Origin, accumulation and fate of dissolved organic matter in an extreme hypersaline shallow lake.

Hypersaline endorheic aquatic systems (H-SEAS) are lakes/shallow playas in arid and semiarid regions that undergo extreme oscillations in salinity and severe drought episodes. Although their geochemical uniqueness and microbiome have been deeply studied, very little is known about the availability and quality of dissolved organic matter (DOM) in the water column.. A H-SEAS from the Monegros Desert (Zaragoza, NE Spain) was studied during a hydrological wetting-drying-rewetting cycle. DOM analysis included: (i) a dissolved organic carbon (DOC) mass balance; (ii) spectroscopy (absorbance and fluorescence) and (iii) a molecular characterization with Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The studied system stored a large amount of DOC and under the highest salinity conditions, salt-saturated waters (i.e., brines with salinity > 30%) accumulated a disproportionate quantity of DOC, indicating a significant in-situ net DOM production. Simultaneously, during the hydrological transition from wet to dry, the DOM pool showed strong alterations of it molecular composition. Spectroscopic methods indicated that aromatic and degraded DOM was rapidly replaced by fresher, relatively small, microbial-derived moieties with a large C/N ratio. FT-ICR-MS highlighted the accumulation of small, saturated and oxidized molecules (molecular O/C > 0.5), with a remarkable increase in the relative contribution of highly oxygenated (molecular O/C>0.9) compounds and a decrease of aliphatic and carboxyl-rich alicyclic moleculesThese results indicated that H-SEAS are extremely active in accumulating and processing DOM, with the notable release of organic solutes probably originated from decaying microplankton under large osmotic stress at extremely high salinities.

Dissolved organic matter in a tropical saline-alkaline lake of the East African Rift Valley.

Saline-alkaline lakes of the East African Rift are known to have an extremely high primary production supporting a potent carbon cycle. To date, a full description of carbon pools in these lakes is still missing. More specifically, there is not detailed information on the quality of dissolved organic matter (DOM), the main carbon energy source for heterotrophs prokaryotes. We report the first exhaustive description of DOM molecular properties in the water column of a meromictic saline-alkaline lake of the East African Rift. DOM availability, fate and origin were studied either quantitatively, in terms of dissolved organic carbon (DOC) and nitrogen (DON) or qualitatively, in terms of optical properties (absorbance) and molecular characterization of solid-phase extracted DOM (SPE-DOM) through negative electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). DOM availability was high (DOC ∼ 8.1 mM in surface waters) and meromixis imprinted a severe quantitative and qualitative change on DOM pool. At the surface, DOM was rich in aliphatic and moderately in aromatic molecules and thus mirroring autochthonous microbial production together with photodegradation. At the bottom changes were extreme: DOC increased up to 5 times (up to 50 mM) and, molecular signature drifted to saturated, reduced and non-aromatic DOM suggesting intense microbial activity within organic sediments. At the chemocline, DOC was retained indicating that this interface is a highly reactive layer in terms of DOM processing. These findings underline that saline-alkaline lakes of the East African Rift are carbon processing hot spots and their investigation may broaden our understanding of carbon cycling in inland waters at large.

Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for childhood central nervous system tumors.

Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue has been evaluated in the treatment of children and young adults with brain tumors for whom conventional therapy is either too toxic (for example, radiotherapy in infants) or ineffective (for example, recurrent malignant tumors). With this strategy, myeloablative chemotherapy is administered to patients after initial surgery, and standard-dose chemotherapy. The success of myeloablative chemotherapy depends on the histological type of tumor, extent of disease and of surgical resection, and response to prior chemotherapy. Here, we review results of myeloablative chemotherapy with hematopoietic progenitor cell rescue in brain tumors of different histologies.

Hydrological conditions control in situ DOM retention and release along a Mediterranean river.

Uncertainties exist regarding the magnitude of in situ dissolved organic matter (DOM) processing in lotic systems. In addition, little is known about the effects of extreme hydrological events on in-stream DOM retention or release during downriver transport. This study quantified the net in-stream retention/release efficiencies (η) of dissolved organic carbon (DOC) and its humic and protein-like fluorescent fractions along a Mediterranean river during drought, baseflow and flood conditions. High performance size exclusion chromatography was used to describe the apparent size distributions of the humic and protein-like DOM moieties. A snapshot mass balance allowed estimating the η values of DOC and humic and protein-like fractions. Significant DOM net retention (η < 0) was detected during the drought condition and the protein-like fraction was more retained than the humic-like fraction and bulk DOC. In addition, small substances were more efficiently retained than larger substances. DOC retention decreased under baseflow conditions, but it remained significant. The humic and protein-like net efficiencies exhibited high variability, but the net retention were not significant. From a longitudinal perspective, the entire fluvial corridor contributed net retention of DOC and humic and protein-like moieties net retention during drought condition. In contrast, net retention/release efficiencies exhibited spatial variability during baseflow condition. The flood preferentially mobilized large size DOM molecules and the fluvial corridor behaved as a homogeneous passive DOM (η = 0) conduit. This research highlights the relevance of hydrological extreme events on the magnitude of DOM retention/release mass balance and emphasizes the need to perform measurements during these conditions to quantify the impact of fluvial corridors on DOM fate and transport.

The effects of sediment depth and oxygen concentration on the use of organic matter: An experimental study using an infiltration sediment tank.

Water flowing through hyporheic river sediments or artificial recharge facilities promotes the development of microbial communities with sediment depth. We performed an 83-day mesocosm infiltration experiment, to study how microbial functions (e.g., extracellular enzyme activities and carbon substrate utilization) are affected by sediment depth (up to 50 cm) and different oxygen concentrations. Results indicated that surface sediment layers were mainly colonized by microorganisms capable of using a wide range of substrates (although they preferred to degrade carbon polymeric compounds, as indicated by the higher ß-glucosidase activity). In contrast, at a depth of 50 cm, the microbial community became specialized in using fewer carbon substrates, showing decreased functional richness and diversity. At this depth, microorganisms picked nitrogenous compounds, including amino acids and carboxyl acids. After the 83-day experiment, the sediment at the bottom of the tank became anoxic, inhibiting phosphatase activity. Coexistence of aerobic and anaerobic communities, promoted by greater physicochemical heterogeneity, was also observed in deeper sediments. The presence of specific metabolic fingerprints under oxic and anoxic conditions indicated that the microbial community was adapted to use organic matter under different oxygen conditions. Overall the heterogeneity of oxygen concentrations with depth and in time would influence organic matter metabolism in the sediment tank.

Early injury to cortical and cancellous bone from induction chemotherapy for adolescents and young adults treated for acute lymphoblastic leukemia.

Diminished bone density and skeletal fractures are common morbidities during and following therapy for acute lymphoblastic leukemia (ALL). While cumulative doses of osteotoxic chemotherapy for ALL have been reported to adversely impact bone density, the timing of onset of this effect as well as other changes to bone structure is not well characterized. We therefore conducted a prospective cohort study in pre-adolescent and adolescent patients (10-21years) newly diagnosed with ALL (n=38) to explore leukemia-related changes to bone at diagnosis and the subsequent impact of the first phase of chemotherapy ("Induction"). Using quantitative computerized tomography (QCT), we found that pre-chemotherapy bone properties were similar to age- and sex-matched controls. Subsequently over the one month Induction period, however, cancellous volumetric bone mineral density (vBMD) decreased markedly (-26.8%, p<0.001) with sparing of cortical vBMD (tibia -0.0%, p=0.860, femur -0.7%, p=0.290). The tibia underwent significant cortical thinning (average cortical thickness-1.2%, p<0.001; cortical area-0.4%, p=0.014), while the femur was less affected. Areal BMD (aBMD) concurrently measured by dual-energy X-ray absorptiometry (DXA) underestimated changes from baseline as compared to vBMD. Biochemical evidence revealed prevalent Vitamin D insufficiency and a net resorptive state at start and end of Induction. Our findings demonstrate for the first time that significant alterations to cancellous and cortical bone develop during the first month of treatment, far earlier during ALL therapy than previously considered. Given that osteotoxic chemotherapy is integral to curative regimens for ALL, these results provide reason to re-evaluate traditional approaches toward chemotherapy-associated bone toxicity and highlight the urgent need for investigation into interventions to mitigate this common adverse effect.

Leukemia: stem cells, preleukemia and cure.

Several new or evolving concepts of leukemia biology and treatment are considered including: most leukèmias result from transformation of a stem cell, their phenotype reflecting the site of clonal expansion rather than transformation; most leukemias are preceded by one or more preleukemia phases; and cure may be possible by re-establishing preleukemia or forcing maturation of leukemia cells.

Oncogenes and leukemia.

Cellular or proto-oncogenes are normal cellular genes important in normal cell growth and development. In some instances abnormal expression of these genes is associated with altered cell growth or with malignant transformation. Abnormalities of cellular oncogenes are common in human leukemias. These arise by multiple mechanisms such as mutation, translocation, amplification, and others. Sometimes more than one abnormality is present within a single oncogene. In other instances, a leukemia cell may contain abnormalities of several different oncogenes. Some oncogene abnormalities are relatively specific for certain leukemias and occur in almost all cases; examples include ABL in chronic myelogenous leukemia or MYC in Burkitt leukemia/lymphoma. Other abnormalities are also relatively specific but occur in only some cases such as NRAS in acute myelogenous leukemia or BCL2 in B-cell acute lymphoblastic leukemia. In other leukemias, such as most cases of acute lymphoblastic leukemia and chronic lymphocytic leukemia, oncogene abnormalities are uncommon. The precise role of oncogenes in the pathogenesis of human leukemia is unknown. Retrovirus transduced versions of some of the oncogenes modified in human leukemias cause leukemia in animals. Other oncogenes, modified or unmodified, transform animal and human hematopoietic cells in vitro. Some oncogene products are hematopoietic growth factors or growth factor receptors while others regulate cell proliferation or differentiation by diverse mechanisms. Disruption of the balance between these processes seems the most likely mechanism of oncogene related leukemogenesis. If the role of oncogenes in human leukemias can be defined, innovative diagnostic and therapeutic strategies may be forthcoming.

Controversies in therapy of acute lymphoblastic leukemia.

There are several important controversial in therapy of acute lymphoblastic leukemia including: 1. What is the best initial chemotherapy; 2. Is maintenance chemotherapy effective; 3. How is cure achieved; 4. Are assays of residual leukemia cells useful; 5. Why are some persons currently incurable; 6. What is the best treatment strategy in children; 7. What is the best treatment strategy in adults; and 8. What are new approaches to cure the incurable. Here, we consider these issues. Our conclusion is that more intensive treatment is more effective but that no specific regimen is superior. Further dose escalations are unlikely to increase cures substantially. Maintenance chemotherapy is effective; it may work by controlling the ALL clone so that normal mechanisms regulating B-cell survival operate. Cure of ALL is probably achieved by diverse mechanisms including leukemia eradication in children and leukemia control in adults. Assays of minimal residual leukemia are possible but should not yet be used to direct therapy. There are several reasons why some persons are incurable including treatment resistance and a stem cell origin of leukemia. In most children and adults, chemotherapy is the best strategy followed by allogeneic transplants in those who relapse. Autotransplants are of minimal efficacy. Finally we consider new therapy approaches including immune therapy and regulation of leukemia-related genes.

The role of hematopoietic growth factors in nuclear and radiation accidents.

Molecularly cloned hematopoietic growth factors are likely to be useful in treating persons with bone marrow failure resulting from radiation exposure. Some effects, such as increased granulocytes or platelets, are of clear therapeutic benefit. Other effects, such as a direct action on survival of hematopoietic stem cells and improved granulocyte function, may also increase survival. Many important areas remain to be studied, including which molecularly cloned hematopoietic growth factor(s) to use, optimal dose and timing, and others. Some of these issues can be studied in clinical trials; others require in vitro or animal models. Despite the limited data currently available, it is clear that the availability of molecularly cloned hematopoietic growth factors heralds a new era in treating radiation and nuclear accidents.

Use of hematopoietic growth factors in radiation accidents.

Molecularly cloned hematopoietic growth factors are likely to be useful in treating radiation victims with bone marrow suppression. Some effects, such as increased granulocytes, are clearly beneficial. Other effects, such as altering the probability of survival of hematopoietic stem cells, may also be important. Interesting questions remain to be studied including which molecularly cloned hematopoietic growth factor(s) to use, optimal dose, timing, combinations of growth factors, and other issues. Some can be studied in vitro or in animal models. Others require clinical trials. Molecularly cloned hematopoietic growth factors clearly herald a new era in treating radiation accidents.

Oncogenes in chronic lymphocytic leukemia.

Oncogenes, in the context of retroviruses, are a common cause of leukemia in animals. Recently, activation of cellular oncogenes has been shown to be associated with leukemia in humans. Relatively few studies of oncogene activation in chronic lymphocytic leukemia (CLL) have been reported. In most instances, rearrangement of oncogenes has not been detected. Exceptions include the bcl-1 oncogene in B-cell prolymphocytic leukemia, the tcl-1 oncogene in T-cell CLL, the Hu-ets-1 and Hu-ets-2 oncogenes in small cell lymphocytic lymphoma and c-myc in a Sezary cell leukemia cell/line. Overall, it appears that oncogene abnormalities are less common in CLL than in other leukemias. The reason for it is uncertain and may relate to the relatively few cases evaluated. Alternatively, novel mechanisms of oncogene involvement or gene other than oncogenes may be important in the etiology or pathogenesis of CLL.

Is transplantation in first remission AML more effective than in advanced leukemia?

These data indicate that the increment in the anti-leukemia effect, as expressed as FFR, is comparable for transplants for AML in first remission, advanced leukemia, and in persons never achieving remission. These data are consistent with the notion that the major anti-leukemia effect of HLA-identical bone marrow transplantation in AML results from an immune-mediated graft-versus-leukemia effect rather than from high doses of chemotherapy and radiation. Of course, other factors might explain these results. The superior outcome observed for transplants in first remission versus more advanced disease results not from increased anti-leukemia efficacy of transplants but rather that more persons already cured by chemotherapy receive transplants. Otherwise stated, a substantial portion of the persons cured following transplantation for AML in first remission were cured before receiving a transplant. These data have implications for other aspects of bone marrow transplantation. For example, it is suggested that transplants should be performed earlier in solid tumors when these diseases are more likely to respond to high-dose chemotherapy and radiation. Although this hypothesis may be correct, it need not necessarily be so as evidenced by these data in AML. The data we review show that bone marrow transplants in AML are of comparable anti-leukemia efficacy when performed in first remission, advanced leukemia, and initial resistant disease. Similar conclusions may apply to transplants in CML and ALL. The superior overall outcome observed with transplants in earlier leukemia results from transplanting a greater proportion of subjects already cured by chemotherapy. The increased anti-leukemia efficacy of transplants when compared with chemotherapy is compatible with an anti-leukemia effect other than that of high-dose chemotherapy and radiation. An immune-mediated graft-versus-leukemia effect is a likely explanation. Caution in predicting results of autotransplants in solid tumors is likewise necessary.

Relationship between clonality and transformation in acute leukemia.

In some cases of acute leukemia an initial potentially leukemogenic genetic alteration can result in clonally derived end-cells normal in appearance and numbers. We refer to this clonal expansion as preleukemia. Subsequent alterations, intrinsic or extrinsic, often referred to as transformation, result in abnormal differentiation and/or growth regulation; we refer to this as leukemia. Several issues are unresolved. Where in the hierarchy of hematopoiesis clonal expansion and transformation occur is unknown. It is quite likely that clonal expansion occurs in cells with considerable self-renewal potential--probably stem or progenitor cells. The precise site may vary in different cases and account for the diverse phenotypes of acute leukemia. How the preleukemia clone comes to dominate hematopoiesis and the fate of the residual normal stem cells and their progeny are also unknown. Likewise, there is controversy whether different models of leukemogenesis operate in different subjects. For example, are older persons or those with occupational exposure to potentially leukomogenic agents more likely to exhibit one pattern of leukomogenesis? Finally, it is unknown whether these diverse models of leukemogenesis respond differently to therapy.

BCR/ABL and leukemia.

This review focuses on the role of the chimeric BCR/ABL gene in leukemia development. First, we discuss and update knowledge regarding the molecular biology of BCR/ABL. We then review data regarding transforming activity of BCR/ABL. Third, we discuss the complex interactions between BCR/ABL and leukemia phenotype. We conclude with a brief discussion of possible therapeutic implications of these data.

Autotransplants in leukemia: current state, future progress.

Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?

How important is hepatitis C virus (HCV)-infection in persons with acute leukemia?

Hepatitis C virus (HCV)-infection is common in persons with leukemia. Blood transfusions are the typical source and HCV-related chronic hepatitis a common outcome. Development of HCV-infection and -related hepatitis raises important questions about subsequent leukemia treatment including the natural history of the infection and need for treatment modification. Although the natural history of HCV-infection and -related hepatitis in this setting is unknown, data from normal persons with HCV-infection suggest that short-term survival is not likely to be decreased in persons with leukemia and these complications. In contrast, long-term survival may decrease because of a high rate of chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma. There are no convincing data that HCV-infection or -related hepatitis or alterations in anti-leukemia drug dose or schedule prompted by abnormal liver function tests, alter leukemia outcome. Consequently, it is uncertain whether drug doses and/or schedule should be modified in persons with leukemia and HCV-infection or -related hepatitis. Short-term outcome of blood cell and bone marrow transplants is also unaffected by HCV-infection or -related hepatitis.

GM-CSF incubation prior to treatment with cytarabine or doxorubicin enhances drug activity against AML cells in vitro: a model for leukemia chemotherapy.

We studied the effect of preincubation with recombinant GM-CSF on the activity of cytarabine and doxorubicin against clonogenic acute myeloid leukemia cells (CFU-AML). Leukemia cells from seven persons with AML, three myeloid cell lines (HL60, KG1, K562) and two control cell lines (U937, MOLT3) were tested. Preincubation with GM-CSF (0.01-0.1 microgram/ml) increased DNA synthesis as measured by tritiated thymidine incorporation and intranuclear Ki67 expression in cells from six persons with AML and in HL60 cells. Leukemia cells preincubated with GM-CSF for 6-48 h were exposed to cytarabine (2-200 micrograms/ml) or doxorubicin (0.01-0.1 microgram/ml) for 3 h and CFU-AML assayed. This approach further reduced CFU-AML in samples from six persons with AML and in HL60 and KG1 cells compared to cells not preincubated with GM-CSF prior to drug treatment. In most instances, reduced CFU-AML correlated with GM-CSF induced DNA synthesis. These data suggest a possible strategy of GM-CSF pretreatment to increase anti-leukemia efficacy of chemotherapy in AML.

Therapy of advanced acute myeloblastic leukemia with cytarabine and interleukin 2.

A child with acute myelogenous leukemia who relapsed three months after an allogeneic bone marrow transplant received intermediate-dose cytarabine followed by interleukin 2 (IL-2). Complete remission was achieved after the first cycle of IL-2. Five more combined cycles of cytarabine and IL-2 were given over the next year, during which remission has persisted. IL-2 therapy affected serum tumor necrosis factor (TNF), interferon gamma (IFN gamma) and soluble IL-2 receptor (sIL-2r) levels. In vitro cytotoxicity against leukemia cell lines and recipient leukemia cells was also increased.

T cell depletion in bone marrow transplantation for leukemia: current results and future directions.

T cell depletion reduces the incidence and severity of graft-versus-host disease (GVHD) following bone marrow transplantation in man. Graft-versus-host disease of more than grade 2 severity is decreased from about 45% to about 10% in recipients of HLA-identical transplants. However, T cell depletion also increases the frequency of graft failure and leukemia relapse. Graft failure increases from about 1 to 10% following HLA-identical transplants. In patients with acute leukemia in first remission or with chronic myelogenous leukemia in chronic phase, leukemia relapse increases from about 20% to about 40%. Thus, although T cell depletion decreases GVHD, it increases graft failure and leukemia relapse such that survival is not convincingly improved. Several approaches to these problems are possible including increased pre- or post-transplant immune suppression, more effective antileukemia therapy or selective T cell depletion. Preliminary results of these approaches are discussed and new directions suggested.