Alteration of macroinvertebrate community in tropical aquatic systems in relation to sediment redox potential and overlaying water quality

Limnological studies in two tropical Indian aquatic habitats showed that macroinvertebrate communities have greater diversity than other biotic communities present there. Sediment redox potential is found to be an important factor for alteration of macroinvertebrate communities in aquatic bodies. Anthropogenic activities have influenced the changing of sediment redox potential values of the studied sites and there by affected the macroinvertebrate communities

Identification and HLA-Tetramer-Validation of Human CD4(+) and CD8(+) T Cell Responses against HCMV Proteins IE1 and IE2

Human cytomegalovirus (HCMV) is an important human pathogen. It is a leading cause of congenital infection and a leading infectious threat to recipients of solid organ transplants as well as of allogeneic hematopoietic cell transplants. Moreover, it has recently been suggested that HCMV may promote tumor development. Both CD4+ and CD8+ T cell responses are important for long-term control of the virus, and adoptive transfer of HCMV-specific T cells has led to protection from reactivation and HCMV disease. Identification of HCMV-specific T cell epitopes has primarily focused on CD8+ T cell responses against the pp65 phosphoprotein. In this study, we have focused on CD4+ and CD8+ T cell responses against the immediate early 1 and 2 proteins (IE1 and IE2). Using overlapping peptides spanning the entire IE1 and IE2 sequences, peripheral blood mononuclear cells from 16 healthy, HLA-typed, donors were screened by ex vivo IFN-γ ELISpot and in vitro intracellular cytokine secretion assays. The specificities of CD4+ and CD8+ T cell responses were identified and validated by HLA class II and I tetramers, respectively. Eighty-one CD4+ and 44 CD8+ T cell responses were identified representing at least seven different CD4 epitopes and 14 CD8 epitopes restricted by seven and 11 different HLA class II and I molecules, respectively, in total covering 91 and 98% of the Caucasian population, respectively. Presented in the context of several different HLA class II molecules, two epitope areas in IE1 and IE2 were recognized in about half of the analyzed donors. These data may be used to design a versatile anti-HCMV vaccine and/or immunotherapy strategy

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

Three‐dimensional forward stratigraphic modelling of the sedimentary architecture of meandering‐river successions in evolving half‐graben rift basins

The spatial organisation of meandering‐river deposits varies greatly within the sedimentary fills of rift basins, depending on how differential rates of fault propagation and subsidence interplay with autogenic processes to drive changes in fluvial channel‐belt position and rate of migration, avulsion frequency and mechanisms of meander‐bend cut off. This set of processes fundamentally influences stacking patterns of the accumulated successions. Quantitative predictions of the spatio‐temporal evolution and internal architecture of meandering fluvial deposits in such tectonically active settings remain limited. A numerical forward stratigraphic model—the Point‐Bar Sedimentary Architecture Numerical Deduction (PB‐SAND)—is applied to examine relationships between differential rates of subsidence and resultant fluvial channel‐belt migration, reach avulsion and channel‐deposit stacking in active, fault‐bounded half‐grabens. The model is used to reconstruct and predict the complex morphodynamics of fluvial meanders, their generated channel belts, and the associated lithofacies distributions that accumulate as heterogeneous fluvial successions in rift settings, constrained by data from seismic images and outcrop successions. The 3D modelling outputs are used to explore sedimentary heterogeneity at various spatio‐temporal scales. Results show how the connectivity of sand‐prone geobodies can be quantified as a function of subsidence rate, which itself decreases both along and away from the basin‐bounding fault. In particular, results highlight the spatial variability in the size and connectedness of sand‐prone geobodies that is seen in directions perpendicular and parallel to the basin axis, and that arises as a function of the interaction between spatial and temporal variations in rates of accommodation generation and fault‐influenced changes in river morphodynamics. The results have applied significance, for example, to both hydrocarbon exploration and assessment of groundwater aquifers. The expected greatest connectivity of fluvial sandbody in a half‐graben is primarily determined by the complex interplay between the frequency and rate of subsidence, the style of basin propagation, the rates of migration of channel belts, the frequency of avulsion and the proportion and spatial distribution of variably sand‐prone channel and bar deposits

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio

Joint modeling of progression-free survival and patient-reported outcomes to evaluate the association between disease progression and symptoms among patients with relapsed/refractory multiple myeloma

Background: Here we aim to evaluate the relationship between progression-free survival (PFS) and patient-reported symptoms (measured by health-related quality of life scores) among patients with relapsed/refractory multiple myeloma (RRMM). Methodology: Pain and fatigue were identified as the most common patient-relevant symptoms within RRMM based on a predefined literature review of patient preference/qualitative studies (confirmed by clinical experts). Consequently, the European Organisation for Research and Treatment of Cancer QLQ-C30 pain, QLQ-MY20 disease symptoms (pain in different locations), and QLQ-C30 fatigue domains were selected. Change from baseline scores per symptom domain was jointly modeled with PFS assuming a current slope association structure. For each symptom, we evaluated trial-specific joint models based on individual patient data from 7 RRMM clinical trials. The association between symptoms and PFS was summarized via association-effect hazard ratios (HRs) from the joint models, where a HR > 1 indicates that symptom worsening was associated with an increased hazard of a progression/death event. Meta-analyses were performed to synthesize the joint model HRs from all trials into one summary statistic (meta-HR) per symptom domain. Results: Across trials, worsening in pain and fatigue was associated with an increased hazard of progression events (disease progression/death) based on joint-model-association-effect HRs. Specifically, meta-HRs (95% CI) were 1.10 (1.02, 1.19) for QLQ-C30 pain, 1.10 (1.01, 1.20) for QLQ-MY20 disease symptoms, and 1.11 (1.05, 1.17) for QLQ-C30 fatigue. Conclusions: This study demonstrated that worsening in pain and fatigue was consistently associated with an increased hazard of disease progression or death events across numerous RRMM clinical trials with varying disease severity. This suggests risk of PFS events may align with patient experience in terms of worsening symptom burden

Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM

COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds

Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus - and R. arrhizus -induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization. (Blood. 2009;114:1729-1735