Martinsensalas1093

Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.We describe the intracranial pressure dynamics and cerebral vasomotor reactivity in a coronavirus disease 2019 patient with acute encephalitis treated with cerebrospinal fluid drainage and therapeutic plasma exchange.

Coronavirus disease ICU, Uppsala University Hospital, Sweden.

Case report.

Radiology, intracranial pressure, intracranial compliance (correlation between intracranial pressure amplitude and mean intracranial pressure), cerebral vasomotor reactivity (pressure reactivity index), arterial blood pressure, cerebrospinal fluid chemistry, and treatment.

None.

This is the first reported case of intracranial pressure monitoring in a patient with acute encephalitis following coronavirus disease 2019. Intracranial pressure data exhibited a high incidence of plateau waves with intracranial pressure insults above 40 mm Hg that required cerebrospinal fluid drainage. Intracranial compliance was low, and pressure reactivity was intact. It is probable that the combination of low intracranial compliance n explain the high degree of plateau intracranial pressure waves and intracranial pressure variability. This case illustrates that it could be of value to consider intracranial pressure monitoring in selected coronavirus disease 2019 patients with suspicion of increased intracranial pressure to be able to confirm and treat intracranial hypertension if needed. In this patient, therapeutic plasma exchange was safe and efficacious as the level of neuroinflammation decreased and the patient regained consciousness.To explore demographics, comorbidities, transfers, and mortality in critically ill patients with confirmed severe acute respiratory syndrome coronavirus 2.

Retrospective cohort study.

Data were collected from a large tertiary care public hospital ICU that is part of the largest public healthcare network in the United States.

One-hundred thirty-seven adult (≥ 18 yr old) ICU patients admitted between March 10, 2020, and April 7, 2020, with follow-up collected through May 18, 2020.

None.

Demographic, clinical, laboratory, treatment, and outcome data extracted from electronic medical records.

The majority of patients were male (99/137; 72.3%) and older than 50 years old (108/137; 78.9%). The most reported ethnicity and race were Hispanic (61/137; 44.5%) and Black (23/137; 16.7%). One-hundred six of 137 patients had at least one comorbidity (77.4%). One-hundred twenty-one of 137 (78.1%) required mechanical ventilation of whom 30 (24.8%) moved to tracheostomy and 46 of 137 (33.6%) required new onset renaients. We also describe how a public hospital developed innovative approaches to safely manage a large volume of interhospital transfers and admitted patients.The ICU Liberation (ABCDEF) Bundle can help to improve care and outcomes for ICU patients, but bundle implementation is far from universal. Understanding how ICU organizational characteristics influence bundle implementation could inform quality improvement efforts. We surveyed all hospitals in Michigan with adult ICUs to determine whether organizational characteristics were associated with bundle implementation and to determine the level of agreement between ICU physician and nurse leaders around ICU organizational characteristics and bundle implementation.

We surveyed ICU physician and nurse leaders, assessing their safety culture, ICU team collaboration, and work environment. Using logistic and linear regression models, we compared these organizational characteristics to bundle element implementation, and also compared physician and nurse leaders' perceptions about organizational characteristics and bundle implementation.

All (

= 72) acute care hospitals with adult ICUs in Michigan.

ICU physician anrove bundle implementation and performance.

We identified several specific ICU practices that can facilitate ABCDEF Bundle implementation. Our results can be used to develop effective bundle implementation strategies that leverage safety culture, interprofessional collaboration, and routine checklist use in ICUs to improve bundle implementation and performance.Achieving the directional and long-range droplet transport on solid surfaces is widely preferred for many practical applications but has proven to be challenging. Particularly, directionality and transport distance of droplets on hydrophobic surfaces are mutually exclusive. Here, we report that drain fly, a ubiquitous insect maintaining nonwetting property even in very high humidity, develops a unique ballistic droplet transport mechanism to meet these demanding challenges. The drain fly serves as a flexible rectifier to allow for a directional and long-range propagation as well as self-removal of a droplet, thus suppressing unwanted liquid flooding. Further investigation reveals that this phenomenon is owing to the synergistic conjunction of multiscale roughness, structural periodicity, and flexibility, which rectifies the random and localized droplet nucleation (nanoscale and microscale) into a directed and global migration (millimeter-scale). The mechanism we have identified opens up a new approach toward the design of artificial rectifiers for broad applications.The drug-eluting stent (DES) has become one of the most successful and important medical devices for coronary heart disease, but yet suffers from insufficient endothelial cell (EC) growth and intima repair, eventually leading to treatment failure. Although biomacromolecules such as vascular endothelial growth factor (VEGF) would be promising to promote the intima regeneration, combining hydrophilic and vulnerable biomacromolecules with hydrophobic drugs as well as preserving the bioactivity after harsh treatments pose a huge challenge. Here, we report on a design of hierarchical capillary coating, which composes a base solid region and a top microporous region for incorporating rapamycin and VEGF, respectively. The top spongy region can guarantee the efficient, safe, and controllable loading of VEGF up to 1 μg/cm2 in 1 minute, providing a distinctive real-time loading capacity for saving the bioactivity. Based on this, we demonstrate that our rapamycin-VEGF hierarchical coating impressively promoted the competitive growth of endothelial cells over smooth muscle cells (ratio of EC/SMC~25) while relieving the adverse impact of rapamycin to ECs. We further conducted the real-time loading of VEGF on stents and demonstrate that the hierarchical combination of rapamycin and VEGF showed remarkable endothelium regeneration while maintaining a very low level of in-stent restenosis. This work paves an avenue for the combination of both hydrophobic and hydrophilic functional molecules, which should benefit the next generation of DES and may extend applications to diversified combination medical devices.The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. Temsirolimus For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)-9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR-ACK1 and AR-HOXB13 pathways as key mediators of CRPC recurrence.DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct pathway for mediating DNA double-strand break (DSB) repair. TMEJ is required for the viability of BRCA-mutated cancer cells. It is crucial to identify tumors that rely on POLQ activity for DSB repair, because such tumors are defective in other DSB repair pathways and have predicted sensitivity to POLQ inhibition and to cancer therapies that produce DSBs. We define here the POLQ-associated mutation signatures in human cancers, characterized by short insertions and deletions in a specific range of microhomologies. By analyzing 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures, we found that BRCA-mutated cancers with a higher level of POLQ expression have a greatly enhanced representation of the small insertion and deletion signature 6, as well as single base substitution signature 3. Using human cancer cells with disruptions of POLQ, we further show that TMEJ dominates end joining of two separated DSBs (distal EJ). Templated insertions with microhomology are enriched in POLQ-dependent distal EJ. The use of this signature analysis will aid in identifying tumors relying on POLQ activity.

Optic pathway gliomas (OPGs) are low-grade tumors of the white matter of the visual system with a highly variable clinical course. The aim of the study was to generate a magnetic resonance imaging (MRI)-based predictive model of OPG tumor progression using advanced image analysis and machine learning techniques.

We performed a retrospective case-control study of OPG patients managed between 2009 and 2015 at an academic children's hospital. Progression was defined as radiographic tumor growth or vision decline. To generate the model, optic nerves were manually highlighted and optic radiations (ORs) were segmented using diffusion tractography tools. For each patient, intensity distributions were obtained from within the segmented regions on all imaging sequences, including derivatives of diffusion tensor imaging (DTI). A machine learning algorithm determined the combination of features most predictive of progression.

Nineteen OPG patients with progression were matched to 19 OPG patients without progression.