Mass Movements of Warrumbungle National Park, New South Wales, Australia

The Warrumbungle Range is the mountainous eroded remnant of an Early Miocene shield volcanic complex located in the central west of New South Wales. A high-severity wildfire in Warrumbungle National Park in January 2013 was followed by intense rain, causing a number of debris flows. Several flows impacted on infrastructure such as roads and culverts and posed a severe risk to public safety, prompting a broader assessment of mass movement hazard within the park. High resolution LiDAR DEM revealed 542 locations with evidence of mass movement processes that pre-date the fire. The most common types of mass movement visible in the DEM are rotational slumps (353, 65%). The distribution of these indicated stratigraphic control, with 50% of slumps within 440 m of the volcanics-sandstone geologic contact, and typically occurring within unconsolidated volcanic colluvium and/or in situ deeply weathered volcanics. Debris flows are the next most common mass movement type after rotational slumps. Debris flow scour channels generally occurred on colluvial slopes in more elevated sites, within the volcanic rocks. DEM-extracted morphometric data was used to identify areas of debris flow hazard in WNP. Several large mass movements are morphometrically different, with some evidence for formation under different hydro-climatic conditions. A simple conceptual model of how mass movements contribute to the evolution of the Warrumbungle Range is proposed involving groundwater, deep weathering, slope retreat by mass failure, colluvial deposition and periodic incision by debris flows

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Forest Structure Drives Fuel Moisture Response across Alternative Forest States

Climate warming is expected to increase fire frequency in many productive obligate seeder forests, where repeated high-intensity fire can initiate stand conversion to alternative states with contrasting structure. These vegetation–fire interactions may modify the direct effects of climate warming on the microclimatic conditions that control dead fuel moisture content (FMC), which regulates fire activity in these high-productivity systems. However, despite the well-established role of forest canopies in buffering microclimate, the interaction of FMC, alternative forest states and their role in vegetation–fire feedbacks remain poorly understood. We tested the hypothesis that FMC dynamics across alternative states would vary to an extent meaningful for fire and that FMC differences would be attributable to forest structural variability, with important implications for fire-vegetation feedbacks. FMC was monitored at seven alternative state forested sites that were similar in all aspects except forest type and structure, and two proximate open-weather stations across the Central Highlands in Victoria, Australia. We developed two generalised additive mixed models (GAMMs) using daily independent and autoregressive (i.e., lagged) input data to test the importance of site properties, including lidar-derived forest structure, in predicting FMC from open weather. There were distinct differences in fuel availability (days when FMC < 16%, dry enough to sustain fire) leading to positive and negative fire–vegetation feedbacks across alternative forest states. Both the independent (r2 = 0.551) and autoregressive (r2 = 0.936) models ably predicted FMC from open weather. However, substantial improvement between models when lagged inputs were included demonstrates nonindependence of the automated fuel sticks at the daily level and that understanding the effects of temporal buffering in wet forests is critical to estimating FMC. We observed significant random effects (an analogue for forest structure effects) in both models (p < 0.001), which correlated with forest density metrics such as light penetration index (LPI). This study demonstrates the importance of forest structure in estimating FMC and that across alternative forest states, differences in fuel availability drive vegetation–fire feedbacks with important implications for forest flammability

Comparing Glioblastoma Surgery Decisions Between Teams Using Brain Maps of Tumor Locations, Biopsies, and Resections

PURPOSE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity, which depends on the location within the brain. A standard to compare these decisions is lacking. We present a volumetric voxel-wise method for direct comparison between two multidisciplinary teams of glioblastoma surgery decisions throughout the brain. METHODS: Adults undergoing first-time glioblastoma surgery from 2012 to 2013 performed by two neuro-oncologic teams were included. Patients had had a diagnostic biopsy or resection. Preoperative tumors and postoperative residues were segmented on magnetic resonance imaging in three dimensions and registered to standard brain space. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to compare patient referral bias, indication variation, and treatment variation. To evaluate the quality of care, subgroups of differentially resected brain regions were analyzed for survival and functional outcome. RESULTS: One team included 101 patients, and the other included 174; 91 tumors were biopsied, and 181 were resected. Patient characteristics were largely comparable between teams. Distributions of tumor locations were dissimilar, suggesting referral bias. Distributions of biopsies were similar, suggesting absence of indication variation. Differentially resected regions were identified in the anterior limb of the right internal capsule and the right caudate nucleus, indicating treatment variation. Patients with (n = 12) and without (n = 6) surgical removal in these regions had similar overall survival and similar permanent neurologic deficits. CONCLUSION: Probability maps of tumor location, biopsy, and resection provide additional information that can inform surgical decision making across multidisciplinary teams for patients with glioblastoma

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor

Background: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. Methods: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-To-referral, time-To-Treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. Results: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P =. 002). Time-To-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P <. 001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P =. 040). Costs and time investment were comparable for both groups. Conclusion: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-Tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology

Human voltage-gated Na⁺ and K⁺ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons.</p