The FOXP3+ Pro-Inflammatory T Cell: A Potential Therapeutic Target in Crohn's Disease.

BACKGROUND & AIMS: The incidence of Crohn's disease (CD) continues to increase worldwide. The contribution of CD4+ cell populations remains to be elucidated. We aimed to provide an in-depth transcriptional assessment of CD4+ T cells driving chronic inflammation in CD. METHODS: We performed single-cell RNA-sequencing in CD4+ T cells isolated from ileal biopsies of patients with CD compared with healthy individuals. Cells underwent clustering analysis, followed by analysis of gene signaling networks. We overlapped our differentially expressed genes with publicly available microarray data sets and performed functional in vitro studies, including an in vitro suppression assay and organoid systems, to model gene expression changes observed in CD regulatory T (Treg) cells and to test predicted therapeutics. RESULTS: We identified 5 distinct FOXP3+ regulatory Treg subpopulations. Tregs isolated from healthy controls represent the origin of pseudotemporal development into inflammation-associated subtypes. These proinflammatory Tregs displayed a unique responsiveness to tumor necrosis factor-α signaling with impaired suppressive activity in vitro and an elevated cytokine response in an organoid coculture system. As predicted in silico, the histone deacetylase inhibitor vorinostat normalized gene expression patterns, rescuing the suppressive function of FOXP3+ cells in vitro. CONCLUSIONS: We identified a novel, proinflammatory FOXP3+ T cell subpopulation in patients with CD and developed a pipeline to specifically target these cells using the US Food and Drug Administration-approved drug vorinostat.

Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation.

BACKGROUND & AIMS: Although T-cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T-cell differentiation is ill defined, and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored. METHODS: Human naive T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) before being characterized via the transcriptome (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin by sequencing), protein expression (cytometry by time of flight, flow cytometry), metabolism (mitochondrial stress test, ultrahigh performance liquid chromatography-tandem mas spectroscopy) and function (T-cell suppression assay). The in vivo role of G9a was assessed using 3 murine models. RESULTS: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3+ T cells (G9a-inibitors-T regulatory cells [Tregs]) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells, resulting in increased intracellular cholesterol. Metabolomic profiling of G9a-inibitors-Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute trinitrobenzene sulfonic acid-induced colitis secondary to tissue-specific Treg development. Finally, Tregs lacking G9a expression (G9a-knockout Tregs) remain functional chronically and can rescue T-cell transfer-induced colitis. CONCLUSION: G9a inhibition promotes cholesterol metabolism in T cells, favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.

Systemic erythematosus lupus and pregnancy outcomes in a Colombian cohort.

OBJECTIVE: Pregnant women with SLE have higher probabilities of maternal complications. SLE during pregnancy has alternating patterns of remission and flare-ups; however, most pregnant SLE patients tend to worsen with associated poor obstetric and perinatal outcomes. This study aimed to describe obstetric outcomes in pregnant women with SLE. METHODS: This retrospective study was performed between 2011 and 2020 at a highly complex referral health center in Cali, Colombia. Pregnant women with a diagnosis of SLE were included. Demographic, clinical, and laboratory features and obstetric and fetal outcomes, including intensive care unit (ICU) characteristics, were evaluated. RESULTS: Forty-eight pregnant women with SLE were included. The median age was 29 (25-33.7) years. The SLE diagnosis was made before pregnancy in 38 (79.1%) patients, with a median disease duration of 46 (12-84) months. Thirteen (27.1%) patients had lupus nephritis. Preterm labor (34, 70.8%), preeclampsia (25, 52%), and preterm rupture of membranes (10, 20.8%) were the most common obstetric complications. A relationship between a greater systemic lupus erythematosus pregnancy disease activity index (SLEPDAI) and the development of hypertensive disorders during pregnancy was established (preeclampsia = p < 0.0366; eclampsia = p < 0.0153). A relationship was identified between lupus nephritis (LN) and eclampsia (p < 0.01), preterm labor (p < 0.045), and placental abruption (p < 0.01). Seventeen (35.4%) patients required ICU admission; 52.9% of them were due to AID activity, 17.6% for cardiovascular damage, 11.7% for septic shock, and 5.8% for acute kidney failure. Fetal survival was 89.5% (N = 43/48). Among the live births, two (4.2%) newborns were diagnosed with neonatal lupus, and two (4.2%) were diagnosed with congenital heart block. One maternal death was registered due to preeclampsia and intraventricular hemorrhage. CONCLUSIONS: This study is the first to describe SLE during pregnancy in Colombia. SLE was the most prevalent AID in this cohort, and complications included preterm labor, preeclampsia, and postpartum hemorrhage. A higher SLEPDAI and lupus nephritis predicted adverse maternal outcomes.

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD).

Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2Δ/ΔFOXP3+). We find that EZH2 deficiency in FOXP3+ T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2Δ/ΔFOXP3+ T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2Δ/ΔFOXP3+ mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4+ T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4+ T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation.

Caregiver Use of the Core Components of Technology-Enhanced Helping the Noncompliant Child: A Case Series Analysis of Low-Income Families.

Children from low-income families are more likely to develop early-onset disruptive behavior disorders (DBDs) compared to their higher income counterparts. Low-income families of children with early-onset DBDs, however, are less likely to engage in the standard-of-care treatment, behavioral parent training (BPT), than families from other sociodemographic groups. Preliminary between-group findings suggested technology-enhanced BPT was associated with increased engagement and boosted treatment outcomes for low-income families relative to standard BPT. The current study used a case series design to take this research a step further by examining whether there was variability in use of, and reactions to, the smartphone enhancements within technology-enhanced BPT and the extent to which this variability paralleled treatment outcome. Findings provide a window into the uptake and use of technology-enhanced service delivery methods among low-income families, with implications for the broader field of children's mental health.

Incorporating Mobile Phone Technologies to Expand Evidence-Based Care.

Ownership of mobile phones is on the rise, a trend in uptake that transcends age, region, race, and ethnicity, as well as income. It is precisely the emerging ubiquity of mobile phones that has sparked enthusiasm regarding their capacity to increase the reach and impact of health care, including mental health care. Community-based clinicians charged with transporting evidence-based interventions beyond research and training clinics are in turn, ideally and uniquely situated to capitalize on mobile phone uptake and functionality to bridge the efficacy to effectiveness gap. As such, this article delineates key considerations to guide these frontline clinicians in mobile phone-enhanced clinical practice, including an overview of industry data on the uptake of and evolution in the functionality of mobile phone platforms, conceptual considerations relevant to the integration of mobile phones into practice, representative empirical illustrations of mobile-phone enhanced assessment and treatment, and practical considerations relevant to ensuring the feasibility and sustainability of such an approach.

Technology-enhanced program for child disruptive behavior disorders: development and pilot randomized control trial.

Early onset disruptive behavior disorders are overrepresented in low-income families; yet these families are less likely to engage in behavioral parent training (BPT) than other groups. This project aimed to develop and pilot test a technology-enhanced version of one evidence-based BPT program, Helping the Noncompliant Child (HNC). The aim was to increase engagement of low-income families and, in turn, child behavior outcomes, with potential cost-savings associated with greater treatment efficiency. Low-income families of 3- to 8-year-old children with clinically significant disruptive behaviors were randomized to and completed standard HNC (n = 8) or Technology-Enhanced HNC (TE-HNC; n = 7). On average, caregivers were 37 years old; 87% were female, and 80% worked at least part-time. More than half (53%) of the youth were boys; the average age of the sample was 5.67 years. All families received the standard HNC program; however, TE-HNC also included the following smartphone enhancements: (a) skills video series, (b) brief daily surveys, (c) text message reminders, (d) video recording home practice, and (e) midweek video calls. TE-HNC yielded larger effect sizes than HNC for all engagement outcomes. Both groups yielded clinically significant improvements in disruptive behavior; however, findings suggest that the greater program engagement associated with TE-HNC boosted child treatment outcome. Further evidence for the boost afforded by the technology is revealed in family responses to postassessment interviews. Finally, cost analysis suggests that TE-HNC families also required fewer sessions than HNC families to complete the program, an efficiency that did not compromise family satisfaction. TE-HNC shows promise as an innovative approach to engaging low-income families in BPT with potential cost-savings and, therefore, merits further investigation on a larger scale.

Coparenting experiences in African American families: an examination of single mothers and their nonmarital coparents.

African American youth from single-mother homes continue to be overrepresented in statistics on risk behavior and delinquency, a trend that many be attributed to father-absence, socioeconomic disadvantage, and compromises in parenting more typical of single than two-parent families. Yet, this risk-focused perspective ignores a long-standing strength of the African American community, the involvement and potential protective impact of extended family members in childrearing. This study describes the experiences of 95 African American single mothers and their nonmarital coparents who participated in a study of African American single-mother families with an 11-16-year-old child. Specifically, the study examines: (a) the extent to which nonmarital coparents are involved in childrearing; (b) the relative levels of risk (i.e., depression, mother-coparent conflict) and protective (i.e., parenting) associated with maternal and coparent involvement; and (c) how similarly and/or differently coparent and mother variables operate with regard to youth externalizing problems. Findings reveal that a range of family members and other adults actively participate in childrearing in African American single-mother families, coparents do not differ from mothers on certain study variables (i.e., depression and mother-coparent conflict) but do for others (parenting), and coparent involvement is associated with youth adjustment in ways that are similar to our more established understanding of maternal involvement. The potential clinical implications of the findings are discussed and future research directions are highlighted.

Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Effectiveness of Robotics in Stroke Rehabilitation to Accelerate Upper Extremity Function: Systematic Review.

Objective: To examine the effectiveness of robot-assisted therapy (RAT) combined with conventional therapy (CT) compared to CT alone in accelerating upper extremity (UE) recovery poststroke. Data Sources. We searched five databases: Ovid, MEDLINE, CINAHL, PubMed, and Scopus Study Selection. Studies were selected for this review using the following inclusion criteria: randomized controlled trials of adults, RAT combined with CT compared to CT, and Fugl-Meyer Assessment (FMA) as an outcome measure. Studies focused on children with neurological impairments, and studies that used RAT to facilitate lower extremity recovery and/or improve gait were excluded. Data Extraction. The initial search yielded 3,019 citations of articles published between January 2011 and May 2021. Fourteen articles met the inclusion criteria. Randomization, allocation sequence concealment, blinding, and other biases were assessed. Data Synthesis. Current evidence suggests that the use of RAT along with CT may accelerate upper extremity recovery, measured by FMA, in the beginning of rehabilitation. However, the progress fades over time. More empirical research is needed to validate this observation. Also, the findings related to cost-benefit analyses of RAT are inconclusive. Conclusions: It is unclear whether RAT accelerates UE recovery poststroke when used in conjunction with conventional therapy. Given the capital and maintenance costs involved in developing and delivering RAT, more controlled studies examining the effectiveness and cost-benefit analysis of RAT are needed before it can be used widely. This trial is registered with CRD42021270824.

Simulation in Nurse Anesthesia Educational Programs: A Report by the AANA Simulation Subcommittee.

Simulation is an integral part of the healthcare educational landscape and a key element in the future of graduate professional education. For the past three decades, simulation-based educational methodology has been gaining popularity in nurse anesthesia educational programs (NAEP). There is currently limited objective evidence documenting modalities used or educational outcomes addressed through simulation in NAEPs. In 2018, the American Association of Nurse Anesthesiology (AANA) established a Simulation Subcommittee of the AANA Education Committee and tasked the group with two primary goals: 1) to gain a better understanding of the current state of simulation education and 2) to review responses with regard to how NAEPs could best incorporate simulation elements within their curriculum to meet requirements while adhering to the guidelines of the Council on Accreditation of Nurse Anesthesia Educational Programs. A survey tool was developed and distributed to all programs to assess the utilization of simulation, available simulation resources, ongoing faculty development efforts, and barriers to use of this educational approach. Survey results indicated that simulation is valued as an effective method within NAEPs for a variety of teaching and learning activities and is utilized to support achievement of both technical and nontechnical learning outcomes for student registered nurse anesthetists.

Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL.

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.

Neighborhood context and adjustment in African American youths from single mother homes: the intervening role of hopelessness.

African American youths from single mother homes are more likely to live in neighborhoods characterized by greater risk and fewer resources than youth from two parent homes or European American youths; in turn, such adverse conditions are associated with increased adjustment problems. Despite this well-established vulnerability, relatively little is known about variables linking neighborhood context to youth adjustment. With the aim of identifying a potential youth-focused intervening variable amenable to intervention, this study examined the intervening role of hopelessness in the association between neighborhood context and adjustment problems in a sample of 171 African American youths (11-16 year olds) from single mother homes. Findings revealed direct associations between neighborhood context and youth adjustment, as well as indirect associations through youth hopelessness, although findings varied by the marker of neighborhood context (sense of community or perceived crime) and adjustment (internalizing or externalizing problems). Building on prior work noting that hopelessness is amenable to psychosocial intervention, the present findings suggest that hopelessness may afford a valuable target for prevention and intervention programming among African American youths from single mother homes in the context of adverse neighborhood conditions.

Diagnostic accuracy of Achenbach scales in detecting youths' substance use disorders.

It is vital to identify substance use disorders (SUDs) in youths and adults early and accurately. Previous studies have investigated the validity and reliability of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR) for other related anxiety, mood, and behavior problems. The present study tested if the CBCL and YSR substance use items can discriminate adolescents with versus without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework. N = 422 outpatient adolescents (age 9-18) and their caregivers completed semistructured diagnostic interviews. Caregivers completed CBCL, and adolescents completed the YSR. K-SADS-PL + diagnoses indicated that 34 youths met Diagnostic and Statistical Manual (DSM)-IV criteria for SUDs. Receiver Operating Characteristics (ROC) models estimated the likelihood of having Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (KSADS-PL) + SUDs based on substance use scores of CBCL or YSR. Scores on all scales significantly identified KSADS-PL-diagnosed SUDs in adolescents: Area under the curve (AUCCBCL = .90, p < .0005; AUCYSR = .84, p < .0005). There was no significant difference in the accuracy comparing each informant used separately; CBCL showed incremental value above the YSR report when both were included in logistic regression models. CBCL and YSR substance items demonstrated diagnostic and clinical utility in identifying SUDs in adolescents. Findings suggest that Achenbach Scales could be a valuable intake instrument in detecting adolescents SUDs. A supplemental clinical vignette illustrates the clinical application of the study findings. It will be important for future research to replicate use of these measures across varying clinical scenarios and settings. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Dyslexia knowledge, perceived preparedness, and professional development needs of in-service educators.

The purpose of this study was to investigate New Jersey educators' dyslexia knowledge and misconceptions, professional development perceptions and needs, and perceived preparedness regarding teaching students with dyslexia. A second purpose was to investigate what factors predicted New Jersey educators' knowledge about dyslexia. A total of 705 in-service educators completed a survey about their dyslexia knowledge, perceived preparedness, and professional development perceptions. Participants had accurate overall knowledge about dyslexia, but some prevailing misconceptions were still present. The greatest predictor of dyslexia knowledge was years of experience in working with students with dyslexia. Reading specialists, educators with greater perceived preparedness and those educators who had training in multi-sensory approaches to instruction had significantly more dyslexia knowledge than other educators. Approximately half of the participants felt prepared to teach students with dyslexia and that working with students with dyslexia prepared them the most. Participants perceived that multi-sensory approaches were the most effective professional development and their undergraduate education was the least effective. Most participants were in support of further professional development on the topic of dyslexia. Implications for in-service educators' professional development and future research directions are discussed.

Optimizing Engagement in Behavioral Parent Training: Progress Toward a Technology-Enhanced Treatment Model.

Low-income families are more likely to have a child with an early-onset Behavior Disorder (BD); yet, socioeconomic strain challenges engagement in Behavioral Parent Training (BPT). This study follows a promising pilot to further examine the potential to cost-effectively improve low-income families' engagement in and the efficiency of BPT. Low-income families were randomized to (a) Helping the Noncompliant Child (HNC; McMahon & Forehand, 2003), a weekly, mastery-based BPT program that includes both the parent and child or (b) Technology-Enhanced HNC (TE-HNC), which includes all of the standard HNC components plus a parent mobile application and therapist web portal that provide between-session monitoring, modeling, and coaching of parent skill use with the goal of improved engagement in the context of financial strain. Relative to HNC, TE-HNC families had greater homework compliance and mid-week call participation. TE-HNC completers also required fewer weeks to achieve skill mastery and, in turn, to complete treatment than those in HNC without compromising parent satisfaction with treatment; yet, session attendance and completion were not different between groups. Future directions and clinical implications are discussed.

BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease.

FOXP3+ Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3+ cells led to systemic inflammation. BMI1-deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17-like proinflammatory cells, a transition relevant to human Crohn's disease associated CD4+ T cells.

Undifferentiated uterine sarcoma presenting as a pathologic humerus fracture.

BACKGROUND: Undifferentiated uterine sarcomas are rare malignancies often presenting at advanced stage. CASE: A female in her ninth decade presented to our MEDCEN emergency department complaining of onset of severe right arm pain while performing activities of daily living. A pathologic humeral fracture was diagnosed and subsequent orthopedic evaluation resulted in a biopsy and placement of her arm in a cooptation splint and sling. An abdominal exam revealed a 10-cm mass in the right lower quadrant that was thought to originate from the uterus. Computed tomography imaging was concerning for a primary endometrial process and she was referred to gynecologic oncology. Her humeral biopsy was consistent with a poorly differentiated metastatic sarcoma. An endometrial biopsy was consistent with undifferentiated uterine sarcoma, the origin of her humeral lesion. CONCLUSION: Humeral metastasis is an uncommon presentation for undifferentiated endometrial sarcomas.