Translatability of helminth therapy in inflammatory bowel diseases

Modern hygienic lifestyles are associated with the emergence of inflammatory bowel disease (IBD) which now afflicts millions of people in highly-developed countries. Meticulous hygiene interrupts conduits of transmission required for ubiquitous exposure to parasitic worms (helminths). We proposed that loss of exposure to helminths permits development of IBD. Early clinical trials suggested that exposure to helminths such as Trichuris suis or Necator americanus can improve IBD. Over the last several years, processes to “medicinalize” T. suis have been developed and use of this helminth is now being studied in large multi-center clinical trials. Concurrently, we and others have identified some of the immune regulatory mechanisms elicited by helminth exposure that suppress inappropriate intestinal inflammation. These efforts could soon result in new therapies for patients with IBD.     

布拉酵母对炎症性肠病的治疗作用

炎症性肠病包括溃疡性结肠炎和克罗恩病, 其病因与发病机制尚未完全明确。大量研究表明, 肠道微生物在炎症性肠病的发生、发展中发挥重要作用。布拉酵母是一种有益于人体健康的肠道微生物, 研究发现能有效改善炎症性肠病症状, 可能与其抑制肠道致病菌、增强肠屏障功能、调节肠道黏膜免疫反应等有关。     

Effects of lithium on thrombopoiesis in patients with low platelet cell counts following chemotherapy or radiotherapy

Therapy for neoplasma is limited by hematological side effects of tumor-destructive therapy and, in part, makes expensive supportive care necessary to overcome and treat leukopenia and thrombocytopenia and their consequences. Thrombocytopenia is a major clinical problem caused by chemotherapy and radiotherapy. An effective and very cost-effective option for treating moderate neutropenia is the administration of lithium carbonate. Lithium induces the release of colony-stimulating factors (CSF) and therefore stimulates proliferation of neutrophil granulocytes. Other cytokines, such as interleukin-1 (IL-1), IL-6, and tumor-necrosis factor-α (TNF-α), are also stimulated. Apart from granulocyte-macrophage-CSF (GM-CSF), there have as yet been no reports of lithium salts inducing early activating factors for the megakaryocytic lineage, such as IL-3, IL-11, stem cell factor and flt-3 ligand, or maturation factors, such as thrombopoietin (TPO). A statistically significant increase in the mean number of platelets for patients with cell counts below 150,000/μL on the commencement of treatment with lithium carbonate could be observed. Patient tolerability of lithium carbonate therapy is very good. Patients with persistent leukopenia and thrombocytopenia following chemotherapy or radiotherapy can be treated with this trace element very cost-effectively. Unfortunately this treatment has not gained acceptance in clinical oncology in the face of extremely cost-intensive treatment with recombinant GM-CSF, IL-11 or, potentially, thrombopoietin.     

Design of nanozymes for inflammatory bowel disease therapy

Science China Life Sciences -     

硫酸亚铁对缺铁性贫血小鼠肠道健康的影响

【目的】旨在探究硫酸亚铁(FeSO4)对缺铁性贫血(iron deficiency anemia, IDA)小鼠肠道健康的影响。【方法】选取45只24日龄体重(16.0±1.2) g的雄性昆明小鼠,随机分成3组,每组15只,即对照组(正常饲料,饮蒸馏水)、IDA组(低铁饲料造模2周,饮去离子水)、IDA-Fe²⁺组(造模结束后灌胃FeSO₄ 3周,饮去离子水),实验结束时采样。【结果】试验结束时,与IDA组相比,IDA-Fe²⁺组小鼠的红细胞、血红蛋白、红细胞压积、平均红细胞体积、平均红细胞血红蛋白量、平均红细胞血红蛋白浓度等贫血指标均恢复至正常水平(P>0.05),表明FeSO4具有改善IDA的功能;与对照组相比,IDA和IDA-Fe²⁺组小鼠的氧化应激指标和肿瘤坏死因子α均显著升高(P<0.01)、紧密连接蛋白Occludin显著降低(P<0.001),IDA-Fe²⁺组与IDA组除结肠总抗氧化能力(TAC)外均无差异显著性(P>0.05)。结肠组织...     

Effect of 5-lipoxygenase inhibition on events associated with inflammatory bowel disease in rats

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LOX) in the production of leukotrienes makes it a likely therapeutic target for inflammatory conditions like asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). The aim of the present study was to evaluate the effect of zileuton, an orally active selective 5-LOX inhibitor against the events associated with dextran sodium sulphate-induced colitis in a rat model of IBD. The animals were administered simultaneously zileuton (100mg/kg) or sulphasalazine (100mg/kg) orally for 7 days. On day eight, rats were sacrificed, and distal colon isolated to determine myeloperoxidase activity, in vivo superoxide dismutase activity, prostaglandin E2 levels and histological examination. Both zileuton and sulphasalazine significantly prevented the development of inflammatory events associated with colitis. The effect of zileuton was more pronounced towards reducing myeloperoxidase activity and increasing PGE2 levels in distal colon. The results show that chemotactic leukotrienes are responsible for inflammatory surge in damaged colon and, zileuton, significantly improved healing by inhibition of neutrophil recruitment and indirectly through increase in prostaglandins at the site of inflammation. It is suggested that inhibitors of 5-LOX enzyme may have useful therapeutic role in the treatment of chronic intestinal inflammation.     

MIN score predicts primary response to infliximab/adalimumab and vedolizumab therapy in patients with inflammatory bowel diseases

Infliximab/adalimumab (IFX/ADA) and vedolizumab (VDZ) are the most widely used biologics in inflammatory bowel diseases. Current models used to predict their efficacies are restricted to either Crohn's disease or ulcerative colitis or to only one type of biologic, which makes them limited in external validation. We therefore designed a comprehensive comparison among these models to identify the most meaningful predictors for patient responses. Several biomarkers and models were compared for their abilities to predict both IFX/ADA and VDZ responses by receiver operating characteristic curves. Least absolute shrinkage and selection operator regression was adopted to determine a simplified gene signature. Verification was performed in biopsy samples by immunohistochemical staining. The GIMATS module (based on counts of IgG plasma cells, inflammatory monocytes, activated T cells, and stromal cells) had the best overall performance for response prediction in both biologics (IFX/ADA, AUC = 0.720–0.853; VDZ, AUC = 0.661–0.728). Based on this module, patients were equally divided into 3 groups: M type (GIMATS-low, metabolism), with a preference for IFX/ADA; I type (GIMATS-high, immune), with a preference for VDZ; and N type (GIMATS-medium, normal), with no preference for either treatment. Furthermore, to improve clinical utility, a simplified 6-gene model, MIN score, was established to determine the baseline expression of G0S2, S100A9, SELE, CHI3L1, MMP1 and CXCL13 and function as a substitute for GIMATS module. Our study suggested that the classification of metabolic or immune type by MIN score was valuable for IBD diagnosis to assist with selection of IFX/ADA and VDZ.     

Enhanced platelet adhesion induces angiogenesis in intestinal inflammation and inflammatory bowel disease microvasculature

Although angiogenesis is viewed as a fundamental component of inflammatory bowel disease (IBD) pathogenesis, we presently lack a thorough knowledge of the cell type(s) involved in its induction and maintenance in the inflamed intestinal mucosa. This study aimed to determine whether platelet (PLT) adhesion to inflamed intestinal endothelial cells of human origin may favour angiogenesis. Unstimulated or thrombin‐activated human PLT were overlaid on resting or tumour necrosis factor (TNF)‐α‐treated human intestinal microvascular endothelial cells (HIMEC), in the presence or absence of blocking antibodies to either vascular cell adhesion molecule (VCAM)‐1, intercellular adhesion molecule (ICAM)‐1, integrin α_vβ₃, tissue factor (TF) or fractalkine (FKN). PLT adhesion to HIMEC was evaluated by fluorescence microscopy, and release of angiogenic factors (VEGF and soluble CD40L) was measured by ELISA. A matrigel tubule formation assay was used to estimate PLT capacity to induce angiogenesis after co‐culturing with HIMEC. TNF‐α up‐regulated ICAM‐1, α_vβ₃ and FKN expression on HIMEC. When thrombin‐activated PLT were co‐cultured with unstimulated HIMEC, PLT adhesion increased significantly, and this response was further enhanced by HIMEC activation with TNF‐α. PLT adhesion to HIMEC was VCAM‐1 and TF independent but ICAM‐1, FKN and integrin α_vβ₃ dependent. VEGF and sCD40L were undetectable in HIMEC cultures either before or after TNF‐α stimulation. By contrast, VEGF and sCD40L release significantly increased when resting or activated PLT were co‐cultured with TNF‐α‐pre‐treated HIMEC. These effects were much more pronounced when PLT were derived from IBD patients. Importantly, thrombin‐activated PLT promoted tubule formation in HIMEC, a functional estimate of their angiogenic potential. In conclusion, PLT adhesion to TNF‐α‐pre‐treated HIMEC is mediated by ICAM‐1, FKN and α_vβ₃, and is associated with VEGF and sCD40L release. These findings suggest that inflamed HIMEC may recruit PLT which, upon release of pro‐angiogenic factors, actively contribute to inflammation‐induced angiogenesis.     

粪菌移植在儿童炎症性肠病中的应用

炎症性肠病（IBD）是一种病因尚不明确的非特异性肠道炎症性疾病。越来越多的证据表明肠道菌群失调与IBD的发生发展密切相关。粪菌移植是通过各种方式将健康捐赠者的粪便菌群移植入患者消化道内,旨在重建患者肠道菌群从而达到对肠道内外疾病治疗的目的。肠道微生物稳态及失调在疾病发生发展中发挥作用,其中包括炎症性肠病（IBD）。越来越多的研究报道了FMT在IBD中的治疗作用,现主要阐述粪菌移植在儿童IBD中的应用。     

Lymphocyte DNA damage and oxidative stress in patients with iron deficiency anemia

Oxidant stress has been shown to play an important role in the pathogenesis of iron deficiency anemia. The aim of this study was to investigate the association between lymphocyte DNA damage, total antioxidant capacity and the degree of anemia in patients with iron deficiency anemia. Twenty-two female with iron deficiency anemia and 22 healthy females were enrolled in the study. Peripheral DNA damage was assessed using alkaline comet assay and plasma total antioxidant capacity was determined using an automated measurement method. Lymphocyte DNA damage of patients with iron deficiency anemia was significantly higher than controls (p<0.05), while total antioxidant capacity was significantly lower (p<0.001). While there was a positive correlation between total antioxidant capacity and hemoglobin levels (r=0.706, p<0.001), both total antioxidant capacity and hemoglobin levels were negatively correlated with DNA damage (r=-0.330, p<0.05 and r=-0.323, p<0.05, respectively). In conclusion, both oxidative stress and DNA damage are increased in IDA patients. Increased oxidative stress seems as an important factor that inducing DNA damage in those IDA patients. The relationships of oxidative stress and DNA damage with the severity of anemia suggest that both oxidative stress and DNA damage may, in part, have a role in the pathogenesis of IDA.     

肠内营养支持治疗对炎症性肠病患者肠黏膜屏障功能及炎症反应的影响

目的 探讨早期肠内营养（EN）支持治疗对炎症性肠病（IBD）患者肠黏膜屏障功能及炎症反应的影响。方法 将80例IBD患者按营养支持治疗途径分为EN组（48例）和肠外营养（PN）组（32例）,在常规治疗的基础上分别给予早期EN、PN支持治疗。比较治疗前后2组患者营养学相关指标[白蛋白（ALB）、前白蛋白（PA）、转铁蛋白（TF）]、肠黏膜屏障功能指标（内毒素、D-乳酸）及炎症相关指标[C-反应蛋白（CRP）、降钙素原（PCT）、粪便钙卫蛋白（FCP）]水平。结果 治疗前,2组患者各观察指标水平差异无统计学意义（P>0.05）;治疗后,与治疗前相比,2组患者血清ALB、PA及TF水平均显著升高（P0.05）。结论 在常规治疗的基础上,早期EN支持治疗对IBD患者肠黏膜屏障功能的改善及炎症缓解作用优于PN支持治疗。     

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts

Background

Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100?×?10⁹/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100?×?10⁹/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100?×?10⁹/L are reported.

Methods

Ruxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability.

Results

By week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75?×?10⁹/L. Seven patients experienced platelet count increases ≥15?×?10⁹/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1 for grade 4 thrombocytopenia.

Conclusions

Results suggest that a low starting dose of ruxolitinib with escalation to 10 mg BID may be appropriate in myelofibrosis patients with low platelet counts.

Trial registration

ClinicalTrials.gov:NCT01348490.

     

Standardized flow cytometric method for the accurate determination of platelet counts in patients with severe thrombocytopenia

BACKGROUND: The therapeutic option of prophylactic platelet (PLT) transfusion in cases of severe thrombocytopenia critically depends on the availability of accurate and precise counts because clinical decisions are widely based on decision or trigger points. Although often applied in current practice at a level of 20 Gpt/L, there is increasing evidence that the trigger points could safely be reduced to 10 or even 5 Gpt/L. In order to facilitate this downward revision, it is necessary to have PLT counting methods that are able to provide reliable results in the appropriate decision range. METHODS: Postchemotherapy-induced pancytopenia PLT counting was performed in patients with hematological malignant disorders. This study describes a novel flow cytometric method that utilizes a PLT-specific monoclonal antibody (CD41a) in conjunction with fluorescent reference beads in order to derive absolute platelet numbers. RESULTS: Applying a mathematical model, this flow cytometric method was shown to have a detection limit of 0.24 Gpt/L and a lower limit of quantification (coefficient of variation [CV] = 10%) of 1.1 Gpt/L. These values are a substantial improvement on previously reported results for the Technicon H1 automated instrument or manual hemocytometry. Moreover, although the flow cytometry and Technicon H3 methods were found by supplementary analyses to show a reasonably good correlation, the hematology instrument showed a distinct tendency to overestimate PLT counts at low levels. CONCLUSION: It is proposed that this standardized immunoplatelet method offers the best approach in evaluating, at the clinical level, the possibility of lower PLT transfusion triggers. It can be used to evaluate the performance limitations of automated hematology analyzers that are widely used at the present time.