Summary Background Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this ...treatment combination provided greater survival benefit than did chlorambucil or fludarabine. Methods 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. Findings There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p<0·0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0·006 and 0·04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0·00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (VH ) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
The consensus views of an expert roundtable meeting are presented as updated management guidelines for using alemtuzumab in chronic lymphocytic leukemia. Since the publication of previous management ...guidelines in 2004, clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy and subcutaneous administration of alemtuzumab. The updated recommendations include (1) alemtuzumab monotherapy can be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow; (3) alemtuzumab treatment should be continued for 12 weeks (36 doses) whenever possible, and bone marrow examination may be considered at week 12 to evaluate response; (4) monitoring CMV reactivation by weekly PCR is mandated during therapy; when CMV reactivation becomes symptomatic or viremia increases, alemtuzumab therapy should be interrupted and anti-CMV therapy started; (5) subcutaneous administration is safe, easy to perform and appears equally effective compared with intravenous infusion and (6) our strong recommendation is that alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies.
Abstract
The genomes of non-bilaterian metazoans are key to understanding the molecular basis of early animal evolution. However, a full comprehension of how animal-specific traits, such as nervous ...systems, arose is hindered by the scarcity and fragmented nature of genomes from key taxa, such as Porifera.
Ephydatia muelleri
is a freshwater sponge found across the northern hemisphere. Here, we present its 326 Mb genome, assembled to high contiguity (N50: 9.88 Mb) with 23 chromosomes on 24 scaffolds. Our analyses reveal a metazoan-typical genome architecture, with highly shared synteny across Metazoa, and suggest that adaptation to the extreme temperatures and conditions found in freshwater often involves gene duplication. The pancontinental distribution and ready laboratory culture of
E. muelleri
make this a highly practical model system which, with RNAseq, DNA methylation and bacterial amplicon data spanning its development and range, allows exploration of genomic changes both within sponges and in early animal evolution.
It has been recognized that numerous synthetic compounds like Bisphenol A (BPA) and nonylphenols (NP) are present in effluents from wastewater treatment plants (WWTP) at levels of parts per billion ...(μgL−1) or even parts per trillion (ngL−1) with a high potential to cause endocrine disruption in the aquatic environment. Constructed wetlands (CW) are a cost-effective wastewater treatment alternative with promising performance to treat these afore mentioned compounds. This research was aimed to evaluate the efficacy of CW treatment of WWTP effluent for mitigating the effects endocrine disrupting compounds (EDCs). This research goal was accomplished by (1) quantifying the removal of BPA and NP in CWs; (2) isolating CW fungal strains and testing for laccase production; and (3) performing endocrine disruption (reproduction) bioassays using the fruit fly Drosophila melanogaster. Three pilot scale horizontal subsurface flow constructed wetlands (HSSF-CW) were operated for eight weeks: one planted with Phragmites australis; one planted with Heliconia psitacorum; and one unplanted. The Heliconia CW showed a removal efficiency of 73.3(±19%) and 62.8(±20.1%) for BPA and NP, respectively; while the Phragmites CW demonstrated a similar removal for BPA (70.2±27%) and lower removal efficiency for NP 52.1(±37.1%).The unplanted CW achieved 62.2 (±33%) removal for BPA and 25.3(±37%) removal for NP. Four of the eleven fungal strains isolated from the Heliconia-CW showed the capacity to produce laccase. Even though complete removal of EDCs was not achieved by the CWs, the bioassay confirmed a significant improvement (p<0.05) in fly viability for all CWs, with Heliconia sp. being the most effective at mitigating adverse effects on first and second generational reproduction. This study showed that a CW planted with a native Heliconia sp. CW demonstrated a higher removal of endocrine disrupting compounds and better mitigation of reproductive disruption in the bioassay.
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•Constructed wetlands were evaluated for BPA and NP removal and environmental risk•Heliconia sp. CW showed a higher capacity for removing BPA and NP•Fungal strains isolated from the Heliconia-CW showed the capacity to produce laccase•Negative impacts in aquatic wild life may be reduced treating wastewater with CW
We demonstrate the first successful growth of large-area (200 × 200 μm2) bilayer, Bernal stacked, epitaxial graphene (EG) on atomically flat, 4H-SiC (0001) step-free mesas (SFMs) . The use of SFMs ...for the growth of graphene resulted in the complete elimination of surface step-bunching typically found after EG growth on conventional nominally on-axis SiC (0001) substrates. As a result heights of EG surface features are reduced by at least a factor of 50 from the heights found on conventional substrates. Evaluation of the EG across the SFM using the Raman 2D mode indicates Bernal stacking with low and uniform compressive lattice strain of only 0.05%. The uniformity of this strain is significantly improved, which is about 13-fold decrease of strain found for EG grown on conventional nominally on-axis substrates. The magnitude of the strain approaches values for stress-free exfoliated graphene flakes. Hall transport measurements on large area bilayer samples taken as a function of temperature from 4.3 to 300 K revealed an n-type carrier mobility that increased from 1170 to 1730 cm2 V–1 s–1, and a corresponding sheet carrier density that decreased from 5.0 × 1012 cm–2 to 3.26 × 1012 cm–2. The transport is believed to occur predominantly through the top EG layer with the bottom layer screening the top layer from the substrate. These results demonstrate that EG synthesized on large area, perfectly flat on-axis mesa surfaces can be used to produce Bernal-stacked bilayer EG having excellent uniformity and reduced strain and provides the perfect opportunity for significant advancement of epitaxial graphene electronics technology.
As a two-dimensional semimetal, graphene offers clear advantages for plasmonic applications over conventional metals, such as stronger optical field confinement, in situ tunability, and relatively ...low intrinsic losses. However, the operational frequencies at which plasmons can be excited in graphene are limited by the Fermi energy E F, which in practice can be controlled electrostatically only up to a few tenths of an electronvolt. Higher Fermi energies open the door to novel plasmonic devices with unprecedented capabilities, particularly at mid-infrared and shorter-wave infrared frequencies. In addition, this grants us a better understanding of the interaction physics of intrinsic graphene phonons with graphene plasmons. Here, we present FeCl3-intercalated graphene as a new plasmonic material with high stability under environmental conditions and carrier concentrations corresponding to E F > 1 eV. Near-field imaging of this highly doped form of graphene allows us to characterize plasmons, including their corresponding lifetimes, over a broad frequency range. For bilayer graphene, in contrast to the monolayer system, a phonon-induced dipole moment results in increased plasmon damping around the intrinsic phonon frequency. Strong coupling between intrinsic graphene phonons and plasmons is found, supported by ab initio calculations of the coupling strength, which are in good agreement with the experimental data.
T cells from patients with chronic lymphocytic leukemia may play an important role in contributing to the onset, sustenance, and exacerbation of the disease by providing survival and proliferative ...signals to the leukemic clone within lymph nodes and bone marrow.
By performing chemotaxis assays towards CXCL12, CCL21 and CCL19, we sought to evaluate the migratory potential of T cells from chronic lymphocytic leukemia patients. We next analyzed the chemokine-induced migration of T cells, dividing the chronic lymphocytic leukemia samples according to their expression of the poor prognostic factors CD38 and ZAP-70 in leukemic cells determined by flow cytometry.
We found that T cells from patients with chronic lymphocytic leukemia are less responsive to CXCL12, CCL21 and CCL19 than T cells from healthy adults despite similar CXCR4 and CCR7 expression. Following separation of the patients into two groups according to ZAP-70 expression, we found that T cells from ZAP-70-negative samples showed significantly less migration towards CXCL12 compared to T cells from ZAP-70-positive samples and that this was not due to defective CXCR4 down-regulation, F-actin polymerization or to a lesser expression of ZAP-70, CD3, CD45, CD38 or CXCR7 on these cells. Interestingly, we found that leukemic cells from ZAP-70-negative samples seem to be responsible for the defective CXCR4 migratory response observed in their T cells.
Impaired migration towards CXCL12 may reduce the access of T cells from ZAP-70-negative patients to lymphoid organs, creating a less favorable microenvironment for leukemic cell survival and proliferation.
Summary
Chronic lymphocytic leukaemia (CLL) is characterized by the accumulation of long‐lived B lymphocytes blocked in G0/1 by impaired apoptosis. As insulin‐like growth factor‐I (IGF‐I) is known ...for its antiapoptotic effects in different cell types, we investigated whether IGF‐I and its receptor (IGF‐IR) participate in autocrine/paracrine loops affecting the survival of CLL cells. IGF‐IR protein and mRNA was present in CLL cells in 44% and 59% of patients respectively. IGF‐IR expression in CLL patients was positively correlated with the expression of the antiapoptotic protein Bcl‐2 and was involved in CLL cell survival in vitro. Serum IGF‐I was elevated in CLL patients, but growth hormone (GH) was normal. CLL cells expressed IGF‐I mRNA and secreted the growth factor in vitro. Therefore, local production of IGF‐I can account for the increased levels of serum IGF‐I, independently of GH, and may be related to autocrine/paracrine control of lymphocyte survival acting at IGF‐IR. This is the first demonstration of IGF‐IR expression in a subgroup of CLL patients and of its antiapoptotic effects in vitro, highlighting the importance of this growth factor receptor as a possible therapeutic target in CLL.
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