AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells.

Tropical peat composition may provide a negative feedback on fire occurrence and severity.

Loss of peat through increased burning will have major impacts on the global carbon cycle. In a normal hydrological state, the risk of fire propagation is largely controlled by peat bulk density and moisture content. However, where humans have interfered with the moisture status of peat either via drainage, or indirectly via climate change, we hypothesise that its botanical composition will become important to flammability, such that peats from different latitudes might have different compositionally-driven susceptibility to ignition.

Age, sex, and lung volume dependence of dissolved xenon-129 MRI gas exchange metrics.

Purpose: To characterize the dependence of Xe-MRI gas transfer metrics upon age, sex, and lung volume in a group of healthy volunteers.

Methods: Sixty-five subjects with no history of chronic lung disease were assessed with Xe-MRI using a four-echo 3D radial spectroscopic imaging sequence and a dose of xenon titrated according to subject height that was inhaled from a lung volume of functional residual capacity (FRC). Imaging was repeated in 34 subjects at total lung capacity (TLC).

A comparison of free amino nitrogen and yeast-assimilable nitrogen measurement methods for use in alcoholic fermentation of whey.

The continued efficient use of whey as a fermentable substrate to produce alcoholic beverages will benefit from improving the measurement of key components relevant to the fermentability of whey. One component of fermentation that is not well studied in whey is the concentration of fermentable nitrogen, either as free amino nitrogen (FAN) or yeast-assimilable nitrogen (YAN). Fermentable nitrogen in media is essential for yeast cells to replicate.

Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear.

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension.

Background: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media.

PhysVENeT: a physiologically-informed deep learning-based framework for the synthesis of 3D hyperpolarized gas MRI ventilation.

Functional lung imaging modalities such as hyperpolarized gas MRI ventilation enable visualization and quantification of regional lung ventilation; however, these techniques require specialized equipment and exogenous contrast, limiting clinical adoption. Physiologically-informed techniques to map proton (H)-MRI ventilation have been proposed. These approaches have demonstrated moderate correlation with hyperpolarized gas MRI.

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells.

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using H and Xe Lung MRI.

Background: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear.

Research Question: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using H and Xe MRI between 6 and 52 weeks following hospitalization?

Study Design And Methods: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary H and Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022.

A hybrid model- and deep learning-based framework for functional lung image synthesis from multi-inflation CT and hyperpolarized gas MRI.

Background: Hyperpolarized gas MRI is a functional lung imaging modality capable of visualizing regional lung ventilation with exceptional detail within a single breath. However, this modality requires specialized equipment and exogenous contrast, which limits widespread clinical adoption. CT ventilation imaging employs various metrics to model regional ventilation from non-contrast CT scans acquired at multiple inflation levels and has demonstrated moderate spatial correlation with hyperpolarized gas MRI.

Implementable Deep Learning for Multi-sequence Proton MRI Lung Segmentation: A Multi-center, Multi-vendor, and Multi-disease Study.

Background: Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton ( H)-MRI lung segmentation. However, previous deep learning studies have utilized single-center data and limited acquisition parameters.

Purpose: Develop a generalizable CNN for lung segmentation in H-MRI, robust to pathology, acquisition protocol, vendor, and center.

Systematic hydration neutron reflectometry study on Nafion thin films.

Reported herein is a neutron reflectometry (NR) study on hydrated Nafion thin films (∼30 nm) on a silicon substrate with native oxide. The Nafion morphology is investigated systematically across the whole relative humidity range using both HO and DO vapours to enable a comparative study. By utilising this systematic approach two key results have been obtained.

A Dual-Channel Deep Learning Approach for Lung Cavity Estimation From Hyperpolarized Gas and Proton MRI.

Background: Hyperpolarized gas MRI can quantify regional lung ventilation via biomarkers, including the ventilation defect percentage (VDP). VDP is computed from segmentations derived from spatially co-registered functional hyperpolarized gas and structural proton ( H)-MRI. Although acquired at similar lung inflation levels, they are frequently misaligned, requiring a lung cavity estimation (LCE).

Imaging biomarkers of lung ventilation in interstitial lung disease from Xe and oxygen enhanced H MRI.

Purpose: To compare imaging biomarkers from hyperpolarised Xe ventilation MRI and dynamic oxygen-enhanced MRI (OE-MRI) with standard pulmonary function tests (PFT) in interstitial lung disease (ILD) patients. To evaluate if biomarkers can separate ILD subtypes and detect early signs of disease resolution or progression.

Study Type: Prospective longitudinal.

Image Phenotyping of Preterm-Born Children Using Hyperpolarized Xe Lung Magnetic Resonance Imaging and Multiple-Breath Washout.

Preterm birth is associated with low lung function in childhood, but little is known about the lung microstructure in childhood. We assessed the differential associations between the historical diagnosis of bronchopulmonary dysplasia (BPD) and current lung function phenotypes on lung ventilation and microstructure in preterm-born children using hyperpolarized Xe ventilation and diffusion-weighted magnetic resonance imaging (MRI) and multiple-breath washout (MBW). Data were available from 63 children (aged 9-13 yr), including 44 born preterm (⩽34 weeks' gestation) and 19 term-born control subjects (⩾37 weeks' gestation).

Large-scale investigation of deep learning approaches for ventilated lung segmentation using multi-nuclear hyperpolarized gas MRI.

Respiratory diseases are leading causes of mortality and morbidity worldwide. Pulmonary imaging is an essential component of the diagnosis, treatment planning, monitoring, and treatment assessment of respiratory diseases. Insights into numerous pulmonary pathologies can be gleaned from functional lung MRI techniques.

Acute extracorporeal shockwave lithotripsy for ureteric stones - 7-years' experience from a busy district general hospital.

Objectives: To demonstrate the efficacy and cost-effectiveness of acute extracorporeal shockwave lithotripsy (ESWL) for ureteric stones we present our experience of ESWL in 530 ureteric stone cases, in the largest UK series we are aware of to date. ESWL is underutilised in ureteric stone management. The Getting It Right First Time (GIRFT) report showed just four units nationally treated >10% of acute ureteric stones with ESWL.

A dual center and dual vendor comparison study of automated perfusion-weighted phase-resolved functional lung magnetic resonance imaging with dynamic contrast-enhanced magnetic resonance imaging in patients with cystic fibrosis.

For sensitive diagnosis and monitoring of pulmonary disease, ionizing radiation-free imaging methods are of great importance. A noncontrast and free-breathing proton magnetic resonance imaging (MRI) technique for assessment of pulmonary perfusion is phase-resolved functional lung (PREFUL) MRI. Since there is no validation of PREFUL MRI across different centers and scanners, the purpose of this study was to compare perfusion-weighted PREFUL MRI with the well-established dynamic contrast-enhanced (DCE) MRI across two centers on scanners from two different vendors.

Life before Stonehenge: The hunter-gatherer occupation and environment of Blick Mead revealed by sedaDNA, pollen and spores.

The Neolithic and Bronze Age construction and habitation of the Stonehenge Landscape has been extensively explored in previous research. However, little is known about the scale of pre-Neolithic activity and the extent to which the later monumental complex occupied an 'empty' landscape. There has been a long-running debate as to whether the monumental archaeology of Stonehenge was created in an uninhabited forested landscape or whether it was constructed in an already partly open area of pre-existing significance to late Mesolithic hunter-gatherers.

Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells.

MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1.

Xenon ventilation MRI in difficult asthma: initial experience in a clinical setting.

Background: Hyperpolarised gas magnetic resonance imaging (MRI) can be used to assess ventilation patterns. Previous studies have shown the image-derived metric of ventilation defect per cent (VDP) to correlate with forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) and FEV in asthma.

Objectives: The aim of this study was to explore the utility of hyperpolarised xenon-129 (Xe) ventilation MRI in clinical care and examine its relationship with spirometry and other clinical metrics in people seen in a severe asthma service.

Evidence for the Continued Occurrence of Chorioretinopathy in Working Sheep Dogs in New Zealand in 2010.

A study in conducted 1987 by Hughes et al., found that 39% of working sheep dogs had multifocal retinitis. One of the identified causes was ocular larval migrans, which were a result of migrating ascarid larvae.

Integrated Cardiopulmonary MRI Assessment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous condition that can affect the lung parenchyma, pulmonary vasculature, and cardiac chambers. Accurate diagnosis often requires multiple complex assessments of the cardiac and pulmonary systems. MRI is able to comprehensively assess cardiac structure and function, as well as lung parenchymal, pulmonary vascular, and functional lung changes.