Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.

Development of a Cloud-Based Clinical Decision Support System for Ophthalmology Triage Using Decision Tree Artificial Intelligence.

Purpose: Clinical decision support systems (CDSS) are an emerging frontier in teleophthalmology, drawing on heuristic decision making to augment processes such as triage and referral. We describe the development and implementation of a novel cloud-based decision tree CDSS for on-call ophthalmology consults. The objective was to standardize the triage and referral process while providing a more accurate provisional diagnosis and urgency. Design: Prospective comparative cohort study. Subjects: On-call referrals to a Canadian community ophthalmology clinic. Methods: A web-based decision tree algorithm was developed using current guidelines and expert opinion. The algorithm collected tailored information on the patient's ophthalmic concern, and outputted a provisional diagnosis and urgency before sending an electronic referral to the on-call ophthalmology clinic. Data were described using descriptive statistics. Spearman-rho correlations and Cohen's kappa coefficient were used to characterize the observed relationships. Post hoc analysis was conducted using analysis of contingency tables and adjusted residuals. Main Outcome Measures: Diagnostic category, provisional diagnosis, and urgency for the referring provider, CDSS, and ophthalmologist. Results: Ninety-six referrals were processed. Referring providers included medical doctors (76.0%, n = 73), optometrists (20.8%, n = 20), and nurse practitioners (3.1%, n = 3). The CDSS (κ = 0.5898; 95% confidence interval [CI], 0.4868-0.6928; P < 0.0001) performed equally well with 66.7% agreement in determining category when compared with referring providers (κ = 0.5880; 95% CI, 0.4798-0.6961; P < 0.0001). The CDSS (agreement = 53.1%; κ = 0.4999; 95% CI, 0.4021-0.5978; P < 0.0001) performed better than referring providers (agreement = 43.8%; κ = 0.4191; 95% CI, 0.3194-0.5188; P < 0.0001) in determining a diagnosis. The CDSS (ρ = 0.5014; 95% CI, 0.3092-0.6935; P < 0.0001) also performed better than referring providers (ρ = 0.4035; 95% CI, 0.2406-0.5665; P < 0.0001) in determining urgency. The CDSS assigned a lower level of urgency in 22 cases (22.9%) compared with referring providers in 6 cases (6.3%). Conclusions: To our knowledge, this is the first cloud-based CDSS in ophthalmology designed to augment the triage and referral process. The CDSS achieves a more accurate diagnosis and urgency, standardizes information collection, and overcomes antiquated paper-based consults. Future directions include developing a random forest model or integrating convolutional neural network-based machine learning to refine the speed and accuracy of triage and referral processes, with emphasis on increasing sensitivity of the CDSS.

Precise Quantification of Behavioral Individuality From 80 Million Decisions Across 183,000 Flies.

Individual animals behave differently from each other. This variability is a component of personality and arises even when genetics and environment are held constant. Discovering the biological mechanisms underlying behavioral variability depends on efficiently measuring individual behavioral bias, a requirement that is facilitated by automated, high-throughput experiments. We compiled a large data set of individual locomotor behavior measures, acquired from over 183,000 fruit flies walking in Y-shaped mazes. With this data set we first conducted a "computational ethology natural history" study to quantify the distribution of individual behavioral biases with unprecedented precision and examine correlations between behavioral measures with high power. We discovered a slight, but highly significant, left-bias in spontaneous locomotor decision-making. We then used the data to evaluate standing hypotheses about biological mechanisms affecting behavioral variability, specifically: the neuromodulator serotonin and its precursor transporter, heterogametic sex, and temperature. We found a variety of significant effects associated with each of these mechanisms that were behavior-dependent. This indicates that the relationship between biological mechanisms and behavioral variability may be highly context dependent. Going forward, automation of behavioral experiments will likely be essential in teasing out the complex causality of individuality.

Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis.

Growth differentiation factor 11 (GDF11) is a transforming factor-ß superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.

Medication Errors at a Tertiary Hospital Intensive Care Unit.

Background The intensive care unit (ICU) generates more medication prescriptions per patient day than any other unit in the hospital. The dynamics of the ICU environment, coupled with the complexity of patient pathology, increases the risk of medication errors. This study aimed to evaluate the incidence and spectrum of medication errors in an adult general ICU in Johannesburg, South Africa. Methods A retrospective chart review was conducted at a 19-bed ICU in a tertiary-level hospital in Johannesburg. Data were independently collected by two of the study investigators. The doctors' prescription and the nurses' administration section of patient bedside charts were scrutinized for drug prescription and administration errors. Results Of the 656 patient days studied, 3237 drugs (5.6 drugs per patient day) were prescribed. There were a total of 359 medication errors, comprising 237 (66.0%) prescription and 122 (34.0%) administration errors. The total error rate per 1000 patient days was 621.1, while the total error rate per 1000 drug prescriptions was 110.9. The most common errors were incorrect dose prescribed (n=69, 19.2%), incorrect dosing interval prescribed (n=48, 13.4%), incorrect dose administered (n=42, 11.7%) and failure to administer the prescribed drug (n=38, 10.6%). Conclusion The overall occurrence of medication errors is high but is in keeping with general international trends. Targeted interventions should be implemented to minimize the frequency of medication errors in the ICU and consequent risk to patients.

Is the History of Erectile Dysfunction a Reliable Risk Factor for New Onset Acute Myocardial Infarction? A Systematic Review and Meta-Analysis.

Acute myocardial infarction (AMI) occurs as a manifestation of coronary atherosclerotic disease. The occurrence of erectile dysfunction (ED) following AMI is well documented and this association and pathophysiology is often interrelated. Few studies have objectively assessed the diagnostic value of ED as a risk factor for AMI, in general. In this review, we aimed to better outline the diagnostic predictability of ED as a precursor for 'first/new onset' AMI. This review was performed using selective search terms, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The Cochrane, Embase, PubMed, Scopus and Web of Science databases were searched (September 2018). Selected studies were further assessed for relevance and quality (Critical Appraisal Skills Program tool-Oxford). Four studies [573 participants; mean 143 (SD ± 76.3604) and median 141 participants] were eligible for analysis. Meta-analysis of the studies resulted in a pooled sensitivity of 51.36% (95% CI: 47.37-55.33%). For the single study which reported true negative and false positive cases, a specificity of 76.53% (95% CI: 68.57-83.00%) was calculated. The results of this systematic review and meta-analysis suggest that a history of ED should be used as a risk factor for new onset AMI.

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells.

Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential.

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.

Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells.

Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling. The best-established mechanism of mTOR activation in cancer is via PI3K/Akt signaling, but mTOR activity can also be stimulated by CDK4 and PIM kinases. In this study, we show that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation. TSC2 or PIK3CA mutations obviate the requirement for PIM kinase and circumvent the inhibition of S6 phosphorylation by abemaciclib. Combination with a PI3K inhibitor restored suppression of S6 phosphorylation and synergized to curtail cell growth. By combining abemaciclib with a PI3K inhibitor, three pathways (Akt, PIM, and CDK4) to mTOR activation are neutralized, suggesting a potential combination strategy for the treatment of PIK3CA-mutant ER+ breast cancer.

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.

The ultrasound 'twinkling artefact' in the diagnosis of urolithiasis: hocus or valuable point-of-care-ultrasound? A systematic review and meta-analysis.

Presentation to the emergency department with renal colic has been reported as between 6.7 and 27.9 per 1000 emergency department visits. Clinicians rely on various radiological investigations for the prompt and accurate diagnosis of urolithiasis. This review assesses the validity of the colour Doppler ultrasonographic twinkling artefact (TA) sign as a diagnostic tool for the presence of urolithiasis. A systematic search of the Cochrane Database of Systematic Reviews, Embase, PubMed, Scopus and Web of Science databases was performed (October 2018) using specific search terms. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines and the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool were applied to rank and evaluate selected studies. Twenty-two articles that included 4389 participants were assessed. The median sample size was 102.5 (interquartile range: 47-292.5) and the age range of participants was 4-91 years. Meta-analysis of the studies that provided sufficient data resulted in a pooled sensitivity and specificity for the ultrasonographic TA sign of 88.16 [95% confidence interval (CI): 87.07-89.19%] and 79.22% (95% CI: 73.41-84.26%) respectively, with an estimated summary effect of 3.84 (95% CI: 1.08-6.60, P 0.006) in log odds ratio terms. There was significant interstudy heterogeneity as suggested by an I-statistic of 94.51% (95% CI: 94.51-99.58) and an estimated τ parameter of 7.21 (SE: 7.44). Despite the suboptimal pooled sensitivity and specificity of the TA sign and the large heterogeneity between published studies, the current body of evidence suggests that the colour Doppler ultrasonographic TA sign may be useful as a complementary tool in the diagnostic workup of patients with suspected urolithiasis.

Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy.

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.

[Pharmacological Effects of CDK4 & 6 Selective Inhibitor Abemaciclib in Hormone Receptor-Positive Breast Cancer].

Abemaciclib, a selective cyclin dependent kinases 4 and 6(CDK4 & 6)inhibitor, is under development for the treatment of hormone receptor(HR)-positive, HER2-negative breast cancer. CDK4 & 6 inhibitors attenuate Rb phosphorylation resulting in a G1 arrest and tumor growth inhibition. Abemaciclib potently inhibits both CDK4 and CDK6, with 14-fold higher potency for CDK4-cyclin D1 complexes than CDK6-cyclin D3 in enzymatic assays. Low frequency of severe neutropenia requiring drug holiday in clinical trials of abemaciclib in breast cancer patients enables continuous daily dosing. Abemaciclib's preclinical difference in selectivity for CDK4 vs CDK6 could help explain its safety profile and ability to be dosed on a continuous schedule. Continuous inhibition of CDK4 & 6 by abemaciclib results in irreversible growth inhibition through induction of senescence and apoptosis in breast cancer cell lines. Abemaciclib shows its growth inhibitory effect particularly in estrogen receptor(ER)- positive breast cancer, and sensitivity to abemaciclib is associated with high ER levels and Rb positivity. In animals bearing ERpositive breast cancer, significant tumor growth inhibition was shown by single-agent and combination with anti-estrogen agents. Abemaciclib penetrates the blood-brain barrier and showed antitumor activity in glioma models. As described above, there are some characteristics demonstrate differences of abemaciclib and other CDK4 & 6 inhibitors. In clinical studies, abemaciclib has demonstrated efficacy and generally tolerable safety profile in HR-positive, HER2-negative breast cancer patients.

Single-cell transcriptomic profiling of the aging mouse brain.

The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand-receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell-type specific manner, even at times in opposite directions. These data reveal that aging, rather than inducing a universal program, drives a distinct transcriptional course in each cell population, and they highlight key molecular processes, including ribosome biogenesis, underlying brain aging. Overall, these large-scale datasets (accessible online at https://portals.broadinstitute.org/single_cell/study/aging-mouse-brain ) provide a resource for the neuroscience community that will facilitate additional discoveries directed towards understanding and modifying the aging process.

Growth differentiation factor 11 (GDF11) has pronounced effects on skin biology.

Growth differentiation factor 11 (GDF11) belongs to the TGF-ß superfamily of proteins and is closely related to myostatin. Recent findings show that GDF11 has rejuvenating properties with pronounced effects on the cardiovascular system, brain, skeletal muscle, and skeleton in mice. Several human studies were also conducted, some implicating decreasing levels of circulating GDF11 with age. To date, however, there have not been any reports on its role in human skin. This study examined the impact of GDF11 on human skin, specifically related to skin aging. The effect of recombinant GDF11 on the function of various skin cells was examined in human epidermal keratinocytes, dermal fibroblasts, melanocytes, dermal microvascular endothelial cells and 3D skin equivalents, as well as in ex vivo human skin explants. GDF11 had significant effects on the production of dermal matrix components in multiple skin models in vitro and ex vivo. In addition, it had a pronounced effect on expression of multiple skin related genes in full thickness 3D skin equivalents. This work, for the first time, demonstrates an important role for GDF11 in skin biology and a potential impact on skin health and aging.

The 'John Thomas' sign and pelvic fractures-Fact or humorous myth?: A systematic review and meta-analysis.

OBJECTIVES: An incidental and sometimes humorous finding on an Antero-Posterior (AP) pelvis X-ray view is that of the John Thomas Sign (JTS), which is defined as positive, when the penile shadow points towards the side of a hip or pelvic fracture in male patients. Despite previous research reports and studies performed on the JTS sign, uncertainty with regards to its clinical relevance still remains. The objective of this review was to assess the clinical validity and accuracy of this sign by performing a systematic review and meta-analysis. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search was performed (May 2017), using the following databases: BMJ best practice, Cochrane Database of Systematic Reviews, EMBASE, PubMed and Scopus. Studies comparing the predictability of the JTS were critically appraised. The summary effect (and 95% CI) was estimated using a random effect model and the Restricted Maximum Likelihood Method. The pooled sensitivity as well as the summary effect log odds ratio was determined. Selected studies were further ranked for quality and relevance using the Critical Appraisal Skills Program (CASP) (Oxford 2013) tool. RESULTS: In total, nine articles were isolated and assessed. A total of 1942 participants were included. The mean sample size amongst these included studies was 243 participants with a median of 198 participants. Since the necessary data needed for the Meta-analysis was only present in the 6/9 studies assessed, these 6 were analyzed further. The JTS was positive in 1089 out of 1439 patients with a pooled sensitivity of 75.7% (95%CI, 73.4%-77.9%). There was a large variation in the sensitivity and specificity amongst studies, accounting for a non-significant summary Odds Ratio effect of -0.03. CONCLUSIONS: Based on this review, there is insufficient statistical evidence to support the reliability of the JTS to predict the laterality in the case of a hip fracture on the standard AP pelvis x-ray.

Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene.

Loss-of-function mutations in the retinoblastoma gene RB1 are common in several treatment-refractory cancers such as small-cell lung cancer and triple-negative breast cancer. To identify drugs synthetic lethal with RB1 mutation (RB1 mut), we tested 36 cell-cycle inhibitors using a cancer cell panel profiling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest RB1 association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against RB1 mut cancer cells and leads to durable regression of RB1 mut tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identification of a synthetic lethal interaction between RB1 and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-deficient malignancies, including patients progressing on CDK4/6 inhibitors.See related commentary by Dick and Li, p. 169.This article is highlighted in the In This Issue feature, p. 151.

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice.

Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.