Explore the vast range of titles available.

Background: Adult diffuse gliomas represent one of the most aggressive types of brain tumors. Proton therapy offers a minimally invasive treatment option whose biological effectiveness may be enhanced through nuclear reactions involving boron atoms, leading to the emission of high-LET α-particles. In this study, we investigated the potential enhancement of radiation-induced damage of a novel boron-conjugated, ATP-competitive SRC kinase inhibitor, in the U-87 MG glioma cell line and its isogenic cell line stably expressing the IDH1 R132H mutation. Methods: Glioma cells were exposed to either proton or X-ray irradiation to assess whether any enhancement associated with this boron-delivery strategy was specific to proton interactions. Cell survival assays and analyses of DNA damage responses were conducted in both cell lines. Results: While no significant synergistic effects were observed in survival endpoints, differences emerged at the level of early DNA damage effects, with IDH1-mutant glioma cells displaying an enhanced acute response following combined treatment with proton irradiation. Conclusions: These findings support further pharmacological development of boron-based SRC-targeted strategies and underscore the importance of tailoring therapeutic approaches to specific glioma molecular subtypes.

: Adult diffuse gliomas represent one of the most aggressive types of brain tumors. Proton therapy offers a minimally invasive treatment option whose biological effectiveness may be enhanced through nuclear reactions involving boron atoms, leading to the emission of high-LET α-particles. In this study, we investigated the potential enhancement of radiation-induced damage of a novel boron-conjugated, ATP-competitive SRC kinase inhibitor, in the U-87 MG glioma cell line and its isogenic cell line stably expressing the IDH1 R132H mutation. : Glioma cells were exposed to either proton or X-ray irradiation to assess whether any enhancement associated with this boron-delivery strategy was specific to proton interactions. Cell survival assays and analyses of DNA damage responses were conducted in both cell lines. While no significant synergistic effects were observed in survival endpoints, differences emerged at the level of early DNA damage effects, with IDH1-mutant glioma cells displaying an enhanced acute response following combined treatment with proton irradiation. These findings support further pharmacological development of boron-based SRC-targeted strategies and underscore the importance of tailoring therapeutic approaches to specific glioma molecular subtypes.

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors. The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation.

Background Mindfulness practice has gained interest in the management of Chronic Migraine associated with Medication Overuse Headache (CM-MOH). Mindfulness is characterized by present-moment self-awareness and relies on attention control and emotion regulation, improving headache-related pain management. Mindfulness modulates the Default Mode Network (DMN), Salience Network (SN), and Fronto-Parietal Network (FPN) functional connectivity. However, the neural mechanisms underlying headache-related pain management with mindfulness are still unclear. In this study, we tested neurofunctional changes after mindfulness practice added to pharmacological treatment as usual in CM-MOH patients. Methods The present study is a longitudinal phase-III single-blind Randomized Controlled Trial (MIND-CM study; NCT03671681). Patients had a diagnosis of CM-MOH, no history of neurological and severe psychiatric comorbidities, and were attending our specialty headache centre. Patients were divided in Treatment as Usual (TaU) and mindfulness added to TaU (TaU + MIND) groups. Patients underwent a neuroimaging and clinical assessment before the treatment and after one year. Longitudinal comparisons of DMN, SN, and FPN connectivity were performed between groups and correlated with clinical changes. Vertex-wise analysis was performed to assess cortical thickness changes. Results 177 CM-MOH patients were randomized to either TaU group or TaU + MIND group. Thirty-four patients, divided in 17 TaU and 17 TaU + MIND, completed the neuroimaging follow-up. At the follow-up, both groups showed an improvement in most clinical variables, whereas only TaU + MIND patients showed a significant headache frequency reduction ( p  = 0.028). After one year, TaU + MIND patients showed greater SN functional connectivity with the left posterior insula (p-FWE = 0.007) and sensorimotor cortex (p-FWE = 0.026). In TaU + MIND patients only, greater SN-insular connectivity was associated with improved depression scores ( r = -0.51, p  = 0.038). A longitudinal increase in cortical thickness was observed in the insular cluster in these patients ( p  = 0.015). Increased anterior cingulate cortex thickness was also reported in TaU + MIND group (p-FWE = 0.02). Conclusions Increased SN-insular connectivity might modulate chronic pain perception and the management of negative emotions. Enhanced SN-sensorimotor connectivity could reflect improved body-awareness of painful sensations. Expanded cingulate cortex thickness might sustain improved cognitive processing of nociceptive information. Our findings unveil the therapeutic potential of mindfulness and the underlying neural mechanisms in CM-MOH patients. Trial Registration Name of Registry; MIND-CM study; Registration Number ClinicalTrials.gov identifier: NCT0367168; Registration Date: 14/09/2018

RationaleIn patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population.MethodsIn this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO2) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO2 ≥96% with fractional inspired oxygen (FiO2) ≤30% or partial pressure of arterial carbon dioxide/FiO2 ratio >300 mm Hg).ResultsAmong 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference −8.2% (95% CI −18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI −1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference −3.3% (95% CI −9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8–17) vs 11 (IQR 7–20) days, absolute risk difference −1.0% (95% CI −3.1% to +1.1%)).ConclusionsAmong patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support.Trial registration number NCT04655638.

Objective In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. Methods In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy‐seven ALSpts performed 3T MRI scans to measure cortical thickness. Between‐group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. Results Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non‐lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). Interpretation Our cross‐sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well‐being that is not limited to the motor status, proving instead that loneliness can impact on disease‐related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

Air quality observations are performed globally to monitor the status of the atmosphere and its level of pollution and to assess mitigation strategies. Regulations of air quality monitoring programmes in various countries demand high-precision measurements for harmful substances often at low trace concentrations. These requirements can only be achieved by using high-quality calibration gases including high-purity zero gas. For volatile organic compound (VOC) observations, zero gas is defined as being hydrocarbon-free and can be, for example, purified air, nitrogen or helium. It is essential for the characterisation of the measurement devices and procedures, for instrument operation as well as for calibrations. Two commercial and one self-built gas purifiers were tested for their VOC removal efficiency following a standardised procedure. The tested gas purifiers included one adsorption cartridge with an inorganic media and two types of metal catalysts. A large range of VOCs were investigated, including the most abundant species typically measured at air monitoring stations. Both catalysts were able to remove a large range of VOCs whilst the tested adsorption cartridge was not suitable to remove light compounds up to C4. Memory effects occurred for the adsorption cartridge when exposed to higher concentration. This study emphasises the importance of explicitly examining a gas purifier for its intended application before applying it in the field.

Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5′ fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements.

Nature Biotechnology asks a selection of researchers about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ~10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.