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Cultures in Mediterranean climate zones (MCZs) around the world have long been reliant on groundwater and springs as freshwater sources. While their ecology and cultural sustainability are recognized as critically important, inter-relationships between springs and culture in MCZs have received less attention. Here we augmented a global literature review with case studies in MCZ cultural landscapes to examine the diversity and intensity of cultural and socio-economic relationships on spring ecohydrogeology. MCZs are often oriented on western and southern coasts in tectonically active landscapes which control aquifer structure, the prevalence of westerly winds, and aridity, and generally expose associated habitats and cultures to harsh afternoon sunlight. Cultural appreciation and appropriation of springs ranges widely, from their use as subsistence water supplies to their roles in profound traditions such as Greco-Roman nymphalea as well as Asian and Abrahamic spiritual cleansing and baptism. The abandonment of traditional ways of life, such as rural livestock production, for urban ones has shifted impacts on aquifers from local to regional groundwater exploitation. The commoditization of water resources for regional agricultural, industrial (e.g., mining, water bottling, geothermal resorts), and urban uses is placing ever-increasing unsustainable demands on aquifers and spring ecosystems. When the regional economic value of springs approaches or exceeds local cultural values, these irreplaceable aquatic ecosystems are often degraded, over-looked, and lost. Sustainable stewardship of springs and the aquifers that support them is a poorly recognized but central conservation challenge for modern Mediterranean societies as they face impending impacts of global climate change. Solutions to this crisis require education, societal dialogue, and improved policy and implementation. [ABSTRACT FROM AUTHOR]

The geological heritage of Australia's landscapes and World Heritage areas has generally been underpromoted to the public by the tourism industry. However, in 2008, the fledgling world of geotourism in Australia received a significant boost with two events: the Inaugural Global Geotourism Conference 'Discover the Earth beneath our Feet' held in Fremantle, Western Australia, and the declaration of the UNESCO Kanawinka Global Geopark, which linked volcanic regions in South Australia and Victoria. Simultaneously the Australian Federal Government launched the 'Australian National Landscapes' (ANL) program. However, this impetus was not sustained when the Kanawinka Global Geopark was deregistered as a UNESCO-branded geopark in 2012, and the ANL program faded within a decade. Despite these setbacks, as an outcome of the 2008 Fremantle conference, several productive lines of geotourism have developed across Australia. This paper reviews the history of Australian geotourism since 2008. It examines the impacts of the experiences, lessons learned, problems for geology as perceived by National Parks and the Environment movement, geological communication problems, and the subsequent evolution of Australian geotourism. From these issues, new non-government bodies and initiatives have arisen, including the Australian Geoparks Network, the Australian Geoscience Council, and the recent development of a National Geotourism Strategy. Strong elements emerging from these initiatives are the increasing development of geotrails (which suit the large Australian continent) and the new Australian concept of 'GeoRegions'. These are in response to an awareness that geotourism requires a flexible outlook to widen the appreciation and appeal of geological heritage and landscapes to the broader public. A further new direction is suggested: for Australian geotourism to combine with some elements of ICOMOS Cultural Routes. An outstanding example, the ICOMOS Overland Telegraph Line (OTL) Cultural Route that crosses Australia from south to north, is considered. For 2000 km, the construction of this line in the 1870s followed the regional geology and hydrology, relying upon the available biota but bringing about a clash of human cultures. The six colonies of Australia were finally linked to the world by wire, but the arrival of the OTL had a significant impact on the country's Indigenous inhabitants. In Australia and globally, geotourism is incorporating the A–B–Cs (abiotic, biotic and cultural elements) to more effectively encourage the public to value their landscapes and the associated stories. The OTL provides an example of a newly introduced fourth dimension for geotourism, which gives consideration to the socio-political context of landscape adaptation. [ABSTRACT FROM AUTHOR]

Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors., AML is a predominantly fatal hematopoietic malignancy (1-3). Even when leukemia cells appear to have been eradicated from the bone marrow after chemotherapy treatment, most patients relapse eventually. Therefore, it [...]

To improve complete remission (CR) rates by reducing toxicity and enhancing delivery, we created a modified hyper-CVAD/MA regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) by reducing the cytarabine dose (3 g/m2 to 2 g/m2) and number of cycles (eight to six). We conducted a phase II trial in the pre-rituximab era in the intermediate–high international prognostic index (IPI) (≥2) de novo diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) (ACTRN12605000105640). CR rates were compared with reported IPI-stratified rates. Sixty-three patients (n = 26 PTCL; n = 37 DLBCL) were evaluated; median follow-up of 30 months. CR rates for PTCL and DLBCL patients were 46% and 49%, respectively, similar with reported CR rates with CHOP-like chemotherapy (p =.6). Of the patients, 51 (81%) experienced ≥1 unplanned hospital admission; only 41 (65%) completed six cycles. The cytarabine modifications did not prevent significant toxicity. Modified hyper-CVAD/MA resulted in similar outcomes to CHOP-like chemotherapy in aggressive lymphomas and was associated with significant toxicity. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data. Results: Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types. Conclusions: Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at http://code.google.com/p/edmr/. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the five-year survival rates of lymphoma patients in South Australia (SA) from 1977 to 2007. It notes that survival measurements indicate the care given to cancer patients, adding that population data offer more information on care trends. Findings show that patients with Hodgkin lymphoma (HL) posted a 7.6%-point increase from 1997 to 1984 while non-HL (NHL) patients had an 18.7%-point rise in the same period. It cites age as a factor in survival in lymphoma.

We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies. [ABSTRACT FROM AUTHOR]

Limited cell numbers in a unit restricts cord blood transplantation (CBT) in adults. We evaluated whether cotransplantation of placental mesenchymal stromal cells (MSCs) would enhance engraftment. Plastic adherent cells from placenta demonstrated typical characteristics of MSCs. In six individual experiments, 4 cohorts of 24 nonobese diabetic/ severe combined immune deficient (NOD/SCID) mice were evaluated. Cohort 1 received 5 x 104 CD34+ cells from unit (U) one (SCBT); cohort 2 received 5 x 104 CD34+ cells from Ul + 4 x 104 MSCs (SCBT+MSCs); cohort 3 received 2.5 x 10" CD34+ cells from Ul + 2.5 x 104 CD34+ cells from 112 (double cord blood transplant [DCBT]); cohort 4 received 2.5 x 104 CD34+ cells from Ul + 2.5 x 104 CD34+ cells from U2 + 4 x 104 MSCs (DCBT+MSCs). Hematopoietic engraftment evaluated after 6 to 8 weeks, was similar in recipients of SCBT and DCBT. MSC cotransplantation demonstrated enhanced engraftment in DCBT (51.8 ▒ 6.8% versus 14.9 ▒ 6.5%; p = .04) with an increased trend in SCBT (48.7 ▒ 7.7% versus 17.5 ▒ 6.1%; p = .07). In DCBT, cotransplantation of placental MSCs reduced single cord dominance. Self-renewal capacity was assessed by serial transplantation in secondary recipients infused with engrafted human cells from primary mice transplanted with or without MSCs. In secondary transplant experiments, 13 of 17 Θvaluable mice engrafted at levels of 1% to 6.5%. Despite enhanced engraftment in primary mice, long-term engraftment capacity was unaltered with MSC cotransplantation. Imaging studies showed MSCs migrated to pelvic region and improved cord blood (CB) CD34+ homing. Cotransplantation of placental MSCs enhanced cord blood engraftment and may act by improving homing of CD34+ cells. Stem Cells 2009:27:2293-2300 [ABSTRACT FROM AUTHOR]

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 – 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 – 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cells×106 L-1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support. [ABSTRACT FROM AUTHOR]

Abstract: The cenotes near Mt Gambier are circular, cliffed, collapse dolines containing water-table lakes up to 125m deep, floored by large rubble cones. They lie in a flat, coastal plain composed of mid-Tertiary limestone. Most of the deepest cenotes are concentrated in two small areas located along trends sub-parallel to the main joint direction in the limestone. The cenotes do not connect to underwater phreatic passages, and water chemistry data confirm that they are not part of an interconnected karst network. They formed by collapse into large chambers (up to >1 million m3) that extended 125m or more below the land surface. Several cenotes have actively growing stromatolites on the sub-vertical walls that started growing at ∼8000years BP. The caves that collapsed to form the deep Mt Gambier cenotes are much larger than shallow and deep phreatic caves in the area, and do not connect into deep phreatic systems. They were not formed by freshwater/seawater mixing, responsible for many of the well-known Yucatan cenotes, because they are not associated with locations of the mixing zone during previous high sea levels, and are much larger than caves presently forming along the mixing zone near Mt Gambier. Instead dissolution was most likely due to a process whereby acidified groundwater containing large amounts of volcanogenic CO2 ascended up fractures from the magma chambers that fed the Pleistocene–Holocene volcanic eruptions in the area; deep reservoirs of volcanogenic CO2 occur nearby. Cave dissolution could have been due to release of CO2 during the Mt Gambier eruption ∼28,000years ago, followed by collapse to form cenotes during the low sea levels of the Last Glacial Maximum ∼20,000years ago. The cenotes then flooded ∼8000years ago as sea level rose, and stromatolites began to grow on the walls. [Copyright &y& Elsevier]

Objective. To determine the bone marrow homing efficiency (20 hours) of cultured compared to noncultured umbilical cord blood (UCB)-derived human hematopoietic cells in the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse, and to explain the difference in homing between these populations.Methods. Human UCB CD34+ cells were cultured for up to 5 days, reselected, and used for transplantation, phenotype analysis, and functional studies, including adhesion and trans-endothelial migration assays. Seeding of CD34+ cells was measured after labeling of cells with 111-Indium, while homing of colony-forming cells (CFC) and SCID-repopulating (SRC) cells was determined using functional assays.Results. Short-term culture was associated with a decrease in the 20-hour homing of CD34+ cells, CFC, and SRC to the BM. Although cultured compared to noncultured cells showed increased expression and function (adhesion/migration) of several cell adhesion molecules described to play a role in homing and engraftment, culture also induced expression of Fas/CD95 and rendered cells more susceptible to apoptosis. Finally, we demonstrate that the level of Fas/CD95 on cultured cells was inversely related to the ability of CFC to home to the BM, and that the homing of cultured CFC could be restored by incubating cells prior to transplantation with Fas/CD95-blocking mAb ZB4.Conclusion. These data implicate Fas/CD95 in the homing defect of cultured human hematopoietic cells in the NOD/SCID transplant model and suggest that prevention of apoptosis may be an important strategy to improve engraftment of ex vivo–manipulated HSC in a clinical setting. [Copyright &y& Elsevier]

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novelmutations were identified, including missensemutations within important functional domains and start-loss and splicingmutations predicted to result in truncated proteins.We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inheritedand acquiredmutations in thisgene being identified, further studyof howDDX41 disruption leads to hematologicmalignancies is critical. [ABSTRACT FROM AUTHOR]

Abstract: An allogeneic hematopoietic cell transplantation from an HLA-identical donor after high-dose (myeloablative) pretransplantation conditioning is an effective therapy for some people with chronic lymphocytic leukemia (CLL). Because CLL is a highly radiosensitive cancer, we hypothesized that total body irradiation (TBI) conditioning regimens may be associated with better outcomes than those without TBI. To answer this, we analyzed data from 180 subjects with CLL receiving myeloablative doses of TBI (n = 126) or not (n = 54), who received transplants from an HLA-identical sibling donor between 1995 and 2007 and reported to the Center for International Blood & Marrow Transplant Research. At 5 years, treatment-related mortality was 48% (95% confidence interval [CI], 39% to 57%) versus 50% (95% CI, 36% to 64%); P = NS. Relapse rates were 17% (95% CI, 11% to 25%) versus 22% (95% CI, 11% to 35%); P = NS. Five-year progression-free survival and overall survival were 34% (95% CI, 26% to 43%) versus 28% (95% CI, 15% to 42%); P = NS and 42% (95% CI, 33% to 51%) versus 33% (95% CI, 19% to 48%); P = NS, respectively. The single most common cause of death in both cohorts was recurrent/progressive CLL. No variable tested in the multivariate analysis was found to significantly affect these outcomes, including having failed fludarabine. Within the limitations of this study, we found no difference in HLA-identical sibling transplantation outcomes between myeloablative TBI and chemotherapy pretransplantation conditioning in persons with CLL. [Copyright &y& Elsevier]

Abstract: Krüppel-like factor 5 (KLF5) has been implicated as a tumor suppressor in various solid tumors such as breast and prostate, and recent studies have demonstrated a role for this protein in neutrophil differentiation of acute promyelocytic leukemia cells in response to ATRA. Here, we show that KLF5 expression increases during primary granulocyte differentiation and that expression of KLF5 is a requirement for granulocyte differentiation of 32D cells. In AML, we show that KLF5 mRNA expression levels are reduced in multiple French–American–British subtypes compared to normal controls, and also in leukemic stem cells relative to normal hematopoietic stem cells. We demonstrate that in selected AML cases, reduced expression is associated with hypermethylation of the KLF5 locus in the proximal promoter and/or intron 1, suggesting that this may represent a Class II genetic lesion in the development of AML. [Copyright &y& Elsevier]