The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable ...outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and ...optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine–piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
We discuss specific challenges and solutions in infant MEG, which is one of the most technically challenging areas of MEG studies. Our results can be generalized to a variety of challenging scenarios ...for MEG data acquisition, including clinical settings. We cover a wide range of steps in pre-processing, including movement compensation, suppression of magnetic interference from sources inside and outside the magnetically shielded room, suppression of specific physiological artifact components such as cardiac artifacts. In the assessment of the outcome of the pre-processing algorithms, we focus on comparing signal representation before and after pre-processing and discuss the importance of the different components of the main processing steps. We discuss the importance of taking the noise covariance structure into account in inverse modeling and present the proper treatment of the noise covariance matrix to accurately reflect the processing that was applied to the data. Using example cases, we investigate the level of source localization error before and after processing. One of our main findings is that statistical metrics of source reconstruction may erroneously indicate that the results are reliable even in cases where the data are severely distorted by head movements. As a consequence, we stress the importance of proper signal processing in infant MEG.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the ...Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
A3667 is the archetype of a merging cluster with radio relics. The northwest (NW) radio relic is the brightest cluster relic or halo known and is believed to be due to a strong merger shock. We have ...observed the NW relic for {approx}40 ks of net XMM-Newton time. We observe a global decline of temperature across the relic from 6 to 1 keV, similar to the Suzaku results. Our new observations reveal a sharp change of both temperature and surface brightness near the position of the relic. The increased X-ray emission on the relic can be equivalently well described by either a thermal or nonthermal spectral model. The parameters of the thermal model are consistent with a Mach number M{approx}2 shock and a shock speed of {approx}1200 km s{sup -1}. The energy content of the relativistic particles in the radio relic can be explained if they are (re)-accelerated by the shock with an efficiency of {approx}0.2%. Comparing the limit on the inverse Compton X-ray emission with the measured radio synchrotron emission, we set a lower limit to the magnetic field in the relic of 3 {mu}G. If the emission from the relic is nonthermal, this lower limit is in fact the required magnetic field.
Although the health care reform movement has brought about positive changes, lingering inefficiencies and communication gaps continue to hamper system-wide progress toward achieving the overarching ...goal—higher quality health care and improved population health outcomes at a lower cost. The multiple interrelated barriers to improvement are most evident in care for the population of patients with multiple chronic conditions. During transitions of care, the lack of integration among various silos and inadequate communication among providers cause delays in delivering appropriate health care services to these vulnerable patients and their caregivers, diminishing positive health outcomes and driving costs ever higher. Long-entrenched acute care-focused treatment and reimbursement paradigms hamper more effective deployment of existing resources to improve the ongoing care of these patients. New models for care coordination during transitions, longitudinal high-risk care management, and unplanned acute episodic care have been conceived and piloted with promising results. Utilizing existing resources, Mobile Integrated Healthcare is an emerging model focused on closing these care gaps by means of a round-the-clock, technologically sophisticated, physician-led interprofessional team to manage care transitions and chronic care services on-site in patients' homes or workplaces.
Word learning is a significant milestone in language acquisition. The second year of life marks a period of dramatic advances in infants’ expressive and receptive word-processing abilities. Studies ...show that in adulthood, language processing is left-hemisphere dominant. However, adults learning a second language activate right-hemisphere brain functions. In infancy, acquisition of a first language involves recruitment of bilateral brain networks, and strong left-hemisphere dominance emerges by the third year. In the current study we focus on 14-month-old infants in the earliest stages of word learning using infant magnetoencephalography (MEG) brain imagining to characterize neural activity in response to familiar and unfamiliar words. Specifically, we examine the relationship between right-hemisphere brain responses and prospective measures of vocabulary growth. As expected, MEG source modeling revealed a broadly distributed network in frontal, temporal and parietal cortex that distinguished word classes between 150–900 ms after word onset. Importantly, brain activity in the right frontal cortex in response to familiar words was highly correlated with vocabulary growth at 18, 21, 24, and 27 months. Specifically, higher activation to familiar words in the 150–300 ms interval was associated with faster vocabulary growth, reflecting processing efficiency, whereas higher activation to familiar words in the 600–900 ms interval was associated with slower vocabulary growth, reflecting cognitive effort. These findings inform research and theory on the involvement of right frontal cortex in specific cognitive processes and individual differences related to attention that may play an important role in the development of left-lateralized word processing.
Abstract Objective To measure truncated face and open face versions of the biological fixation (BFX) cup in a three‐dimensional (3D) model simulating the ventrodorsal radiographic projection with ...different cup and pelvis positions. Study design Computer simulation. Methods Simulated ventrodorsal views were generated in silico using 3D models of a BFX cup and a medium‐sized canine pelvis. Truncated face and open face versions of the BFX cup were defined and measured with various angles of cup version, cup inclination, and pelvic extension. Results Truncated face version was different from and underestimated open face version by 12° to 22° ( p < .001). Open face version varied with inclination while truncated face version was unaffected by inclination. Open face version was dependent on the degree of pelvic extension while truncated face version was unaffected. Conclusion Open face version differed from truncated face version. Changes in open face version were not consistently matched by a change in truncated face version. Clinical significance The open face of the cup may be excessively retroverted without this being reflected by truncated face retroversion as seen on a ventrodorsal radiographic view. However, in this study, BFX cups placed with truncated face version and inclination in the normal range and an ALO of 45° yielded predictable open face version.
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in
, encoding the serine/threonine kinase ALK2. Despite being ...an amenable drug target, little has been done to-date to systematically evaluate the role of
in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo1,5-apyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M,
R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.
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