Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

Dots and spots: A retrospective review of T2-hyperintense white matter lesions in pediatric patients with and without headache.

OBJECTIVE: We aimed to determine if T2-weighted hyperintense white matter lesions (WMLs) on brain magnetic resonance imaging (MRI) occur more frequently in pediatric patients with migraine and other primary headache disorders compared to the general pediatric population. BACKGROUND: Small foci of T2 hyperintensity in the white matter are frequently identified on brain MRI during the workup of pediatric headache. Such lesions have been reported to be more common among adults with migraine versus adults without migraine; however, this association has not been well established in the pediatric population. METHODS: We performed a retrospective cross-sectional single-center study of electronic medical records and radiologic studies, examining pediatric patients from 3 to 18 years old who underwent brain MRI between 2016 and 2021. Patients with existing intracranial disease or abnormalities were excluded. Patients with reports of headache were categorized. Imaging was reviewed to determine the number and location of WMLs. Headache-associated disability scores (Pediatric Migraine Disability Assessment) were noted, when available. RESULTS: Brain MRI of 248 patients with a diagnosis of headache (144 with migraine, 42 with non-migraine primary headache, and 62 with headache that could not be further classified) and 490 controls were reviewed. WMLs were encountered commonly among all study participants, with a prevalence of 40.5% (17/42) to 54.1% (265/490). There was no statistically significant difference comparing the number of lesions between each of the headache groups and the control group: migraine group versus control group median [interquartile range (IQR)], 0 [0-3] versus 1 [0-4], incidence rate ratio [95% confidence interval (CI)], 0.99 [0.69-1.44], p = 0.989, non-migraine headache group versus control group median [IQR], 0 [0-3] versus 1 [0-4], 0.71 [0.46-1.31], p = 0.156, headache not otherwise specified group versus control group median [IQR], 0 [0-4] versus 1 [0-4], 0.77 [0.45-1.31], p = 0.291. There was no significant correlation between headache-associated disability and the number of WMLs (0.07 [-0.30 to 0.17], rho [95% CI]). CONCLUSION: T2 hyperintense WMLs are common within the pediatric population and are not encountered more frequently in pediatric patients with migraine or other primary headache disorders. Thus, such lesions are presumably incidental and unlikely related to headache history.

Clinical and Financial Impact of a Diagnostic Stewardship Program for Children with Suspected Central Nervous System Infection.

OBJECTIVE: To investigate the optimal implementation and clinical and financial impacts of the FilmArray Meningitis Encephalitis Panel (MEP) multiplex polymerase chain reaction testing of cerebrospinal fluid (CSF) in children with suspected central nervous system infection. STUDY DESIGN: A pre-post quasiexperimental cohort study to investigate the impact of implementing MEP using a rapid CSF diagnostic stewardship program was conducted at Children's Hospital Colorado (CHCO). MEP was implemented with electronic medical record indication selection to guide testing to children meeting approved use criteria: infants <2 months, immunocompromised, encephalitis, and ≥5 white blood cells/µL of CSF. Positive results were communicated with antimicrobial stewardship real-time decision support. All cases with CSF obtained by lumbar puncture sent to the CHCO microbiology laboratory meeting any of the 4 aforementioned criteria were included with preimplementation controls (2015-2016) compared with postimplementation cases (2017-2018). Primary outcome was time-to-optimal antimicrobials compared using log-rank test with Kaplan-Meier analysis. RESULTS: Time-to-optimal antimicrobials decreased from 28 hours among 1124 preimplementation controls to 18 hours (P < .0001) among 1127 postimplementation cases (72% with MEP testing conducted). Postimplementation, time-to-positive CSF results was faster (4.8 vs 9.6 hours, P < .0001), intravenous antimicrobial duration was shorter (24 vs 36 hours, P = .004), with infectious neurologic diagnoses more frequently identified (15% vs 10%, P = .03). There were no differences in time-to-effective antimicrobials, hospital admissions, antimicrobial starts, or length of stay. Costs of microbiologic testing increased, but total hospital costs were unchanged. CONCLUSIONS: Implementation of MEP with a rapid central nervous system diagnostic stewardship program improved antimicrobial use with faster results shortening empiric therapy. Routine MEP testing for high-yield indications enables antimicrobial optimization with unchanged overall costs.

Headache and Sleep Disturbances in the Pediatric Population.

The relationship between sleep disturbances and headaches in the pediatric population is bidirectional. Common underlying molecular mechanisms of sleep and headaches have been speculated to explain the clinical connection. We will summarize various sleep disturbances and their known relationships to headache, focusing on the pediatric population. Careful recognition and assessment of sleep disturbances in patients with headache is critical and may help guide treatment. First line therapies for sleep disturbances consist of behavioral approaches, though surgical and pharmacologic strategies are utilized in particular circumstances.

Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding.

BACKGROUND: Early microbiota perturbations are associated with disorders that involve immunological underpinnings. Cesarean section (CS)-born babies show altered microbiota development in relation to babies born vaginally. Here we present the first statistically powered longitudinal study to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. METHODS: Using 16S rRNA gene sequencing, we followed the microbial trajectories of multiple body sites in 177 babies over the first year of life; 98 were born vaginally, and 79 were born by CS, of whom 30 were swabbed with a maternal vaginal gauze right after birth. FINDINGS: Compositional tensor factorization analysis confirmed that microbiota trajectories of exposed CS-born babies aligned more closely with that of vaginally born babies. Interestingly, the majority of amplicon sequence variants from maternal vaginal microbiomes on the day of birth were shared with other maternal sites, in contrast to non-pregnant women from the Human Microbiome Project (HMP) study. CONCLUSIONS: The results of this observational study prompt urgent randomized clinical trials to test whether microbial restoration reduces the increased disease risk associated with CS birth and the underlying mechanisms. It also provides evidence of the pluripotential nature of maternal vaginal fluids to provide pioneer bacterial colonizers for the newborn body sites. This is the first study showing long-term naturalization of the microbiota of CS-born infants by restoring microbial exposure at birth. FUNDING: C&D, Emch Fund, CIFAR, Chilean CONICYT and SOCHIPE, Norwegian Institute of Public Health, Emerald Foundation, NIH, National Institute of Justice, Janssen.

Studying clonal dynamics in response to cancer therapy using high-complexity barcoding.

Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.