Spectral characteristics and the extent of paleosols of the Palouse formation

Three spectral models defining the spatial distribution of soil areas by levels of amorphous iron, organic carbon, and the ratio of amorphous iron to organic carbon were developed and field verification studies were conducted. The models used particular Thematic Mapper band ratios selected by statistical correlation with soil chemical data. The ability of the models to indicate erosion severity and to differentiate between iron enriched and carbonate paleosols is discussed. In addition, the effect of vegetation cover on paleosols is addressed

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

Background There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Methods We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Results Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. Conclusions Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition

Geology and Wine 3. Terroirs of the Walla Walla Valley appellation, southeastern Washington State, USA

Terroir of the Walla Walla Valley appellation of Washington State is influenced by 1) the rain shadow effect and volcanic tephra of the Cascade Mouncain Range, 2) soils derived from Quaternary glacial sediments and wind-blown loess overlying Miocene basalt, and 3) a warm, dry climate with abundant sunshine and cool nights due to high latitude (45-48°N) and elevation. Wine flavours of Walla Walla Valley varietals (including Cabernet Sauvignon, Chardonnay, Merlot, and Syrah) appear to be influenced by low humidity, long growing season (1500-1800°C degree days), soil type and drainage, drip irrigation, pruning to restrict vine vigour, trellising methods, and overall topographic climatic setting of the vineyards. Microclimates within the Walla Walla Valley appellation, combined with variations in soil and bedrock stratigraphy, yield a range of wine styles as great as many larger regions and some countries. Résumé Le terroir de la vallée de Walla Walla d'appellation de l'État de Washington est caractérisé par 1) l'effet parapluie de la topographie locale et la nature téphritiquedes dépôts de la chaîne des monts Cascade, 2) les sols issus de dépôts glaciaires et de loess éoliens recouvrant un basalte Miocène, et 3) un climat chaud et sec très ensoleillé, avec les nuits fraîches deshautes latitudes (N45° à N48°) et de l'altitude élevée. Les goûts des vins des variétés de la vallée de Walla Walla (incluant le Cabernet Sauvignon, le Chardonnay, le Merlot, et le Syrah) semblent dépendre de la faible humidité de la région, sa saison végétative longue (1 500°C à 1 800°C degrés-jours), de la nature de son sol et de son drainage, d'une irrigation goutte à goutte, de la taille de la vigne pour en restreindre la vigueur végétative, des méthodes de treillages et, des conditions topographiques et climatiques générales où baignent ces vignobles. L'effet combiné des microclimats de la région d'appellation de la vallée de Walla Walla avec les variétés de ses sols et de la stratigraphie du substratum rocheux régional permet la production de styles de vin aussi prestigieux que bien des régions reconnues et même de certains pays

Geology and Wine 6. Terroir of the Red Mountain Appellation, Central Washington State, U.S.A.

Red Mountain is the newest of five appellations in Washington State and like the majority of Washington vineyards its terroir is influenced by 1) the rain shadow effect and volcanic tephra of the Cascade Mountain Range, 2) soils derived from Quaternary glacial sediments and wind-blown loess overlying Miocene basalt, and 3) a warm, dry climate with abundant sunshine and cool nights due to high latitude (N 46e) and topography. Variations of rooting depth, textures, calcium carbonate content, and other properties of vineyard soils are directly influenced by Quaternary glacial flood deposits in the back-eddy of Red Mountain and by the variable nature of the loess and dune cover on the flood deposits. This is the first demonstration of the effect of paleohydrology on vineyard site characteristics. In the past two years, wines made from Red Mountain grapes have received nine scores of > 94 out of 100 in independent blind tastings and merlot wine made from Red Mountain grapes has been ranked as the best in the United States for each of the past two years by two different national wine magazines. Red Mountain is one of the warmest and driest viticultural sites in Washington State, having heat summation (growing degree days) and total sunshine similar to Napa Valley, California which is 1000 km farther south. Other wine regions that have been influenced by the worldwide glacial processes that were so important in the development of Washington vineyards include the gravel mounds that underlie most of the first growth vineyards of Graves-Médoc, Bordeaux, France and some of the outwash gravel plains of New Zealand. Résumé L'appellation Red Mountain est la plus récente des cinq appellations de l'État de Washington et, comme c'est le cas pour la plupart des vignobles de l'État de Washington, son terroir dépend 1) de l'effet parapluie de la chaîne des monts Cascade et de ses cendres volcaniques, 2) des sols dérivés des sédiments glaciaires quaternaires et des loess éoliens recouvrant le basalte miocène et, 3) d'un climat chaud et sec avec un fort ensoleillement, avec des nuits fraîches dues à la latitude (N 46°) et à la topographie. Les variations de la profondeur d'enracinement, de texture, de contenu en carbonate de calcium et d'autres propriétés pédologiques des vignobles varient selon le patron de dépôt des alluvions glaciaires quaternaires par écoulement tourbillonnaire de Red Mountain et de la variation de composition du loess et de la couverture des dunes des dépôts alluvionnaires. Cela constitue la première démonstration des effets paléohydrologiques sur les propriétés des sites vinicoles. Au cours des deux dernières années, les vins des raisins de Red Mountain ont reçu neuf cotes de plus de 94% lors de dégustation anonyme, et les vins merlots provenant de raisins de Red Mountain ont été jugés les meilleurs aux USA pour chacune des deux dernières années, par deux revues spécialisées d'envergure nationale. La région de Red Mountain constitue l'un des sites viticoles les plus chauds et les plus secs de l'État de Washington, possédant un bilan thermique (degré-jour de croissance) et un ensoleillement comparable à ceux de la valléede Napa en Californie, laquelle est située à 1 000 km plus au sud. Parmi d'autres régions ayant subi l'influence de processus glaciairemondiaux et qui se sont avérés si déterminant dans le développement des vignobles de l'État de Washington, on retrouve celle des collines graveleuses constituant le lieux de croissance de la plupart des vignobles de première génération de Graves-Médoc de la région de Bordeaux en France, et d'autres sur des plaines d'alluvions en Nouvelle-Zélande

BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms

This dataset includes the text, figures and supplementary material associated with the Oncogene submission MS#ONC-2022-0172

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM