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Constitutional trisomy 21 (T21) is a state of aneuploidy associated with high incidence of childhood acute myeloid leukemia (AML). T21-associated AML is preceded by transient abnormal myelopoiesis (TAM), which is triggered by truncating mutations in GATA1generating a short GATA1isoform (GATA1s). T21-associated AML emerges due to secondary mutations in hematopoietic clones bearing GATA1s. Since aneuploidy generally impairs cellular fitness, the paradoxically elevated risk of myeloid malignancy in T21 is not fully understood. We hypothesized that individuals with T21 bear inherent genome instability in hematopoietic lineages that promotes leukemogenic mutations driving the genesis of TAM and AML. We found that individuals with T21 show increased chromosomal copy number variations (CNVs) compared to euploid individuals, suggesting that genome instability could be underlying predisposition to TAM and AML. Acquisition of GATA1senforces myeloid skewing and maintenance of the hematopoietic progenitor state independently of T21; however, GATA1sin T21 hematopoietic progenitor cells (HPCs) further augments genome instability. Increased dosage of the chromosome 21 (chr21) gene DYRK1Aimpairs homology-directed DNA repair as a mechanism of elevated mutagenesis. These results posit a model wherein inherent genome instability in T21 drives myeloid malignancy in concert with GATA1smutations.

Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce the leukemogenic MLL-AF9translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impart the clinical heterogeneity of AML.

Three hundred and twenty-four data points on the saturated hydraulic conductivity (k) of various hard rock mine tailings are collected from previous publications. The applicability of existing empirical equations for hard rock mine tailings is assessed based on this database collected. Results show that with a greater exponent of d10, the correlation between the measured and predicted kis greatly improved. An empirically modified version of the Kozeny–Carman equation is then proposed for predicting the saturated kof tailings and compared with the database. The proposed equation gives the best fit with a varying exponent greater than 2 for d10. Finally, the impact of particle shape on kis discussed.

Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor fitness gain ectopic, dysregulated self-renewal secondary to somatic mutations via undefined mechanisms. Here, in the context of the prototypical IBMFS Fanconi anemia (FA), we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1insertions and deletions (indels), generating a model of IBMFS-associated MDS. We observed that compared to the failure state, FA MDS cells show mutant RUNX1-mediated blunting of the G1/S cell cycle checkpoint that is normally activated in FA in response to DNA damage. RUNX1indels also lead to activation of innate immune signaling, which stabilizes the homologous recombination (HR) effector BRCA1, and this pathway can be targeted to abrogate viability and restore sensitivity to genotoxins in FA MDS. Together, these studies develop a paradigm for modeling clonal evolution in IBMFSs, provide basic understanding of the pathogenesis of MDS, and uncover a therapeutic target in FA-associated MDS.

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Roychowdhury, Poulami. Capable women, incapable states: negotiating violence and rights in India. Oxford, 2020. 256p bibl index ISBN 9780190881894 doth, $99.00; ISBN 9780190881900 pbk, $29.95; ISBN 9780190881924 ebook, contact publisher [...]

Time and method dependencies, lack of sufficient capillary connections, and wetting-drying hysteresis may cause inaccurate results from filter paper tests (FPTs) when used for suction measurements of geosynthetic clay liners (GCLs). These limitations of the filter paper method for suction measurements of GCLs were investigated using initially dry contact, initially wet contact, and noncontact FPTs. Wetting-drying hysteresis was observed in the initially dry contact and noncontact FPTs and was significantly higher in the latter. The initially wet contact and initially dry contact FPTs were reliable in measuring matric and total suction, respectively. These two methods can provide suction measurements from both the cover and the carrier geotextile sides of the GCLs (i.e., from the hydratable surfaces of the GCL after installation on site), thus allowing suction measurements without impacting the integrity of the geotextile-bentonite-geotextile structure. Suction measurements on a granular bentonite-based GCL showed higher time dependency compared with powdered bentonite-based GCLs. For the specific GCLs and conditions tested, the woven and nonwoven scrim-reinforced geotextile structure causes pronounced capillary break effects on the hydratable surface of GCL. In contrast, the woven geotextile structure has a minimal impact. When the FPT procedures are applied to GCLs, the interpretation of the results requires careful consideration of the method and time dependencies, wetting-drying hysteresis, capillary breaks, and how the measurements of total or matric suction are performed.

Fanconi anemia (FA) is a disorder of DNA repair that manifests as bone marrow (BM) failure. The lack of accurate murine models of FA has refocused efforts toward differentiation of patient-derived induced pluripotent stem cells (IPSCs) to hematopoietic progenitor cells (HPCs). However, an intact FA DNA repair pathway is required for efficient IPSC derivation, hindering these efforts. To overcome this barrier, we used inducible complementation of FANCA-deficient IPSCs, which permitted robust maintenance of IPSCs. Modulation of FANCA during directed differentiation to HPCs enabled the production of FANCA-deficient human HPCs that recapitulated FA genotoxicity and hematopoietic phenotypes relative to isogenic FANCA-expressing HPCs. FANCA-deficient human HPCs underwent accelerated terminal differentiation driven by activation of p53/p21. We identified growth arrest specific 6 (GAS6) as a novel target of activated p53 in FANCA-deficient HPCs and modulate GAS6 signaling to rescue hematopoiesis in FANCA-deficient cells. This study validates our strategy to derive a sustainable, highly faithful human model of FA, uncovers a mechanism of HPC exhaustion in FA, and advances toward future cell therapy in FA.

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human–rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

Leukemia phenotypes vary with age of onset. Delineating mechanisms of age specificity in leukemia could improve disease models and uncover new therapeutic approaches. Here, we used heterochronic transplantation of leukemia driven by MLL/KMT2A translocations to investigate the contribution of the age of the hematopoietic microenvironment to age-specific leukemia phenotypes. When driven by MLL-AF9, leukemia cells in the adult microenvironment sustained a myeloid phenotype, whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukemia. In MLL-ENL leukemia, the neonatal microenvironment potentiated B-lymphoid differentiation compared with the adult. Ccl5 elaborated from adult marrow stroma inhibited B-lymphoid differentiation of leukemia cells, illuminating a mechanism of age-specific lineage commitment. Our study illustrates the contribution of the developmental stage of the hematopoietic microenvironment in defining the age specificity of leukemia.

Platelets are essential for hemostasis; however, several studies have identified age-dependent differences in platelet function. To better understand the origins of fetal platelet function, we have evaluated the contribution of the fetal-specific RNA binding protein Lin28bin the megakaryocyte/platelet lineage. Because activated fetal platelets have very low levels of P-selectin, we hypothesized that the expression of platelet P-selectin is part of a fetal-specific hematopoietic program conferred by Lin28b. Using the mouse as a model, we find that activated fetal platelets have low levels of P-selectin and do not readily associate with granulocytes in vitro and in vivo, relative to adult controls. Transcriptional analysis revealed high levels of Lin28band Hmga2in fetal, but not adult, megakaryocytes. Overexpression of LIN28Bin adult mice significantly reduces the expression of P-selectin in platelets, and therefore identifies Lin28bas a negative regulator of P-selectin expression. Transplantation of fetal hematopoietic progenitors resulted in the production of platelets with low levels of P-selectin, suggesting that the developmental regulation of P-selectin is intrinsic and independent of differences between fetal and adult microenvironments. Last, we observe that the upregulation of P-selectin expression occurs postnatally, and the temporal kinetics of this upregulation are recapitulated by transplantation of fetal hematopoietic stem and progenitor cells into adult recipients. Taken together, these studies identify Lin28bas a new intrinsic regulator of fetal platelet function.

Platelets are essential for hemostasis; however, several studies have identified age-dependent differences in platelet function. To better understand the origins of fetal platelet function, we have evaluated the contribution of the fetal-specific RNA binding protein Lin28b in the megakaryocyte/platelet lineage. Because activated fetal platelets have very low levels of P-selectin, we hypothesized that the expression of platelet P-selectin is part of a fetal-specific hematopoietic program conferred by Lin28b. Using the mouse as a model, we find that activated fetal platelets have low levels of P-selectin and do not readily associate with granulocytes in vitro and in vivo, relative to adult controls. Transcriptional analysis revealed high levels of Lin28b and Hmga2 in fetal, but not adult, megakaryocytes. Overexpression of LIN28B in adult mice significantly reduces the expression of P-selectin in platelets, and therefore identifies Lin28b as a negative regulator of P-selectin expression. Transplantation of fetal hematopoietic progenitors resulted in the production of platelets with low levels of P-selectin, suggesting that the developmental regulation of P-selectin is intrinsic and independent of differences between fetal and adult microenvironments. Last, we observe that the upregulation of P-selectin expression occurs postnatally, and the temporal kinetics of this upregulation are recapitulated by transplantation of fetal hematopoietic stem and progenitor cells into adult recipients. Taken together, these studies identify Lin28b as a new intrinsic regulator of fetal platelet function.

LIN28 is an RNA-binding protein that regulates the maturation of the let-7 family of microRNAs by bipartite interactions with let-7 precursors through its two distinct cold shock and zinc-knuckle domains. Through inhibition of let-7 biogenesis, LIN28 functions as a pluripotency factor, as well as a driver of tumorigenesis. Here, we report a fluorescence polarization assay to identify small-molecule inhibitors for both domains of LIN28 involved in let-7 interactions. Of 101,017 compounds screened, six inhibit LIN28:let-7 binding and impair LIN28-mediated let-7 oligouridylation. Upon further characterization, we demonstrate that the LIN28 inhibitor TPEN destabilizes the zinc-knuckle domain of LIN28, while LI71 binds the cold shock domain to suppress LIN28’s activity against let-7in leukemia cells and embryonic stem cells. Our results demonstrate selective pharmacologic inhibition of individual domains of LIN28 and provide a foundation for therapeutic inhibition of the let-7 biogenesis pathway in LIN28-driven diseases.

A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.

For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.

Cell engineering has brought us tantalizingly close to the goal of deriving patient-specific hematopoietic stem cells (HSCs). While directed differentiation and transcription factor-mediated conversion strategies have generated progenitor cells with multilineage potential, to date, therapy-grade engineered HSCs remain elusive due to insufficient long-term self-renewal and inadequate differentiated progeny functionality. A cross-species approach involving zebrafish and mammalian systems offers complementary methodologies to improve understanding of native HSCs. Here, we discuss the role of conserved developmental timing processes in vertebrate hematopoiesis, highlighting how identification and manipulation of stage-specific factors that specify HSC developmental state must be harnessed to engineer HSCs for therapy.

BackgroundLung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL.ObjectivesWe explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer.DesignSemistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis.ResultsPatients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients’ HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit.ConclusionsWe conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members.

(BJOG. 2020;127:1665–1675)The UK has higher rates of stillbirth and neonatal mortality than similar countries. A 2015 UK-wide confidential inquiry, Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), identified key issues contributing to perinatal death, including inadequate maternal monitoring, errors in fetal monitoring, and failure to recognize the transition from the latent phase of labor to the active phase. The majority of deaths included in MBRRACE-UK occurred in hospital obstetric units (OUs), but the proportion of births occurring in midwifery-led settings in England is increasing. While there is no evidence that midwifery-led settings experience higher rates of intrapartum-related perinatal deaths compared with OU, contributing factors to perinatal deaths in midwifery settings may differ. Enhancing the safety of Midwifery-led births Enquiry (ESMiE) reviewed the quality of care in pregnancy, labor, birth, and postpartum in births resulting in intrapartum-related deaths in midwifery-led settings and compared the findings with those of MBRRACE-UK.

Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aorta–gonad–mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)–cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA–CREB and BMP pathways in isolated AGM VE-cadherin+ cells from mid-gestation embryos, we demonstrate that PKA–CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA–CREB–BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-to-hematopoietic transition.

A new, simple, semianalytic technique for modeling contaminant migration through an unfractured clayey liner underlain by fractured soil or rock and an aquifer is described. The model is implemented on a microcomputer and allows consideration of advectivediffusivedispersive transport through the liner including sorption, where appropriate, advectivedispersive transport through the fractures, matrix diffusion from the fractures into the adjacent soil, sorption on the fracture surface and in the soil matrix, and finite mass of contaminant in the landfill and dilution in the aquifer. The application of the model is illustrated by considering migration from a hypothetical landfill separated from an underlying aquifer by fractured till. Consideration is given to impact without a liner and with a reworked till as a compacted clay liner underlain by fractured till. The results obtained by modeling migration through the compacted liner and fractured till are compared with what would be obtained using approximate approaches that consider either the liner alone or consider the full thickness to be fractured.

A convenient and computationally efficient technique for analyzing the one-dimensional consolidation of periodically layered deposits is developed. This technique involves the use of a Laplace transform and an analytic solution to the governing equations is determined in transformed space. The transform is then inverted numerically. This technique requires minimal computational storage or calculation. The technique is then used to examine the response of periodically layered deposits. Particular emphasis is given to the effects of pumping from an underlying aquifer and to the time required to establish steady state flow from an overlying (possibly polluted) aquifer. The consolidation of deposits with a linear initial excess pore pressure distribution and impermeable or permeable base is also fly examined.

The finite element method is used to predict the behavior of two centrifugal reinforced soil wall models, one reinforced with a geogrid, the other with a nonwoven geotextile. Comparisons between the observed and calculated behavior indicate good agreement. Sensitivity studies were also performed in order to investigate some of the uncertainties adopted in the numerical modeling. These studies show that in the geotextilereinforced model the effect of the intermediate layers that form part of the wrapback facing is significant. In the geogridreinforced model, it is found that the interface shear strength between the fill and the reinforcement is an important factor, but the effects of the fill/facing interface shear strength, facing panel continuity, and location of panel connections are relatively less important. The finite element analyses also provide detailed information relating to the soil/structure interaction in these models. The results presented in this paper are considered to be useful in advancing the understanding of the behavior of reinforced soil walls constructed with extensible reinforcement.

A technique for the analysis of 1D pollutant migration through a clay layer of finite depth is presented. This formulation includes dispersive and advective transport in the clay as well as geochemical reactions and permits consideration of the depletion of contaminant in the landfill with time as well as the effect of groundwater flow in a permeable stratum beneath the clay layer. A limited parametric study is presented to illustrate the effect of considering these factors in the analysis. It is shown that for most practical situations the concentration of contaminant within the ground water beneath the landfill will reach a peak value at a specific time and will then decrease with subsequent time. It is shown that the magnitude of this peak concentration and the time required for it to occur are highly dependent upon the mass of contaminant within the landfill and the sorption capacity of the clay. Other important factors which are examined include the thickness of the clay layer, the advection velocity relative to the dispersivity, and the groundwater flow velocity in any permeable strata beneath the clay layer. The implications of these results for optimizing the design of clay liners is then discussed.

A technique for the analysis of periodically layered soil deposits is developed. This technique requires minimal data preparation and is compu tationally very efficient. The technique is used to determine the deformations of a periodically layered half space subjected to a uniform circular applied pres sure. Consideration is given to the center settlement, edge settlement and hor izontal displacement at the edge. Results are presented for a wide range of geometries and soil conditions. The validity of two approximate approaches which represent the deposit as a single homogeneous layer are then evaluated. It is shown that simple approaches will suffice for a wide range of conditions, and parametric solutions are provided for certain situations where simple ap proaches are not appropriate.

A numerical technique for the analysis of geotextile reinforced em bankments is outlined. This technique permits consideration of soilreinforcement interaction, slip at the soilfabric interface, plastic failure within the soil and large deformations. The applicability of the approach has been assessed by examining the observed and predicted performance of a number of reinforced embankments constructed on soft foundations. In this paper, the application of the approach is illustrated by reference to an embankment constructed on a soft peat deposit. Finally, the paper presents a practical design procedure which involves the use of simple design charts. The use of this design procedure is illustrated by means of a worked example using a typical set of design charts.

High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-rB-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis.

Hematopoiesis changes over life to meet the demands of maturation and aging. Here, we find that the definitive hematopoietic stem and progenitor cell (HSPC) compartment is remodeled from gestation into adulthood, a process regulated by the heterochronic Lin28b/let-7axis. Native fetal and neonatal HSPCs distribute with a pro-lymphoid/erythroid bias with a shift toward myeloid output in adulthood. By mining transcriptomic data comparing juvenile and adult HSPCs and reconstructing coordinately activated gene regulatory networks, we uncover the Polycomb repressor complex 1 (PRC1) component Cbx2 as an effector of Lin28b/let-7’s control of hematopoietic maturation. We find that juvenile Cbx2−/−hematopoietic tissues show impairment of B-lymphopoiesis, a precocious adult-like myeloid bias, and that Cbx2/PRC1 regulates developmental timing of expression of key hematopoietic transcription factors. These findings define a mechanism of regulation of HSPC output via chromatin modification as a function of age with potential impact on age-biased pediatric and adult blood disorders.

Based on case histories and the latest research, this paper examines municipal solid waste landfills as a system comprised of three primary subsystems (the hydrogeology and barrier system below the waste; the waste and landfill operations; and the landfill cover and landfill gas control system) that exists in a broader social/regulatory/administrative/economic system. Issues discussed include the effects of waste type and waste management risks, landfill leachate and leachate collection, landfill gas and gas collection, the hydrogeology and barrier subsystem required to contain contaminants in leachate and landfill gas from escape by both advection and diffusion, the dependence of a landfill design on the type and amount of waste and the operational model, materials specifications, and construction issues. Lessons to be learnt from the past problems are discussed together with the implications for modern waste management. The success of modern systems are noted together with the need to maintain vigilance and avoid complacency with respect to landfill siting, design, approval, construction, operations, after-use, and in approving subsequent surrounding land use. The importance of considering the interactions between the different components of the landfill system is discussed in the context of the need to ensure that changes in terms of waste stream or modes of landfill operations are carefully researched and considered in developing designs to provide long-term environmental protection.Based on case histories and the latest research, this paper examines municipal solid waste landfills as a system comprised of three primary subsystems (the hydrogeology and barrier system below the waste; the waste and landfill operations; and the landfill cover and landfill gas control system) that exists in a broader social/regulatory/administrative/economic system. Issues discussed include the effects of waste type and waste management risks, landfill leachate and leachate collection, landfill gas and gas collection, the hydrogeology and barrier subsystem required to contain contaminants in leachate and landfill gas from escape by both advection and diffusion, the dependence of a landfill design on the type and amount of waste and the operational model, materials specifications, and construction issues. Lessons to be learnt from the past problems are discussed together with the implications for modern waste management. The success of modern systems are noted together with the need to maintain vigilance and avoid complacency with respect to landfill siting, design, approval, construction, operations, after-use, and in approving subsequent surrounding land use. The importance of considering the interactions between the different components of the landfill system is discussed in the context of the need to ensure that changes in terms of waste stream or modes of landfill operations are carefully researched and considered in developing designs to provide long-term environmental protection.

The myocardial extracellular matrix (ECM), an interwoven meshwork of proteins, glycoproteins, proteoglycans, and glycosaminoglycans that is dominated by polymeric fibrils of type I collagen, serves as the mechanical scaffold on which myocytes are arrayed for coordinated and synergistic force transduction. Following ischemic injury, cardiac ECM remodeling is initiated via localized proteolysis, the bulk of which has been assigned to matrix metalloproteinase (MMP) family members. Nevertheless, the key effector(s) of myocardial type I collagenolysis both in vitroand in vivohave remained unidentified. In this study, using cardiac explants from mice deficient in each of the major type I collagenolytic MMPs, including MMP-13, MMP-8, MMP-2, MMP-9, or MT1-MMP, we identify the membrane-anchored MMP, MT1-MMP, as the dominant collagenase that is operative within myocardial tissues in vitro. Extending these observations to an in vivosetting, mice heterozygous for an MT1-MMP–null allele display a distinct survival advantage and retain myocardial function relative to wild-type littermates in an experimental model of myocardial infarction, effects associated with preservation of the myocardial type I collagen network as a consequence of the decreased collagenolytic potential of cardiac fibroblasts. This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction.

Due to multiple factors, including their low incidence, heterogeneity and span of ages of affected patients, both osteosarcoma and Ewing’s sarcoma pose significant challenges to oncologists and patients. Despite these obstacles, significant progress has been made in the last 40 years in improving the survival of patients with localized osteosarcoma and Ewing’s sarcoma through multidisciplinary management. However, patients with primary refractory disease or disseminated disease fare poorly, emphasizing the need for novel therapies. Unfortunately, given their rarity, novel therapies for these tumors are difficult to rigorously trial. Current investigation is focused on identification of active targeted therapies in trials in patients with relapsed or refractory disease. Here we review the past, present and potential future clinical trials of systemic therapy in osteosarcoma and Ewing’s sarcoma.

Human mesenchymal stem cells (hMSCs) localized to bone marrow, nonhematopoietic organs, as well as perivascular niches are postulated to traffic through type I collagen-rich stromal tissues to first infiltrate sites of tissue damage, inflammation, or neoplasia and then differentiate. Nevertheless, the molecular mechanisms supporting the ability of hMSCs to remodel 3-dimensional (3D) collagenous barriers during trafficking or differentiation remain undefined. Herein, we demonstrate that hMSCs degrade and penetrate type I collagen networks in tandem with the expression of a 5-member set of collagenolytic matrix metalloproteinases (MMPs). Specific silencing of each of these proteases reveals that only a single membrane-tethered metalloenzyme, termed MT1-MMP, plays a required role in hMSC-mediated collagenolysis, 3D invasion, and intravasation. Further, once confined within type I collagen-rich tissue, MT1-MMP also controls hMSC differentiation in a 3D-specific fashion. Together, these data demonstrate that hMSC invasion and differentiation programs fall under the control of the pericellular collagenase, MT1-MMP.

The application of a surface, permeable reactive barrier has been implemented at a remote site in the Canadian Arctic for the remediation of soils and water contaminated with polychlorinated biphenyls (PCBs). The initial barrier system was installed in July 2003. Preliminary work in both the field and the laboratory suggested that geotextiles alone may not be adequate for this particular Arctic barrier system, owing to issues related to survivability (specifically the effects of high UV and freeze–thaw) and clogging. Subsequent field and laboratory work demonstrated that granular materials trapped the majority of PCB-contaminated soil without impeding hydraulic performance; however, fines were escaping. Extensive column testing in the laboratory has shown that a nonwoven geotextile filter can be applied with success with a granular permeable reactive barrier system. This paper presents the results of laboratory experiments and field research used in the design of this barrier system.

Results of series of tests examining the effect of different chemical constituents found in municipal solid waste leachate on the degradation of a high-density polyethylene (HDPE) geomembrane are reported. Geomembrane samples were incubated in four synthetic leachates consisting of different combinations of volatile fatty acids, inorganic nutrients, trace metal solution, and surfactant at temperatures of 85°C, 70°C, 55°C, 40°C and 22°C. It is shown that the leachate should be replaced every two weeks to maximise the depletion of antioxidants from the geomembrane. Arrhenius modelling gave activation energies for antioxidant depletion of between 62.5 and 64.0 kJ/mol. The small difference in activation energies implies that the four leachates examined are similar in terms of antioxidant depletion rate. There was no evident effect of the difference in these leachates on crystallinity, MFI, or tensile properties during the testing period. However, the fastest antioxidant depletion was observed for the simplest leachate, comprising trace metals and surfactant in water. Results are also reported for a second series of tests involving 18 different immersion media with different concentrations of trace metals and surfactant. Based on an examination of solutions with pH between 4 and 10, it is found that antioxidant depletion is the fastest for relatively acidic or basic solutions and the slowest for neutral solutions. Antioxidant depletion is the most sensitive to the presence of surfactant. As the surfactant concentration increases to about 1 ml/l the majority of the effect is evident. There was no further increase in effect for any increase in concentration beyond 5 ml/l.Results of series of tests examining the effect of different chemical constituents found in municipal solid waste leachate on the degradation of a high-density polyethylene (HDPE) geomembrane are reported. Geomembrane samples were incubated in four synthetic leachates consisting of different combinations of volatile fatty acids, inorganic nutrients, trace metal solution, and surfactant at temperatures of 85°C, 70°C, 55°C, 40°C and 22°C. It is shown that the leachate should be replaced every two weeks to maximise the depletion of antioxidants from the geomembrane. Arrhenius modelling gave activation energies for antioxidant depletion of between 62.5 and 64.0 kJ/mol. The small difference in activation energies implies that the four leachates examined are similar in terms of antioxidant depletion rate. There was no evident effect of the difference in these leachates on crystallinity, MFI, or tensile properties during the testing period. However, the fastest antioxidant depletion was observed for the simplest leachate, comprising trace metals and surfactant in water. Results are also reported for a second series of tests involving 18 different immersion media with different concentrations of trace metals and surfactant. Based on an examination of solutions with pH between 4 and 10, it is found that antioxidant depletion is the fastest for relatively acidic or basic solutions and the slowest for neutral solutions. Antioxidant depletion is the most sensitive to the presence of surfactant. As the surfactant concentration increases to about 1 ml/l the majority of the effect is evident. There was no further increase in effect for any increase in concentration beyond 5 ml/l.

Although intact geomembranes are excellent barriers to fluid flow, there are still two possible pathways for the transport of organic contaminants into the environment: leakage through defects in the geomembrane, and diffusion through the intact geomembrane. Analytical, semi-analytical and numerical techniques for calculating leakage rates have been developed. However, no previous attempt has been made to rigorously model the interaction between leakage through a hole in a wrinkle and diffusion. To address this shortcoming, finite-element analyses in two-dimensional space are performed to simulate the transport of dichloromethane (DCM) through a leaking HPDE geomembrane (GM) for eight cases involving composite liners, including both compacted clay liners and geosynthetic clay liners. Equations of steady-state seepage and time-dependent diffusion-advection in saturated soils are solved. Transport through the GMs is simulated by a novel, mass-conserving equivalent boundary condition that renders the problem computationally more tractable. Results are compared with those obtained from widely used one-dimensional methods, namely the Rowe equation for leakage through a wrinkle and the POLLUTEv7 program for mass transport. It is shown that predictions of leakage and transport by the one-dimensional method (POLLUTEv7) are within a maximum 30% of two-dimensional values under conditions of perfect mixing in the aquifer. When no horizontal mixing is present, concentrations of DCM are found to increase by up to 43% in two-dimensional analyses. It is concluded that one-dimensional analyses are adequate for most practical purposes.

In an observational study using heparinase-modified thrombelastography, we investigated the percentage of elective cardiothoracic surgical patients receiving low-dose unfractionated heparin (5000 IU 12 hourly subcutaneously) who had a demonstrable systemic heparin effect.Blood samples were obtained at induction from 40 adult elective cardiothoracic surgical patients who had received 5000 IU unfractionated heparin subcutaneously within six hours. Simultaneous kaolin and heparinase-modified thrombelastographies were run on all samples. Fourteen patients (35%; 95% CI: 20 to 50%) had a demonstrable heparin effect(defined as a kaolin thrombelastography R time >25% longer than the heparinase-modified control). Their mean±SD kaolin thrombelastography R time was 13.6±5.9 minutes (normal range 4 to 8 minutes) vs. 7.1±2.0 minutes for the heparinase-modified controls. In 10 patients the thrombelastography R times were >50% longer and in four patients >100% longer, than their respective heparinase-modified controls. In a post hoc analysis, there was little correlation between the extent of the prolongation and patient age (r=0.02), weight (r=-0.31), preoperative creatinine (r=-0.17), or time since administration of heparin (r=0.14).These results indicate that about one third of patients who have received low-dose unfractionated heparin subcutaneously within six hours have a demonstrable heparin effect. The potential for this effect should be considered if central neural blockade is planned.

Geomembranes are highly effective barriers, and are often a key component in the design of composite landfill liner and cover systems. During installation, solar exposure causes some types of geomembrane to buckle locally upwards and form networks of wrinkles (sometimes referred to as waves). These wrinkle networks may be significant in terms of increasing leakage through this barrier system if there is a hole at or near the wrinkle. In this paper, a novel method to quantify geomembrane wrinkles in the field is reported using low-altitude aerial digital photography and image processing techniques. The results of the analysis indicate that, at the date and time the aerial image was captured, the geomembrane contained 100 major wrinkles, which covered 13.9% of the total area of the exposed geomembrane. More importantly from a potential leakage perspective, over 90% of these wrinkles were found to be hydraulically connected over the entire field of view of the exposed geomembrane. This one hydraulically connected wrinkle was found to have an aggregate length of 520 m.

The leaching of hazardous metals and metalloids from mine tailings is a significant problem facing the mining industry. Although, in the past, geosynthetic clay liners (GCLs) have primarily been employed as leachate barriers in landfills, recent times have seen an increase in the variety of their applications, including applications in the mining industry. The capacity of GCLs to attenuate metals and metalloids (As, Al, Cd, Cu, Fe, Mn, Ni, Sr, Zn) from mine acidic rock drainage (ARD) water and a neutral-pH, As-rich water associated with gold mine tailings (GMT) was evaluated. Water-prehydrated GCLs were permeated with GMT and ARD for short (2 and 5 pore volumes, PV) and long (21 PV) periods. The long-term hydraulic conductivity of the GCLs increased from 1.6 × 10-11m/s (water for 5 PV) to 5.0 × 10-11m/s and 1.3 × 10-10m/s after permeation with the GMT and ARD waters, respectively (21 PV). The distribution of metals within the GCL was quantified in order to differentiate between metals associated with precipitated compounds, soluble complexes in porewater, and sorbed metals. Metals sorbed to the GCL are reported in micrograms of metal per gram of bentonite (ppm), and are indicative of the GCL's sorption capacity for a barrier system. Significant differences existed between the soil tested at 2 PV 5 PV and 21 PV It was only at 5 PV that the precipitation of the ferrihydrite occurred in the ARD samples, and gypsum occurred in the GMT samples. These minerals were responsible for retention of metals in addition to the cation exchange of the GCL.The leaching of hazardous metals and metalloids from mine tailings is a significant problem facing the mining industry. Although, in the past, geosynthetic clay liners (GCLs) have primarily been employed as leachate barriers in landfills, recent times have seen an increase in the variety of their applications, including applications in the mining industry. The capacity of GCLs to attenuate metals and metalloids (As, Al, Cd, Cu, Fe, Mn, Ni, Sr, Zn) from mine acidic rock drainage (ARD) water and a neutral-pH, As-rich water associated with gold mine tailings (GMT) was evaluated. Water-prehydrated GCLs were permeated with GMT and ARD for short (2 and 5 pore volumes, PV) and long (21 PV) periods. The long-term hydraulic conductivity of the GCLs increased from 1.6 × 10-11m/s (water for 5 PV) to 5.0 × 10-11m/s and 1.3 × 10-10m/s after permeation with the GMT and ARD waters, respectively (21 PV). The distribution of metals within the GCL was quantified in order to differentiate between metals associated with precipitated compounds, soluble complexes in porewater, and sorbed metals. Metals sorbed to the GCL are reported in micrograms of metal per gram of bentonite (ppm), and are indicative of the GCL's sorption capacity for a barrier system. Significant differences existed between the soil tested at 2 PV 5 PV and 21 PV It was only at 5 PV that the precipitation of the ferrihydrite occurred in the ARD samples, and gypsum occurred in the GMT samples. These minerals were responsible for retention of metals in addition to the cation exchange of the GCL.