Novel light treatment for digital ulcers in systemic sclerosis: a feasibility study

Background

Locally acting, well-tolerated treatments for digital ulcers in patients with systemic sclerosis are needed. We aimed to investigate the safety, feasibility, and tolerability of a novel light treatment, and to tentatively assess treatment efficacy.

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.     

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

BackgroundObesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown.ObjectivesThe aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes.MethodsA screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints.ResultsBecause ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects.ConclusionsThese results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183)     

PR 879-317A enhances in vitro immune activity of peripheral blood mononuclear cells from patients with Down syndrome

Down syndrome is associated with immune deficiencies which result in increased incidences of respiratory infections and lymphocytic leukemia. Peripheral blood mononuclear cells (PBMC) from patients with Down Syndrome were assayed in several in vitro assays following incubation in medium or various concentrations of PR 879-317A (2,3,5,6,7,8-hexahydro-2-phenyl-8,8-dimethoxyimidazo (1,2a) pyridine), a selective immunorestorative agent. PBMC of the patients, incubated in medium, exhibited significantly reduced activities in the natural killer (NK) cell, antibody-dependent cell-mediated cytotoxicity (ADCC), T-cell blastogenesis and leukocyte-inhibition factor (LIF) assays. Incubation in PR 879-317A significantly increased the NK and ADCC activities of PBMC from both patients and healthy subjects. However, the effect was much more pronounced on the patients' cells increasing their NK and ADCC activities to normal levels. Incubation in PR 879-317A augmented to normal levels the responses of patients' cells in various assessments of T-cell immunity including blastogenic responses to phytohemagglutinin and concanavalin A and production of LIF. In addition, the number of patients' cells forming spontaneous rosettes with sheep red blood cells was increased following incubation in PR 879-317A. In contrast this compound did not significantly modify the T-cell responses of cells from the healthy subjects suggesting that this compound does not affect normal T-cell function.     

Matrix metalloproteinases in tumour invasion and metastasis.

The matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes, which are involved in the degradation of many different components of the extracellular matrix. The MMPs have been classified into different groups including collagenases, gelatinases, stromelysins, and others, particularly membrane-type MMPs, based mainly on the in vitro substrate specificity of individual MMPs. There is increasing evidence to indicate that individual MMPs have important roles in tumour invasion and metastasis. However, the current concept of the role of MMPs in tumour invasion is that they not only have a direct role in tumour invasion by facilitating extracellular matrix degradation, but as a consequence they also have an important role in maintaining the tumour micro-environment and thus promoting tumour growth. Inhibiting the action of MMPs represents a new therapeutic approach for the treatment of individual types of cancer and several broad-spectrum, low-molecular-weight MMP inhibitors are currently being assessed for clinical use. This review examines the role of MMPs in tumour invasion and metastasis, with an emphasis on studies of clinical relevance.     

Evaluation of a PCR/DNA Probe Colorimetric Membrane Assay for Identification of Campylobacter spp. in Human Stool Specimens

DNA was extracted from 50 human stool specimens using the QIAamp DNA stool minikit. PCR amplification was followed by post-PCR hybridization to DNA probes specific for the Campylobacter genus, Campylobacter jejuni, and Campylobacter coli in a colorimetric membrane assay. Thirty-two of 38 culture-positive specimens were PCR/DNA probe positive for C. jejuni. The assay is rapid and simple and can be applied to stool specimens for the detection of Campylobacter.     

Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation

Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110δ catalytic subunit activity of class I phosphatidylinositol 3‐kinase (PI3Kp110δ) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110δ‐deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I⁺ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110δ‐deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL‐4. Importantly, adoptive transfer of IL‐4‐treated macrophages derived from WT mice, but not those from PI3Kp110δ‐deficient mice, protects mice during DSS‐induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS‐induced colitis in PI3Kp110δ‐deficient mice.     

Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho‐reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC ?10.1 s.d., height ?5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.