted as an acceptable method of lymph node evaluation in the surgical staging for low-grade endometrial cancer. In this review, we analyze the literature on the utility of SLN mapping in high-grade endometrial cancer. RECENT FINDINGS: SLN mapping in high-grade endometrial cancer demonstrates similar high detection rates and diagnostic accuracy as seen in low-grade endometrial cancers. However, obtaining sufficient operator experience (at least 30 cases) and following SLN mapping algorithm continues to be essential to preserving diagnostic accuracy. Although limited in retrospective study design and short-term follow-up, current studies have not demonstrated inferior survival outcomes of SLN mapping compared to traditional lymphadenectomy. SLN mapping is an acceptable and accurate method of lymph node evaluation in high-grade endometrial cancer. Future prospective studies are needed to evaluate long-term oncologic outcomes between SLN mapping and systematic lymphadenectomy in this patient population.

Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration.

Cardiac injury leads to the loss of cardiomyocytes, which are rapidly replaced by the proliferation of the surviving cells in zebrafish, but not in mammals. In both the regenerative zebrafish and non-regenerative mammals, cardiac injury induces a sustained macrophage response. Macrophages are required for cardiomyocyte proliferation during zebrafish cardiac regeneration, but the mechanisms whereby macrophages facilitate this crucial process are fundamentally unknown. Using heartbeat-synchronized live imaging, RNA sequencing, and macrophage-null genotypes in the larval zebrafish cardiac injury model, we characterize macrophage function and reveal that these cells activate the epicardium, inducing cardiomyocyte proliferation. Mechanistically, macrophages are specifically recruited to the epicardial-myocardial niche, triggering the expansion of the epicardium, which upregulates vegfaa expression to induce cardiomyocyte proliferation. Our data suggest that epicardial Vegfaa augments a developmental cardiac growth pathway via increased endocardial notch signaling. The identification of this macrophage-dependent mechanism of cardiac regeneration highlights immunomodulation as a potential strategy for enhancing mammalian cardiac repair.

The Role of Long-Alkyl-Group Spacers in Glycolated Copolymers for High-Performance Organic Electrochemical Transistors.

Semiconducting polymers with oligoethylene glycol (OEG) sidechains have attracted strong research interest for organic electrochemical transistor (OECT) applications. However, key molecular design rules for high-performance OECTs via efficient mixed electronic/ionic charge transport are still unclear. In this work, new glycolated copolymers (gDPP-TTT and gDPP-TTVTT) with diketopyrrolopyrrole (DPP) acceptor and thiophene (T) and vinylene (V) thiophene-based donor units are synthesized and characterized for accumulation mode OECTs, where a long-alkyl-group (C12 ) attached to the DPP unit acts as a spacer distancing the OEG groups from the polymer backbone. gDPP-TTVTT shows the highest OECT transconductance (61.9 S cm-1 ) and high operational stability, compared to gDPP-TTT and their alkylated counterparts. Surprisingly, gDPP-TTVTT also shows high electronic charge mobility in a field-effect transistor, suggesting efficient ion injection/diffusion without hindering its efficient electronic charge transport. The elongated donor unit (TTVTT) facilitates hole polaron formation to be more localized to the donor unit, leading to faster and easier polaron formation with less impact on polymer structure during OECT operation, as opposed to the TTT unit. This is supported by molecular dynamics simulation. These simultaneously high electronic and ionic charge-transport properties are achieved due to the long-alkyl-group spacer in amphipathic sidechains, providing an important molecular design rule for glycolated copolymers.

Isolation of Cardiac Endothelial Cells for Transcriptomic Analysis of the Zebrafish and Mouse Heart.

Isolation of high quality cardiac endothelial cells is a prerequisite for successful bulk and single cell sequencing for RNA (scRNA-seq). We describe a protocol using both enzymatic and mechanical dissociation and fluorescence-activated cell sorting (FACS) to isolate endothelial cells from larval and adult zebrafish hearts and from healthy and ischemic adult mouse hearts. Endothelial cells with high viability and purity can be obtained using this method for downstream transcriptional analyses applications.

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension.

AIMS: Endothelial cell (EC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterize EC dynamics in PAH at single-cell resolution. METHODS AND RESULTS: We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility, and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and microvasculature. CONCLUSION: This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.

Hooked on heart regeneration: the zebrafish guide to recovery.

While humans lack sufficient capacity to undergo cardiac regeneration following injury, zebrafish can fully recover from a range of cardiac insults. Over the past two decades, our understanding of the complexities of both the independent and co-ordinated injury responses by multiple cardiac tissues during zebrafish heart regeneration has increased exponentially. Although cardiomyocyte regeneration forms the cornerstone of the reparative process in the injured zebrafish heart, recent studies have shown that this is dependent on prior neovascularization and lymphangiogenesis, which in turn require epicardial, endocardial, and inflammatory cell signalling within an extracellular milieu that is optimized for regeneration. Indeed, it is the amalgamation of multiple regenerative systems and gene regulatory patterns that drives the much-heralded success of the adult zebrafish response to cardiac injury. Increasing evidence supports the emerging paradigm that developmental transcriptional programmes are re-activated during adult tissue regeneration, including in the heart, and the zebrafish represents an optimal model organism to explore this concept. In this review, we summarize recent advances from the zebrafish cardiovascular research community with novel insight into the mechanisms associated with endogenous cardiovascular repair and regeneration, which may be of benefit to inform future strategies for patients with cardiovascular disease.

Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.

OBJECTIVE: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280). DATA SOURCES: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials. STUDY ELIGIBILITY CRITERIA: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data. METHODS: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m2 (range, 19.4-43.7 kg/m2). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I2=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I2=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I2=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I2=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I2=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I2=0%). CONCLUSION: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.