Ecological risk assessment of pesticides in sediments of Pampean streams, Argentina.

After their application in agricultural areas, pesticides are dispersed throughout the environment, causing contamination problems. In Argentina, the main promoter of transgenic biotechnology in the region, the total consumption of agrochemicals has increased significantly in recent years. Most chemicals dumped near surface waters eventually end up in bottom sediments and can be toxic to the organisms that live there. However, published data on the mixing of pesticides in this compartment is still scarce. The objective of this work was to detect and quantify pesticide residues in the sediment of rural streams in the Pampas region and to carry out acute and chronic risk assessment in these aquatic ecosystems. The study area comprises the mountainous system of Tandilia, located in one of the most productive agricultural areas in the country. The concentration of atrazine, acetochlor, chlorpyrifos, cypermethrin, and 2,4-D in the sediment of four rural streams was determined in three different seasons, and the toxic units (TU) and the risk ratios (RQ) were calculated. All the compounds analyzed were detected in most of the sampling seasons and study sites, at concentrations higher than those established in the national and international quality guidelines for the protection of aquatic biota in surface waters and for human consumption. Chlorpyrifos, cypermethrin, and acetochlor were the main pesticides contributing to the TU and RQ values, representing a medium or high ecological risk in most of the sites. Therefore, the evaluation of these pesticides in the bottom sediments could be a decisive factor in assessing the risk to the aquatic environment.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides and Sézary syndrome. An updated experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD). METHODS AND PATIENTS: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported. RESULTS: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS. CONCLUSIONS: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

Ecotoxicology and environmental safety toxicity of pyrethroid cypermethrin on the freshwater snail Chilina parchappii: Lethal and sublethal effects.

The aim of the present work was to study the effect of the pyrethroid cypermethrin (CYP) on the non-target freshwater snail Chilina parchappi. Initially, the sensitivity of adult snails to CYP was evaluated via the 96-h LC50 test. Then, snails were exposed to subtethal CYP concentrations (0.1 and 10 mg/l) for 1, 4 and 10 days and the digestive glands were dissected for biomarkers analyses. Enzymatic activity of catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), as well as total glutathione reduced (GSH) levels, were determined. Histological analyses of morphology, intracellular accumulation of lipofucsins and neutral lipids accumulation in the digestive gland were also evaluated. As compared to other molluscs, C. parchappi showed high resistance to CYP exposure evidenced by the 96-h LC50 value (44.59 mg/l). Snails exposed to sublethal CYP concentrations showed a statistically significant increase (p < 0.01) in GST (79-116%) and GPx (45-190%) activities with respect to controls. However, CAT activity showed a tendency to decrease with CYP treatment but was not statistically significantly different compared to control. Only high CYP concentration caused a statistically significant increase (p < 0.01) in GSH content (95-196%). There was evidence of structural changes in the digestive gland of snails exposed to CYP, showing a dose-dependent response. In exposed snails, some of the main symptoms included a reduction in the thickness of the epithelium, vacuolisation of the digestive cells and an increase in the number of excretory cells. Accumulation of lipofuscins (933-1006%) and neutral lipids (403%) were statistically significantly higher (p < 0.05) in snails exposed to CYP compared to control. This study showed that C. parchappii is quite tolerant to CYP exposure and that at sublethal concentrations, GSH metabolism could play a protective role against the pesticide harm in snails. Therefore, it would be interesting to study the response of this organism to other environmental stressors to assess its potential use in monitoring programs.

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.

BACKGROUND: Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. PATIENTS AND METHODS: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. RESULTS: A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. CONCLUSIONS: Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.

Autologous hematopoietic stem cell transplantation has better outcomes than conventional therapies in patients with rapidly progressive systemic sclerosis.

We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically- and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P<0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (P=0.0005). The probability that the ESSG score and mRss would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. This study confirms that the AHSCT is effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.

lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease.

Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations.

INTRODUCTION: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). AREAS COVERED: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. EXPERT OPINION: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option.

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

Taxonomic and nontaxonomic responses to ecological changes in an urban lowland stream through the use of Chironomidae (Diptera) larvae.

Biotic descriptors--both taxonomic (diversity indices, species richness, and indicator species) and nontaxonomic (biomass, oxygen consumption/production, and anatomical deformities)--are useful tools for measuring a stream's ecological condition. Nontaxonomic parameters detect critical effects not reflected taxonomically. We analyzed changes in Chironomidae populations as taxonomic parameters and mentum deformities as a nontaxonomic parameter for evaluating a South-American-plains stream (Argentina). We performed samplings seasonally (March, June, September, and December; 2005) and physical and chemical measurements at three sampling sites of the stream (DC1 at river source, through DC3 downstream). The specimens collected in sediment and vegetation were analyzed to investigate mouth deformities in Chironomidae larvae. We identified a total of 9 taxa from Chironomidae and Orthocladiinae subfamilies. Shannon's diversity index for Chironomidae decreased from 1.6 bits ind⁻¹ (DC1) to 0.3 bits ind⁻¹ (DC3). The total density of the Chironomidae exhibited a great increase in abundance at site DC3, especially that of Chironomus calligraphus. Chironomidae taxonomic composition also changed among the three sites despite their spatial proximity: C. calligraphus, Goeldichironomus holoprasinus, Parachironomus longistilus, and Polypedilum were present at all three; Corynoneura and Paratanytarsu at DC1 only; Cricotopus at DC1 and DC3; Apedilum elachistus notably at DC2 and DC3; and Parametriocnemus only at DC2. C. calligraphus individuals from DC1 showed no mentum deformities; only 2 from DC2 exhibited mouth-structure alterations; while specimens from DC3 presented the most abnormalities, especially during autumn and late winter. Type-II deformities (supernumerary teeth and gaps) were the most common. Anatomical deformities are sublethal effects representing an early alert to chemically caused environmental degradation. Mentum deformities in benthic-Chironomidae larvae constitute an effective biological-surveillance tool for detecting adverse conditions in sediments and evaluating sediment-quality-criteria compliance. Taxonomic (community composition) and nontaxonomic (condition of larval mouth parts) descriptors, used together, can indicate a stream's ecological state.

Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study.

Alemtuzumab is active in chronic lymphocytic leukaemia (CLL) patients refractory to alkylators and fludarabine. The aim of this study was to determine the efficacy and safety of subcutaneous alemtuzumab at low dose (10 mg three times per week, for 18 weeks) to 49 patients with pre-treated CLL. The overall response rate was 53%, including 27% of complete responses; it was 42% in patients over 70 years, and 54% in the fludarabine-resistant patients. Forty-five percent of the patients with an unfavourable karyotype responded, including 60% of those with the 17p- aberration. After a median follow-up of 25 months, the median overall time to disease progression was 8 months (responders 12 months, non-responders 4 months). The median overall time to alternative treatment was 9 months (responders 17 months, non-responders 6 months) and median overall survival was 30 months. The treatment was well tolerated: grade IV neutropenia was observed in 17%, and cytomegalovirus (CMV) reactivation in 24% of the patients, with no CMV disease. We observed a total of 30 infections (50% during treatment and 50% during the 12-month follow-up), only one-third of which was severe. This study confirms that low-dose subcutaneous alemtuzumab is effective in poor prognosis CLL, and has a particularly favourable toxicity profile.

Effects of discharges from the textile industry on the biotic integrity of benthic assemblages.

We explored the effects of a textile industry effluent on water quality, habitat quality and structural and functional responses of benthic communities in a lowland stream. Two sampling sites were selected: site 1 was located 300 m upstream of the outflow from the textile factory and site 2 was 500 m downstream from the discharge point. Samples of water, microbenthos, invertebrates and aquatic plants were taken seasonally. The effluent from the textile industry modified the structure of the microbenthic assemblages downstream, increased the density of organisms and the biomass of primary producers, but diminished the species richness. The oxygen consumption of the microbenthic community was 3 x higher downstream of the effluent and abnormal frustules of diatoms were noticed. The richness and abundance of invertebrate taxa were lower at the impacted site. The invertebrate modes of existence and the functional feeding groups were also significantly affected. This study is an important baseline for assessment of lowland streams with high water residence time and a notable development of hydrophytes. It will also provide a baseline for the monitoring and restoration, or remediation, programs using the metrics of biotic integrity, particularly in South American countries where such metrics are rarely employed.

[Endothelial progenitor cells in systemic sclerosis: their possible role in angiogenesis]. / Progenitori delle cellule endoteliali di origine midollare in corso di sclerosi sistemica: possibile ruolo nell'angiogenesi.

BACKGROUND: Recently, several studies have demonstrated the presence of circulating endothelial progenitors (CEPs) responsible for angiogenesis. Notably, these cells are able to migrate to ischemic tissues and differentiate in situ in mature endothelial cells. Aim of this study was to assess the presence of CEPs in the peripheral blood of patients with Sistemic Sclerosis (SSc) and evaluate their significance as an attempt of re-vascularization MATERIAL AND METHODS: Samples of peripheral blood from 40 healthy subjects and 56 patients with SSc were studied. Five-parameter, 3-color flow cytometry was performed with a FACScan. CEPs were defined as CD45 negative, CD34 and CD133 positive. In addition, plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected by commercial ELISA (R&D Systems). RESULTS: Levels of CEPs (CD133+/CD34+/CD45-) were significantly higher in patients with SSc in comparison to HC (P = 0.01). No correlation was found between CEPs and any clinical parameter of disease neither activity score. CEPs were significantly higher in the group of patients with early disease, while their number decreased in the late phases of disease. Plasma levels of VEGF, but not bFGF, were significantly higher in SSc in comparison to HC (P<0.001) but no correlation was found between VEGF concentrations and CEP number. CONCLUSIONS: The presence of CEPs in patients with SSc suggest that sclerodermic hypoxic tissues could induce the mobilization of bone-marrow derived cells in an attempt to provided new vessels, in the early phase of the disease, at least.

Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes.

Increased angiogenesis has been demonstrated to be a significant prognostic factor in many solid tumors. In the oncohematological setting, it has been associated with myelodysplastic syndromes (MDS), chronic myeloid leukemia, acute lymphoid, and myeloid leukemias. Recently, increased circulating endothelial cells (CECs) have been associated with breast cancer and non-Hodgkin lymphoma (NHL). Based on these premises we analysed total and activated CECs, and endothelial precursors (CEPs) in 50 MDS patients and 20 healthy donors. CECs and CEPs were quantified by flow cytometry. CEC levels were compared with bone marrow (BM) microvessel density (MVD). In addition, some angiogenic factors, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble VEGF-Receptor2 (VEGFR2), were tested in the sera from 25 MDS patients. Total, activated CECs and CEPs were significantly increased in MDS when compared to control group (p<0.0001); whereas in the MDS cases no association was found with French--American--British (FAB), International Prognostic Scoring System (IPSS) subtypes or survival. Patients with higher CECs also showed higher MVD. Among the cytokines analysed, sVEGFR2 was significantly higher in the lower IPSS risk classes, while the levels of bFGF directly correlated with total and activated CECs. Taken together these data strengthen the hypothesis of a possible role of angiogenesis in MDS pathogenesis.