The mosaicking of global planetary data sets allows for the examination of local, regional, and global scale processes on all planetary bodies. Processing techniques that allow us and other users to ...crate mosaics of tens of thousands of images are documented along with the associated errors introduced by each image‐processing algorithm. These techniques (e.g., non‐uniformity correction, running contrast stretches, line and row correlated noise removal, and random noise removal) were originally developed for the 2001 Mars Odyssey Thermal Emission Imaging System (THEMIS) infrared multispectral imager data but can be adapted and applied to other data sets by the alteration of input parameters. The techniques for mosaicking planetary image data sets (e.g., image registration, blending, and normalization) are also presented along with the generation of qualitative and quantitative products. These techniques are then applied to generate THEMIS daytime and nighttime infrared, Viking, Context Imager (CTX), and Mars Orbiter Camera (MOC) visible mosaics using a variety of input and output types at a variety of scales. By creating mosaics of the same area using different data sets such as those that illustrate compositional diversity, thermophysical properties, or small‐scale morphology, it is possible to view the surface of the planet and geologic problems through many different perspectives. In addition to the techniques used to create large‐scale seamless mosaics, we also present the THEMIS daytime and nighttime relative temperature global mosaics, which are the highest resolution (100m/pixel) global scale data sets available for Mars to date.
Abstract
BACKGROUND
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has radio and chemosensitizing effects in preclinical models and penetrates GBM in patients at radiosensitizing ...concentrations. PARP inhibitors sensitize proliferating cells to temozolomide (TMZ) but exacerbate haematological toxicity. Patients with MGMT unmethylated tumours do not benefit from TMZ so it can be withheld, enabling continuous olaparib dosing with radiotherapy (RT). Patients with MGMT methylated tumours benefit from TMZ so olaparib must be combined with chemoradiation (CRT) in an intermittent, low-dose manner. PARADIGM-2 is a clinical trial comprising two parallel phase I studies of olaparib/RT or olaparib/RT/TMZ in newly diagnosed GBM patients stratified by MGMT status.
MATERIAL AND METHODS
GBM patients aged <70 with WHO performance status 0-1 were eligible. Tumour tissue underwent central pyrosequencing testing for MGMT promoter methylation. MGMT unmethylated patients received daily oral olaparib throughout RT (60 Gray in 30#) and for four weeks afterwards. MGMT methylated patients received intermittent olaparib during CRT (60 Gray plus TMZ 75mg/m2 daily) and for four weeks after. In both arms, olaparib dose was escalated in a 3 + 3 cohort design. ISRCTN 51253312.
RESULTS
By January 2023, 24 MGMT methylated patients and 43 MGMT unmethylated patients had been recruited. Dose escalation in MGMT unmethylated patients was completed with no dose-limiting toxicities and the recommended phase II dose (RP2D) of olaparib was established at 300 mg twice daily (the full single agent dose). Maximum tolerated dose was not reached. The RP2D cohort was expanded to 30 patients of whom one was excluded because the diagnosis was revised to anaplastic oligodendroglioma. Median overall survival (OS) of the 42 eligible patients was 14.1 months (80% confidence intervals (CI) 12.2 - 15.9), with 12- and 24-month OS estimates of 64.3% (54.0-72.9) and 16.7% (10.1-24.7) respectively. In the dose expansion cohort, 6 of 29 patients are alive with median follow-up time of 22.9 months. Median OS is 14.2 months (12.2-16.9); 12- and 24-month OS estimates are 69.0% (56.5-78.5) and 24.1% (14.8-34.8) respectively. Updated survival data will be presented at the conference. Dose escalation in MGMT methylated patients continues with the current cohort receiving olaparib 150 mg daily 4 days per week.
CONCLUSION
Pre-treatment stratification by MGMT status in a phase I study in GBM is feasible and enables optimisation of olaparib dosing and scheduling with RT and TMZ. In MGMT unmethylated patients, olaparib can be combined with RT at the full single agent dose (300 mg twice daily) if TMZ is withheld. Of 29 patients receiving this dose, a quarter have survived more than 2 years. In MGMT methylated patients, olaparib can be safely combined with radical CRT when given at lower doses on an intermittent basis (currently 150 mg four days per week).
PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using ...proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.
The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an ...atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.
This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types. We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific.
In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.
Background
Dermatophytosis is a world‐wide distributed common infection. Antifungal drug resistance in dermatophytosis used to be rare, but unfortunately the current Indian epidemic of atypical ...widespread recalcitrant and terbinafine‐resistant dermatophytosis is spreading and has sporadically been reported in Europe.
Objectives
To explore the occurrence of clinical and mycological proven antifungal drug resistance in dermatophytes in Europe.
Methods
A standardized questionnaire was distributed through the EADV Task Force of Mycology network to dermatologists in Europe.
Results
Representatives from 20 countries completed the questionnaires of which 17 (85 %) had observed clinical and/or mycological confirmed antifungal resistance, two countries published cases of antifungal resistance and one country had no known cases.
Conclusions
This pilot study confirms that both clinical and mycological antifungal resistance exist in Europe.
To sustain tumor growth, cancer cells must be able to adapt to fluctuations in energy availability. We have identified a single microRNA that controls glioma cell proliferation, migration, and ...responsiveness to glucose deprivation. Abundant glucose allows relatively high miR-451 expression, promoting cell growth. In low glucose, miR-451 levels decrease, slowing proliferation but enhancing migration and survival. This allows cells to survive metabolic stress and seek out favorable growth conditions. In glioblastoma patients, elevated miR-451 is associated with shorter survival. The effects of miR-451 are mediated by LKB1, which it represses through targeting its binding partner, CAB39 (MO25α). Overexpression of miR-451 sensitized cells to glucose deprivation, suggesting that its downregulation is necessary for robust activation of LKB1 in response to metabolic stress. Thus, miR-451 is a regulator of the LKB1/AMPK pathway, and this may represent a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability.
► miR-451 regulates glioma cell proliferation, migration, and response to low glucose ► In low glucose, reduced miR-451 levels slow growth but enhance migration/survival ► In glioblastoma patients, elevated miR-451 is associated with shorter survival ► miR-451 directly targets CAB39, reducing LKB1 and AMPK signaling
Extracellular vesicles have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly ...understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma that identifies miR-1 as an orchestrator of extracellular vesicle function and glioblastoma growth and invasion. Ectopic expression of miR-1 in glioblastoma cells blocked in vivo growth, neovascularization, and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by extracellular vesicles released by cancer stem-like glioblastoma cells. An extracellular vesicle-dependent phenotype defined by glioblastoma invasion, neurosphere growth, and endothelial tube formation was mitigated by loading miR-1 into glioblastoma-derived extracellular vesicles. Protein cargo in extracellular vesicles was characterized to learn how miR-1 directed extracellular vesicle function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in glioblastoma-derived extracellular vesicles, was found to be a direct target of miR-1 control. In addition, extracellular vesicle-derived miR-1 along with other ANXA2 extracellular vesicle networking partners targeted multiple pro-oncogenic signals in cells within the glioblastoma microenvironment. Together, our results showed how extracellular vesicle signaling promotes the malignant character of glioblastoma and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for glioblastoma management.
Climate model projections have previously been used to compute ice shelf basal melt rates in ice sheet models, but the strategies employed – e.g., ocean input, parameterization, calibration ...technique, and corrections – have varied widely and are often ad hoc. Here, a methodology is proposed for the calculation of circum-Antarctic basal melt rates for floating ice, based on climate models, that is suitable for ISMIP6, the Ice Sheet Model Intercomparison Project for CMIP6 (6th Coupled Model Intercomparison Project). The past and future evolution of ocean temperature and salinity is derived from a climate model by estimating anomalies with respect to the modern day, which are added to a present-day climatology constructed from existing observational datasets. Temperature and salinity are extrapolated to any position potentially occupied by a simulated ice shelf. A simple formulation is proposed for a basal melt parameterization in ISMIP6, constrained by the observed temperature climatology, with a quadratic dependency on either the nonlocal or local thermal forcing. Two calibration methods are proposed: (1) based on the mean Antarctic melt rate (MeanAnt) and (2) based on melt rates near Pine Island's deep grounding line (PIGL). Future Antarctic mean melt rates are an order of magnitude greater in PIGL than in MeanAnt. The PIGL calibration and the local parameterization result in more realistic melt rates near grounding lines. PIGL is also more consistent with observations of interannual melt rate variability underneath Pine Island and Dotson ice shelves. This work stresses the need for more physics and less calibration in the parameterizations and for more observations of hydrographic properties and melt rates at interannual and decadal timescales.
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