Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.

Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST

New Crayfish Species Records from the Sipsey Fork Drainage, Including Lewis Smith Reservoir (Alabama, USA): Native or Introduced Species?

As part of a study of aquatic faunal community changes along riverine-lacustrine transition zones upstream of Lewis Smith Reservoir in northwest Alabama, USA, we collected crayfish from 60 sites in the Sipsey Fork, Brushy Creek, and selected tributaries (Black Warrior River system). After finding two unexpected and possibly-introduced crayfish species, we expanded our investigation of crayfish distributions to include crayfish obtained from stomachs of black bass ( Micropterus spp.) caught at seven sites in the reservoir. To explore what crayfish species were in the drainage historically, we examined museum databases as well as stomach and intestinal contents of a variety of preserved fishes that were caught in the Sipsey Fork and Brushy Creek drainages upstream of the reservoir in the early 1990’s. Of the seven crayfish species collected, one, Orconectes ( Procericambarus ) sp. nr ronaldi , was not previously reported from Alabama, and another, O. lancifer , was not reported from the Black Warrior River system prior to the study. Three are known or possibly introduced species. Upstream of the reservoir, the native species Cambarus obstipus, C. striatus , and O. validus were common. The same three species were found in fish collected in the 1990’s. Orconectes perfectus was found only in the reservoir but may be native to the drainage. Orconectes lancifer was in the reservoir and in stream reaches influenced by the reservoir. Evidence points to O. lancifer being introduced in the drainage, but this is uncertain. Orconectes sp. nr ronaldi was found in a relatively small portion of Brushy Creek and its tributaries, in both flowing and impounded habitats, and may be introduced. Orconectes virilis is introduced in Alabama and was found only in stomachs of fish collected in the reservoir

Comprehensive Record of Volcanic Eruptions in the Holocene (11,000 years) From the WAIS Divide, Antarctica Ice Core

A comprehensive record (WHV2020) of explosive volcanic eruptions in the last 11,000 years is reconstructed from the West Antarctica Ice Sheet Divide deep ice core (WDC). The chronological list of 426 large volcanic eruptions in the Southern Hemisphere and the low latitudes during the Holocene are of the highest quality of all volcanic records from ice cores, owing to the high-resolution chemical measurement of the ice core and the exceptionally accurate WDC timescale. No apparent trend is found in the frequency (number of eruptions per millennium) of volcanic eruptions, and the number of eruptions in the most recent millennium (1,000–2,000 CE) is only slightly higher than the average in the last 11 millennia. The atmospheric aerosol mass loading of climate-impacting sulfur, estimated from measured volcanic sulfate deposition, is dominated by explosive eruptions with extraordinarily high sulfur mass loading. Signals of three major volcanic eruptions are detected in the second half of the 17th century (1700–1600) BCE when the Thera volcano in the eastern Mediterranean was suspected to have erupted; the fact that these signals are synchronous with three volcanic eruptions detected in Greenland ice cores suggests that these are likely eruptions in the low latitudes and none should be attributed exclusively to Thera. A number of eruptions with very high sulfur mass loading took place shortly before and during an early Holocene climatic episode, the so-called 8.2 ka event, and are speculated to have contributed to the initiation and magnitude of the cold event

Perception versus reality: A National Cohort Analysis of the surgery-first approach for resectable pancreatic cancer

INTRODUCTION: Although surgical resection is necessary, it is not sufficient for long-term survival in pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate survival after up-front surgery (UFS) in anatomically resectable PDAC in the context of three critical factors: (A) margin status; (B) CA19-9; and (C) receipt of adjuvant chemotherapy. METHODS: The National Cancer Data Base (2010-2015) was reviewed for clinically resectable (stage 0/I/II) PDAC patients. Surgical margins, pre-operative CA19-9, and receipt of adjuvant chemotherapy were evaluated. Patient overall survival was stratified based on these factors and their respective combinations. Outcomes after UFS were compared to equivalently staged patients after neoadjuvant chemotherapy on an intention-to-treat (ITT) basis. RESULTS: Twelve thousand and eighty-nine patients were included (n = 9197 UFS, n = 2892 ITT neoadjuvant). In the UFS cohort, only 20.4% had all three factors (median OS = 31.2 months). Nearly 1/3rd (32.7%) of UFS patients had none or only one factor with concomitant worst survival (median OS = 14.7 months). Survival after UFS decreased with each failing factor (two factors: 23 months, one factor: 15.5 months, no factors: 7.9 months) and this persisted after adjustment. Overall survival was superior in the ITT-neoadjuvant cohort (27.9 vs. 22 months) to UFS. CONCLUSION: Despite the perceived benefit of UFS, only 1-in-5 UFS patients actually realize maximal survival when known factors highly associated with outcomes are assessed. Patients are proportionally more likely to do worst, rather than best after UFS treatment. Similarly staged patients undergoing ITT-neoadjuvant therapy achieve survival superior to the majority of UFS patients. Patients and providers should be aware of the false perception of \u27optimal\u27 survival benefit with UFS in anatomically resectable PDAC

Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways

Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes

Compaction of Hyaloclastite from the Active Geothermal System at Krafla Volcano, Iceland

Hyaloclastites commonly form high-quality reservoir rocks in volcanic geothermal provinces. Here, we investigated the effects of confinement due to burial following prolonged accumulation of eruptive products on the physical and mechanical evolution of surficial and subsurface (depths of 70 m, 556 m, and 732 m) hyaloclastites from Krafla volcano, Iceland. Upon loading in a hydrostatic cell, the porosity and permeability of the surficial hyaloclastite decreased linearly with mean effective stress, as pores and cracks closed due to elastic (recoverable) compaction up to 22-24 MPa (equivalent to ~1.3 km depth in the reservoir). Beyond this mean effective stress, denoted as P∗, we observed accelerated porosity and permeability reduction with increasing confinement, as the rock underwent permanent inelastic compaction. In comparison, the porosity and permeability of the subsurface core samples were less sensitive to mean effective stress, decreasing linearly with increasing confinement as the samples compacted elastically within the conditions tested (to 40 MPa). Although the surficial material underwent permanent, destructive compaction, it maintained higher porosity and permeability than the subsurface hyaloclastites throughout the experiments. We constrained the evolution of yield curves of the hyaloclastites, subjected to different effective mean stresses in a triaxial press. Surficial hyaloclastites underwent a brittle-ductile transition at an effective mean stress of ~10.5 MPa, and peak strength (differential stress) reached 13 MPa. When loaded to effective mean stresses of 33 and 40 MPa, the rocks compacted, producing new yield curves with a brittle-ductile transition at ~12.5 and ~19 MPa, respectively, but showed limited strength increase. In comparison, the subsurface samples were found to be much stronger, displaying higher strengths and brittle-ductile transitions at higher effective mean stresses (i.e., 37.5 MPa for 70 m sample, >75 MPa for 556 m, and 68.5 MPa for 732 m) that correspond to their lower porosities and permeabilities. Thus, we conclude that compaction upon burial alone is insufficient to explain the physical and mechanical properties of the subsurface hyaloclastites present in the reservoir at Krafla volcano. Mineralogical alteration, quantified using SEM-EDS, is invoked to explain the further reduction of porosity and increase in strength of the hyaloclastite in the active geothermal system at Krafla

A possible role for Phlebotomus (Anaphlebotomus) rodhaini (Parrot, 1930) in transmission of Leishmania donovani

<p>Abstract</p> <p>Background</p> <p>Visceral leishmaniasis (VL, kala azar), caused by <it>Leishmania donovani </it>is a major health problem in Sudan and other East African countries. In this region the only proven vectors of <it>L. donovani </it>are <it>Phlebotomus orientalis </it>in eastern Sudan, Ethiopia and Upper Nile areas of Southern Sudan and <it>Phlebotomus martini </it>in Ethiopia, Kenya and Southern Sudan. In this report, we present the first evidence that <it>Phlebotomus rodhaini </it>may also play a role in maintaining transmission of <it>L. donovani </it>between animal reservoir hosts in eastern Sudan. The study was conducted in a zoonotic focus of visceral leishmaniasis in Dinder National Park, eastern Sudan, where previous work showed high infection rates of <it>L. donovani </it>in <it>P. orientalis</it>. Sand flies, captured by CDC traps were dissected and examined for infection with <it>Leishmania </it>parasites. Parasite isolates were subjected to <it>L. donovani </it>specific PCR. Field experiments were also carried out to compare efficiency of rodent baited and un-baited CDC traps in collection of <it>P. rodhaini </it>and determine its man-biting rate.</p> <p>Results</p> <p>Three female <it>P. rodhain</it>i were found infected with <it>Leishmania </it>parasites in an astonishingly small number of flies captured in three separate field trips. Two of these isolates were typed by molecular methods as <it>L. donovani</it>, while the third isolate was inoculated into a hamster that was subsequently lost. Although <it>P. rodhaini is </it>generally considered a rare species, results obtained in this study indicate that it can readily be captured by rodent-baited traps. Results of human landing collection showed that it rarely bites humans in the area.</p> <p>Conclusion</p> <p>It is concluded that <it>P. rodhaini </it>is a possible vector of <it>L. donovani </it>between animal reservoir hosts but is not responsible for infecting humans. It is suggested that the role of <it>P</it>. <it>rodhaini </it>in transmission of <it>L. donovani </it>in other zoonotic foci of visceral leishmaniasis in Africa should be re-examined.</p

A Systematic Review of How Multiple Stressors from an Extreme Event Drove Ecosystem-Wide Loss of Resilience in an Iconic Seagrass Community

A central question in contemporary ecology is how climate change will alter ecosystem structure and function across scales of space and time. Climate change has been shown to alter ecological patterns from individuals to ecosystems, often with negative implications for ecosystem functions and services. Furthermore, as climate change fuels more frequent and severe extreme climate events (ECEs) like marine heatwaves (MHWs), such acute events become increasingly important drivers of rapid ecosystem change. However, our understanding of ECE impacts is hampered by limited collection of broad scale in situ data where such events occur. In 2011, a MHW known as the Ningaloo Niño bathed the west coast of Australia in waters up to 4°C warmer than normal summer temperatures for almost 2 months over 1000s of kilometres of coastline. We revisit published and unpublished data on the effects of the Ningaloo Niño in the seagrass ecosystem of Shark Bay, Western Australia (24.6 – 26.6o S), at the transition zone between temperate and tropical seagrasses. Therein we focus on resilience, including resistance to and recovery from disturbance across local, regional and ecosystem-wide spatial scales and over the past 8 yearsThermal effects on temperate seagrass health were severe and exacerbated by simultaneous reduced light conditions associated with sediment inputs from record floods in the south-eastern embayment and from increased detrital loads and sediment destabilisation. Initial extensive defoliation of Amphibolis antarctica, the dominant seagrass, was followed by rhizome death that occurred in 60-80% of the bay’s meadows, equating to decline of over 1000 km2 of meadows. This loss, driven by direct abiotic forcing, has persisted, while indirect biotic effects (e.g. dominant seagrass loss) have allowed colonisation of some areas by small fast-growing tropical species (e.g. Halodule uninervis). Those biotic effects also impacted multiple consumer populations including turtles and dugongs, with implications for species dynamics, food web structure, and ecosystem recovery. We show multiple stressors can combine to evoke extreme ecological responses by pushing ecosystems beyond their tolerance. Finally, both direct abiotic and indirect biotic effects need to be explicitly considered when attempting to understand and predict how ECEs will alter marine ecosystem dynamics