Apalutamide for prostate cancer: Multicentre and multidisciplinary real-world study of 227 patients.

OBJECTIVE: To evaluate the efficacy and safety of apalutamide prostate cancer compared to the pivotal trials patients and to identify the first subsequent therapy in a real-world setting. METHODS: The study is prospective and observational based on real-world evidence, performed by different medical disciplines and eight academics centres around Barcelona, Spain. It included all patients with metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide from June 2018 to December 2022. RESULTS: Of 227 patients treated with apalutamide, 10% had ECOG-PS 2, and 41% were diagnosed with new-generation imaging. In the mHSPC group (209 patients), 75 years was the median age, 53% had synchronous metastases, and 22% were M1a. In the nmCRPC (18 patients), 82 years was the median age, and 81% ≤6 months had PSA doubling time. Patients achieved PSA90 in 92% of mHSPC and 50% of nmCRPC and PSA ≤0.2 in 71% of mHSPC and 39% of nmCRPC. Treatment-related adverse events occurred in 40.1% of mHSPC and 44.4% of nmCRPC. After discontinuation of apalutamide due to disease progression, 54.5% in mHSPC and 75% in nmCRPC started chemotherapy, while after discontinuation because of adverse events, 73.3% in mHSPC and 100% in nmCRPC continued with other hormonal-therapies. CONCLUSIONS: The efficacy and safety of apalutamide were similar to that described in the pivotal trials, despite including an older and more comorbid population. Usually, subsequent therapies after apalutamide differed depending on the reason for discontinuation: by disease progression started chemotherapy and by adverse events hormonal sequencing.

Jupiter Science Enabled by ESA's Jupiter Icy Moons Explorer.

ESA's Jupiter Icy Moons Explorer (JUICE) will provide a detailed investigation of the Jovian system in the 2030s, combining a suite of state-of-the-art instruments with an orbital tour tailored to maximise observing opportunities. We review the Jupiter science enabled by the JUICE mission, building on the legacy of discoveries from the Galileo, Cassini, and Juno missions, alongside ground- and space-based observatories. We focus on remote sensing of the climate, meteorology, and chemistry of the atmosphere and auroras from the cloud-forming weather layer, through the upper troposphere, into the stratosphere and ionosphere. The Jupiter orbital tour provides a wealth of opportunities for atmospheric and auroral science: global perspectives with its near-equatorial and inclined phases, sampling all phase angles from dayside to nightside, and investigating phenomena evolving on timescales from minutes to months. The remote sensing payload spans far-UV spectroscopy (50-210 nm), visible imaging (340-1080 nm), visible/near-infrared spectroscopy (0.49-5.56 µm), and sub-millimetre sounding (near 530-625 GHz and 1067-1275 GHz). This is coupled to radio, stellar, and solar occultation opportunities to explore the atmosphere at high vertical resolution; and radio and plasma wave measurements of electric discharges in the Jovian atmosphere and auroras. Cross-disciplinary scientific investigations enable JUICE to explore coupling processes in giant planet atmospheres, to show how the atmosphere is connected to (i) the deep circulation and composition of the hydrogen-dominated interior; and (ii) to the currents and charged particle environments of the external magnetosphere. JUICE will provide a comprehensive characterisation of the atmosphere and auroras of this archetypal giant planet.

Serum miRNAs miR-206, 143-3p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative condition characterized by loss of motor neurones and progressive muscle wasting. There is no diagnostic test for ALS therefore robust biomarkers would not only be valuable for diagnosis, but also for the classification of disease subtypes, monitoring responses to drugs and tracking disease progression. As regulators of gene expression, microRNAs (miRNAs) are increasingly used for diagnostic and prognostic purposes in various disease states with increasing exploration in neurodegenerative disorders. We hypothesize that circulating blood-based miRNAs will serve as biomarkers and use miRNA profiling to determine miRNA signatures from the serum of sporadic ALS patients compared to healthy controls and patients with diseases that mimic ALS. A number of differentially expressed miRNAs were identified in each set of patient comparisons. Validation in an additional patient cohort showed that miR-206 and miR-143-3p were increased and miR-374b-5p was decreased compared to controls. A continued change in miRNA expression persisted during disease progression indicating the potential use of these particular miRNAs as longitudinal biomarkers in ALS.

Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1-/- zebrafish.

Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter (MCU), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1Y431 * mutant zebrafish (Danio rerio) via rescue of mitochondrial respiratory chain function. In contrast, genetic inactivation of the voltage dependent anion channel 1 (VDAC1), located in the outer mitochondrial membrane, did not rescue dopaminergic neurons in PINK1 deficient D. rerio. Subsequent gene expression studies revealed specific upregulation of the mcu regulator micu1 in pink1Y431 * mutant zebrafish larvae and inactivation of micu1 also results in rescue of dopaminergic neurons. The functional consequences of PINK1 deficiency and modified MCU activity were confirmed using a dynamic in silico model of Ca2+ triggered mitochondrial activity. Our data suggest modulation of MCU-mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy in PINK1 mutant PD.

Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death.

Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1(c.1276_1298del) mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.

A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening.

Mutations in the superoxide dismutase gene (SOD1) are one cause of familial amyotrophic lateral sclerosis [ALS; also known as motor neuron disease (MND)] in humans. ALS is a relentlessly progressive neurodegenerative disease and, to date, there are no neuroprotective therapies with significant impact on the disease course. Current transgenic murine models of the disease, which overexpress mutant SOD1, have so far been ineffective in the identification of new therapies beneficial in the human disease. Because the human and the zebrafish (Danio rerio) SOD1 protein share 76% identity, TILLING ('targeting induced local lesions in genomes') was carried out in collaboration with the Sanger Institute in order to identify mutations in the zebrafish sod1 gene. A T70I mutant zebrafish line was characterised using oxidative stress assays, neuromuscular junction (NMJ) analysis and motor function studies. The T70I sod1 zebrafish model offers the advantage over current murine models of expressing the mutant Sod1 protein at a physiological level, as occurs in humans with ALS. The T70I sod1 zebrafish demonstrates key features of ALS: an early NMJ phenotype, susceptibility to oxidative stress and an adult-onset motor neuron disease phenotype. We have demonstrated that the susceptibility of T70I sod1 embryos to oxidative stress can be used in a drug screening assay, to identify compounds that merit further investigation as potential therapies for ALS.

Zebrafish-based small molecule screens for novel cardiovascular drugs.

The zebrafish is increasingly being adopted as an in vivo model of high throughput drug screening. In this brief review we outline the advantages and disadvantages of this approach and summarize recent screens that have attempted to identify novel small molecules with activity on the cardiovascular system.