Association between CD14 gene polymorphisms and disease phenotype in sarcoidosis

SummaryAlthough the etiology of sarcoidosis is unknown, genetic susceptibility has been demonstrated. Granuloma formation is a key feature in the pathophysiology of sarcoidosis and Crohn’s Disease, raising the possibility that these diseases share common pathogenetic pathways. An association between sarcoidosis and the protein “CD14”, a molecule that is part of the lipopolysaccharide (LPS) cell surface receptor complex, has been suggested.In the current study we evaluated the CD14 gene promoter 159 C→T polymorphic site and soluble CD14 levels in a cohort of 74 sarcoidosis patients compared to 85 healthy controls. We further sought to identify correlations between clinical phenotype, specific genotypes and soluble CD14 levels.We found the TT genotype to be more prevalent in the sarcoidosis patient group than in controls (p=0.03). Serum levels of soluble CD14 were higher in the sarcoidosis patients (p=0.001). Within the patient cohort, CC homozygous patients presented at an older age with milder disease as assessed with the SAC score, longer time to diagnosis, and less impairment of pulmonary function tests.Our study suggests a role of CD14 in the pathogenesis of sarcoidosis, and a clinical phenotype-genotype association. Further mechanistic and epidemiologic studies are needed in order to establish the specific role of CD14 in the etiology, pathogenesis and clinical phenotype of sarcoidosis

Digitizing mass spectrometry data to explore the chemical diversity and distribution of marine cyanobacteria and algae.

Natural product screening programs have uncovered molecules from diverse natural sources with various biological activities and unique structures. However, much is yet underexplored and additional information is hidden in these exceptional collections. We applied untargeted mass spectrometry approaches to capture the chemical space and dispersal patterns of metabolites from an in-house library of marine cyanobacterial and algal collections. Remarkably, 86% of the metabolomics signals detected were not found in other available datasets of similar nature, supporting the hypothesis that marine cyanobacteria and algae possess distinctive metabolomes. The data were plotted onto a world map representing eight major sampling sites, and revealed potential geographic locations with high chemical diversity. We demonstrate the use of these inventories as a tool to explore the diversity and distribution of natural products. Finally, we utilized this tool to guide the isolation of a new cyclic lipopeptide, yuvalamide A, from a marine cyanobacterium

Non-invasive monitoring of arthritis treatment response via targeting of tyrosine-phosphorylated annexin A2 in chondrocytes

BACKGROUND: The development and optimization of therapies for rheumatoid arthritis (RA) is currently hindered by a lack of methods for early non-invasive monitoring of treatment response. Annexin A2, an inflammation-associated protein whose presence and phosphorylation levels are upregulated in RA, represents a potential molecular target for tracking RA treatment response. METHODS: LS301, a near-infrared dye-peptide conjugate that selectively targets tyrosine 23-phosphorylated annexin A2 (pANXA2), was evaluated for its utility in monitoring disease progression, remission, and early response to drug treatment in mouse models of RA by fluorescence imaging. The intraarticular distribution and localization of LS301 relative to pANXA2 was determined by histological and immunohistochemical methods. RESULTS: In mouse models of spontaneous and serum transfer-induced inflammatory arthritis, intravenously administered LS301 showed selective accumulation in regions of joint pathology including paws, ankles, and knees with positive correlation between fluorescent signal and disease severity by clinical scoring. Whole-body near-infrared imaging with LS301 allowed tracking of spontaneous disease remission and the therapeutic response after dexamethasone treatment. Histological analysis showed preferential accumulation of LS301 within the chondrocytes and articular cartilage in arthritic mice, and colocalization was observed between LS301 and pANXA2 in the joint tissue. CONCLUSIONS: We demonstrate that fluorescence imaging with LS301 can be used to monitor the progression, remission, and early response to drug treatment in mouse models of RA. Given the ease of detecting LS301 with portable optical imaging devices, the agent may become a useful early treatment response reporter for arthritis diagnosis and drug evaluation

Involvement of CCR6/CCL20/IL-17 Axis in NSCLC Disease Progression

OBJECTIVES: Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth. METHODS: A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation. RESULTS: CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52-15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells. CONCLUSION: Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations

Long-term Accuracy of Breast Cancer Risk Assessment Combining Classic Risk Factors and Breast Density

This study was supported by grant C569/A16891 from Cancer Research UK; research specialist award R50CA211115 from the National Cancer Institute (NCI) (Ms Bowles); grants HHSN261201100031C and P01CA154292 from the NCI-funded Breast Cancer Surveillance Consortium (Dr Buist); and contracts N01-CN-005230, N01-CN-67009, N01-PC-35142, HHSN261201000029C, and HHSN261201300012I from the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, funded by the Surveillance, Epidemiology and End Results Program of the NCI with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington

Time to act: the challenges of working during and after cancer, initiatives in research and practice

Time to act: the challenges of working during and after cancer, initiatives in research and practic

Allogeneic Hematopoietic Stem Cell Transplantation Following the Use of Hypomethylating Agents among Patients with Relapsed or Refractory AML: Findings from an International Retrospective Study

Abstract Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 – 21.7 months), OS reached 29.7 months (95% CI 7.01 – not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT