The CNS microenvironment promotes leukemia cell survival by disrupting tumor suppression and cell cycle regulation in pediatric T-cell acute lymphoblastic leukemia.

A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia cells are capable of infiltrating and residing within the CNS, primarily the leptomeninges, where they interact with the microenvironment and remain sheltered from systemic treatment. These cells can survive in the CNS, by hijacking the microenvironment and disrupting normal functions, thus promoting malignant transformation. While the protective effects of the bone marrow niche have been widely studied, the mechanisms behind leukemia infiltration into the CNS and the role of the CNS niche in leukemia cell survival remain unknown. We identified a dysregulated gene expression profile in CNS infiltrated T-ALL and CNS relapse, promoting cell survival, chemoresistance, and disease progression. Furthermore, we discovered that interactions between leukemia cells and human meningeal cells induced epigenetic alterations, such as changes in histone modifications, including H3K36me3 levels. These findings are a step towards understanding the molecular mechanisms promoting leukemia cell survival in the CNS microenvironment. Our results highlight genetic and epigenetic alterations induced by interactions between leukemia cells and the CNS niche, which could potentially be utilized as biomarkers to predict CNS infiltration and CNS relapse.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Quasi-Parallel Shock Reformation Seen by Magnetospheric Multiscale and Ion-Kinetic Simulations.

Shock waves in collisionless plasmas are among the most efficient particle accelerators in space. Shock reformation is a process important to plasma heating and acceleration, but direct observations of reformation at quasi-parallel shocks have been lacking. Here, we investigate Earth's quasi-parallel bow shock with observations by the four Magnetospheric Multiscale spacecraft. The multi-spacecraft observations provide evidence of short large-amplitude magnetic structures (SLAMS) causing reformation of the quasi-parallel shock. We perform an ion-kinetic Vlasiator simulation of the bow shock and show that SLAMS reforming the bow shock recreates the multi-spacecraft measurements. This provides a method for identifying shock reformation in the future.

Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center.

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades.1 IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.

Vulvar Crohn's Disease: Clinical Features and Outcomes.

INTRODUCTION: Vulvar involvement is a rare complication of Crohn's disease (CD). The optimal treatment of vulvar CD is unknown. METHODS: We conducted a 25-year retrospective cohort study of vulvar CD from 3 referral centers. Clinical features and outcomes were studied. RESULTS: Fifty patients were identified. The most common vulvar symptoms were pain (74%), edema (60%), ulcerations (46%), nodules (36%), and abscess (34%). Medical management leading to symptomatic improvement varied, and 5 patients ultimately required surgery. DISCUSSION: Vulvar CD manifests with a broad spectrum of symptoms. Aggressive medical management was frequently effective, although surgery was required in 10% of cases.

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.

A case report of sevelamer-associated recto-sigmoid ulcers.

BACKGROUND: Optimal phosphorous control is an important aspect of the care of patients with end-stage renal disease, and phosphate binders are usually needed. CASE PRESENTATION: A 74-year-old woman with end-stage renal disease on maintenance hemodialysis presented to the emergency room with abdominal discomfort, rectal pain, and blood-tinged stools. Initial concern was for a rectal carcinoma, based on the symptoms and imaging in initial computerized tomography of the abdomen showing rectal wall thickening, and her clinical presentation. She had been treated with the phosphate binder sevelamer for two months. In this case report, we explore the unique features of sevelamer-associated recto-sigmoid ulcers which led to her symptoms. CONCLUSION: Sevelamer is widely used in chronic kidney disease and end-stage renal disease patients with hyperphosphatemia. It is a crosslinked polymeric amine that binds phosphates and bile acids; it is not systemically absorbed. To the authors' knowledge, this is the first reported case of recto-sigmoid ulcers associated with use of this phosphate binder. Nephrologists, pathologists, and gastroenterology sub-specialists should be aware of this recently-reported entity in patients on sevelamer with suggestive symptoms, as this medication is widely used in renal patients.

Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-ß signaling in CD8+ T lymphocytes.

KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-ß1 (TGF-ß1) signaling in CD4(+) T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-ß receptor II (TGF-ßRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8(+) T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10(-/-) CD8(+) T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8(+) T cells from the spleen of adult mice express lower levels of surface TGF-ßRII (TßRII). Congruently, in vitro activation of KLF10-deficient CD8(+) T cells upregulate TGF-ßRII to a lesser extent compared with wild-type (WT) CD8(+) T cells, which results in attenuated Smad2 phosphorylation following TGF-ß1 stimulation compared with WT CD8(+) T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-ßRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-ßRII among viral-specific KLF10(-/-) CD8(+) T cells and a higher percentage of IFN-γ-producing CD8(+) T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-ßRII in CD8(+) T cells. Thus, KLF10 regulation of TGF-ßRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-ß1/TGF-ßRII signaling pathway is crucial.

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation.

Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-ß1 signaling in both CD8(+) and CD4(+) T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGFßRII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10(-/-) bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6(+)MHCII(+) cells and a reciprocal decrease of the anti-inflammatory LyC6(-)MHCII(+) subset. Additionally, the anti-inflammatory CD11b(+)CX3CR1(hi) subset of colonic macrophages is significantly decreased in KLF10(-/-) compared with WT mice under inflammatory conditions. Molecularly, CD11b(+) colonic macrophages from KLF10(-/-) mice exhibit a proinflammatory cytokine profile with increased production of TNF-α and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGFßRII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGFßRII and display an attenuated Smad-2 phosphorylation following TGF-ß1 stimulation. We further show that KLF10 directly binds to the TGFßRII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGFßRII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis.

Predictors of health-related quality of life and adherence in Crohn's disease and ulcerative colitis: implications for clinical management.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with impaired health-related quality of life (HRQOL) and adherence. Our aim was to identify demographic, clinical, and psychosocial predictors of impaired HRQOL and non-adherence to provider recommendations. METHODS: Adults with Crohn's disease (CD) or ulcerative colitis (UC) residing within the USA were recruited from online IBD support groups for participation in this cross-sectional study. Data were collected online through standardized instruments, including the Inflammatory Bowel Disease Questionnaire and the Medical Outcomes Study (MOS) general adherence scale. Bivariate analyses and multivariate linear regression were used to assess predictors of HRQOL and adherence. RESULTS: We recruited 136 individuals, among whom median age was 35 years (range 18-75), and 82 % were female. 57 % had CD, and 43 % had UC. Predictors of lower HRQOL among CD patients were perceived stress (p < 0.0001), number of CD relapses (p < 0.0001), and female gender (p = 0.0015), while among UC patients they were perceived stress (p < 0.0001) and number of UC relapses (p = 0.0017). Predictors of lower adherence to provider recommendations in CD were perceived stress (p = 0.0007) and older age (p = 0.041), while in UC, perceived stress was the only predictor of lower adherence (p = 0.022). CONCLUSIONS: Among patients with IBD, a higher level of perceived stress is a strong predictor of lower HRQOL and lower adherence to provider recommendations. Additionally, females with CD and patients with higher number of IBD relapses may be at risk of lower HRQOL. Psychological interventions, including physician-facilitated conversations, psychological screeners, and a multidisciplinary approach, may help address impaired HRQOL and adherence and merit further study.

A 1-Year Cross-sectional Inflammatory Bowel Disease Surveillance Colonoscopy Cohort Comparing High-definition White Light Endoscopy and Chromoendoscopy.

BACKGROUND: We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD). METHODS: This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables. RESULTS: A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years' experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years' experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE. CONCLUSIONS: Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.

Certolizumab Trough Levels and Antibodies in Crohn Disease: A Single-Center Experience.

Background: Certolizumab pegol (CZP) has been successfully used for the treatment of Crohn disease (CD); however, real-world data regarding the utility of CZP trough levels (CTLs) are lacking. We aimed to correlate CTL with CD outcomes and to determine frequency of CZP antibodies. Methods: Retrospective evaluation of all CD patients on maintenance CZP with CTL obtained between 2016 and 2019. Outcomes included: median CTL, presence of anti-CZP antibodies, biochemical response (BR), clinical response (CR), radiologic response (RR), radiologic healing (RH), and mucosal healing (MH). Results: Seventy-seven CD patients were included. Median CTL was 18.9 µg/mL (interquartile range, 7.6-35.4). Twenty-three patients (27.3%) had positive antibody levels, with lower median CTL compared to patients with no antibodies (0.0 vs 29.8; P < 0.0001). Median CTL levels were higher in patients with vs without CR (30.4 vs 10.3 µg/mL; P = 0.0015) and RR (29.6 vs 5.8 µg/mL; P = 0.006). CZP dosing at least every 2 weeks was associated with higher odds of achieving MH (odds ratio, 3.2; 95% confidence interval, 1.03-9.97). CTL resulted in change in clinical management in 62.7% of cases and presence of CMZ antibodies was associated with an odds ratio of 5.83 (95% confidence interval, 1.57-21.73) of change in management. Receiver operating characteristic curve and quartile analysis suggested that CTL >19 µg/mL is associated with increased rates of CR and RR. Conclusions: Higher CTL was significantly associated with CR and RR. The rate of CZP antibodies was 27.3%. Our data suggest maintenance CTL of ≥19 µg/mL should be achieved in order to optimize outcomes in clinical practice.

Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease.

OBJECTIVES: The treatment of inflammatory bowel disease (IBD) often includes immunosuppressive medications, which may increase the risk of vaccine-preventable illnesses. We aimed to assess the impact of immunosuppression on immune responses to pneumococcal vaccination in patients with IBD. METHODS: The study design consists of a prospective controlled clinical trial. This study was carried out at a tertiary-care IBD clinic. The subjects for the study belonged to one of the following three groups: adult patients with IBD on combination TNF-blockers and immunomodulators (Group A), those without immunosuppressive therapy (Group B), and age-matched healthy controls (Group C). The treatment consisted of immunization with 23-valent pneumococcal polysaccharide vaccines (PSVs). The main outcome was immune response for five serotypes defined as a twofold or greater increase from pre-vaccination titers and > or =1 microg post-vaccination titer. RESULTS: Sixty-four subjects participated in the study: 20 in Group A, 25 in Group B, and 19 in Group C. Pre-vaccination titers were similar among the three groups. Vaccine responses were lower in Group A than in Group B (P< or =0.01 for four out of five antigens) and Group C (P<0.01 for all five antigens). Overall vaccine response was seen in 45, 80, and 85% of Groups A, B, and C (P=0.01), respectively. CONCLUSIONS: Immune response to PSV-23 is impaired in Crohn's disease (CD) patients on combination immunosuppressive therapy but is normal among non-immunosuppressed patients. Given the unpredictable likelihood for immunosuppressive therapy, newly diagnosed patients with IBD should undergo vaccination before the initiation of immunosuppressive therapy.

Capsule endoscopy in patients with Crohn's disease: diagnostic yield and safety.

BACKGROUND: Capsule endoscopy (CE) is increasingly used in patients with suspected or known Crohn's disease (CD). OBJECTIVE: To determine the diagnostic yield of CE and the distribution of small-bowel (SB) lesions in symptomatic patients with known CD. DESIGN AND SETTING: Retrospective review of CE procedures performed in patients with CD between 2001 and 2005 in a tertiary care center. PATIENTS: One hundred thirty-four patients with an established diagnosis of CD and symptoms suggestive of active disease. INTERVENTIONS: Swallowing the capsule. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of CE and distribution of SB lesions in patients with CD. RESULTS: One hundred forty-six CE procedures were performed on 134 CD patients. Fifty-two (39%) of 134 patients had CE findings diagnostic of active CD (> 3 ulcerations), and 17 (13%) had findings suggestive of active CD (< or = 3 ulcerations). Fifty-seven (42%) patients had normal findings, and 6% had normal but incomplete studies. The distribution of SB lesions was 32% in the duodenum, 53% in the jejunum, 67% in the proximal ileum, and 85% in the distal ileum. CE was comparable to ileoscopy in detecting ileal ulcerations (55% vs 48%), but superior to SB follow-through in detecting CD lesions in the SB (incremental yield of 32%; 95% CI, 9%-54%; P = .0017). LIMITATIONS: Retrospective study from a single center. CONCLUSIONS: CE identified SB lesions in approximately half of symptomatic CD patients. Large-scale prospective studies are needed to evaluate whether positive CE findings may affect disease outcomes.

LDL-cholesterol concentrations: a genome-wide association study.

BACKGROUND: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. METHODS: We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. FINDINGS: In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. INTERPRETATION: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.