In the second half of the 20sup.th Century there was a growing awareness of environmental problems, including the loss of species and habitats, resulting in many national and international ...initiatives, including the creation of organisations, such as the IUCN, treaties and conventions, such as Ramsar and the Berne Convention, and the establishment of networks of protected areas. Natura 2000 is a network of sites in the European Union for selected species and habitats listed in the 1979 Birds Directive and the 1992 Habitats Directive. Under the Habitats Directive a series of seminars and other meetings have been held with agreed criteria to ensure a coherent network. Despite both scientific and political difficulties the network is now nearing completion. Keywords: Natura 2000, Birds Directive, Habitats Directive, Biogeographical seminars
Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been ...broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer.
We employed organoid culture methods and flow cytometric, cytologic, immunofluorescent and immunohistochemical methods to develop and characterize patient-derived pancreatic cancer organoids and multi-cell type organotypic co-culture models of the tumor microenvironment.
We describe the culture and characterization of human pancreatic cancer organoids from resection, ascites and rapid autopsy sources and the derivation of adherent tumor cell monocultures and tumor-associated fibroblasts from these sources. Primary human organoids displayed tumor-like cellular morphology, tissue architecture and polarity in contrast to cell line spheroids, which formed homogenous, non-lumen forming spheres. Importantly, we demonstrate the construction of complex organotypic models of tumor, stromal and immune components of the tumor microenvironment. Activation of myofibroblast-like cancer associated fibroblasts and tumor-dependent lymphocyte infiltration were observed in these models.
These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors in the context of T-cell infiltration.
Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit ...properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends.
We have isolated populations of cells with high ALDH activity (ALDH(high)) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH(high) and ALDH(low) cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice.
We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH(low) cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.
The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association.
The Task Force ...identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document.
The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC.
The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.
IMPORTANCE: It is estimated that pancreatic cancer (PC) will become the second leading cause of cancer-related death in the United States by 2030. OBSERVATIONS: Clinical and preclinical data support ...the understanding that PC metastases occur early in the pathogenesis of this disease, even before the primary tumor can be detected. This has important implications for the clinical management of patients with localized PC, as surgery alone is unlikely to be curative for most patients. The delivery of postoperative adjuvant therapy is problematic in this disease because of the magnitude of the operation needed to remove the primary tumor, which can affect patient recovery and delay (sometimes indefinitely) the delivery of systemic therapy. For these reasons, the use of chemotherapy and/or chemoradiation prior to surgery (neoadjuvant therapy) is increasingly recognized as the preferred strategy for treatment sequencing. Neoadjuvant therapy is recommended for patients with borderline resectable PC and, at some centers, neoadjuvant therapy has been extended to patients with resectable PC as well. Importantly, therapeutic advances in multidrug systemic therapy and radiation therapy have already been adopted in the neoadjuvant setting where treatment toxicity will not be compounded by surgical recovery. In addition, the use of local-regional therapies in highly selected patients with locally advanced PC, following a prolonged period of induction systemic therapy, will be an area of intense scrutiny. Future improvements in diagnostic biomarkers may allow for real-time sequencing of multimodality therapy for individual patients based on a more accurate and timely assessment of treatment response. CONCLUSIONS AND RELEVANCE: Neoadjuvant treatment sequencing allows patients to receive multimodality therapy in a manner that prioritizes early exposure to systemic therapy to maximize the treatment of micrometastatic disease in an immune-competent host prior to surgical intervention. Patients who complete all intended neoadjuvant therapy, including surgery, experience an overall survival benefit that is unmatched by a surgery-first approach.
Rare earth element (REE) concentrations and patterns were measured in surface water, suspended particles (SP) and oysters from the Pearl River Estuary, China. During the rainy season of 2017, higher ...REE concentrations were found at the stations in the estuary (ΣREE = 0.06–0.42 μg L−1) than those at the river mouths (referred to as ‘outlet’ stations, ΣREE = 0.001–0.14 μg L−1). However, the reverse occurred in the dry season of 2016 (ΣREE = 0.07–0.16 μg L−1 in the mid-estuary vs. 0.001–0.02 μg L−1in the outlet stations). Elevated concentrations of Pr, Nd, Dy and Ho, relative to the other REEs were found in water in both seasons at most sampling locations. However, in some estuary stations, no anomalies were detected in the SP or in the oysters while some anomalies were seen in SP from the outlet stations. Significant correlations between REE concentrations in SP and oysters as well as between both total REE concentrations and the La/Yb ratio (reflecting enhanced accumulation of light REEs (LREEs)) in oysters indicate that, in the Pearl River Estuary, the dominant REE uptake pathway in oysters is from particles.
The elevated concentrations of Pr, Nd, Dy and Ho, which are reported here for the first time suggest that elevated levels of these elements may result from REE recycling and other industrialized activities in this area of southern China. Specific REEs could be used to indicate emerging contamination by the modern REE industry; furthermore, REE anomalies and patterns may be suitable tools to track REE sources.
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•Variable REE concentrations in water, particles and oysters in the Pearl River Delta.•Pr, Nd, Dy, Ho anomalies observed in the surface water during dry and rainy seasons.•Specific anomalies of these four REEs could indicate energy-related REE industries.•Particles are shown to be the main pathway of REE exposure to oysters.
Elevated concentrations of Pr, Nd, Dy and Ho, relative to other REEs, were observed for the first time in the surface water of the Pearl River Delta and the REE uptake pathway in oysters was assessed.
Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) ...levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.
Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays.
The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve AUC = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19–9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19–9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19–9 alone).
In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.
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Our exosome-based transcriptomic signature that combines cell-free and exosomal microRNAs has the potential to identify patients with pancreatic ductal adenocarcinoma with high diagnostic accuracy, and offers an important noninvasive assay for early detection of this fatal malignancy.
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