Faculty Bibliography

The notochord is an axial structure required for the development of all chordate embryos, from sea squirts to humans. Over the course of more than half a billion years of chordate evolution, in addition to its structural function, the notochord has acquired increasingly relevant patterning roles for its surrounding tissues. This process has involved the co-option of signaling pathways and the acquisition of novel molecular mechanisms responsible for the precise timing and modalities of their deployment. To reconstruct this evolutionary route, we surveyed the expression of signaling molecules in the notochord of the tunicate Ciona, an experimentally amenable and informative chordate. We found that several genes encoding for candidate components of diverse signaling pathways are expressed during notochord development, and in some instances, display distinctive regionalized and/or lineage-specific patterns. We identified and deconstructed notochord enhancers associated with TGF-β and Ctgf, two evolutionarily conserved signaling genes that are expressed dishomogeneously in the Ciona notochord, and shed light on the cis-regulatory origins of their peculiar expression patterns.

BACKGROUND:Hypertrophic cardiomyopathy is a genetic, life-threatening cardiovascular disease that often goes unidentified in pediatric patients. Patients are often asymptomatic and neither history or physical examination are reliable to detect the disease. The only reliable method to diagnose hypertrophic cardiomyopathy is with echocardiography to look at interventricular septal thickness. Emerging literature has shown that cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians is as effective and accurate compared with cardiac echocardiography performed by pediatric cardiologists. OBJECTIVE:The objective of the study was to determine the diagnostic accuracy of POCUS performed by ultrasound-trained PEM physicians in measuring the interventricular septum end diastole (IVSd) thickness in the pediatric emergency department. METHODS:We conducted a prospective, single-center, observational, diagnostic accuracy study to examine the diagnostic accuracy of POCUS in measuring IVSd thickness in pediatric patients who presented to the pediatric emergency department with symptoms that prompted a cardiac POCUS. Cardiac POCUS findings were interpreted by a PEM physician at the bedside and retrospectively by a pediatric cardiologist. Diagnostic concordance of the measurements obtained by the PEM physician and cardiologist was assessed. RESULTS:Forty-eight patients were enrolled. Median patient age was 13.4 years. There was excellent diagnostic agreement on the measurement of the IVSd thickness between PEM physicians and the pediatric cardiologist (81.25% of cases; 39/48). Disagreement was seen in 18.75% of the cases (9/48). The mean error of disagreement was -0.32, with a 95% confidence interval of -0.37 to -0.28. Overall, the mean error of both agreement and disagreement was -0.046, with 95% confidence interval of -0.08 to -0.01 and P value of 0.008. CONCLUSIONS:Point-of-care ultrasound performed by ultrasound-trained PEM physicians to measure pediatric IVSd thickness has a high diagnostic accuracy with excellent agreement with a pediatric cardiologist.

INTRODUCTION/BACKGROUND:Current guidelines for treatment for locally advanced pancreatic cancer recommend chemotherapy ± radiation, or radiation alone when multimodal therapy is contraindicated. In a subset of patients, guideline-recommended treatment (GRT) achieves sufficient response to qualify for potentially curative resection. This study evaluated trends in treatment utilization and aimed to identify barriers to GRT. METHODS:Patients with clinical T4M0 disease in the National Cancer Database from 2010 to 2017 were included. Potential predictors were assessed by relative risk regression with Poisson distribution and compared by log-link function. RESULTS:In total, 28 056 patients met the criteria. Among 17 059 (67.67%) patients treated primarily with chemotherapy, 41.19% also had radiation and 8.89% went onto resection. Many received no cancer-directed treatment or failed to receive GRT. Another 710 patients had radiation (±surgery) without chemotherapy despite few contraindications to chemotherapy. Over time, patients were more likely to undergo resection after chemotherapy (aRR = 1.58; p < 0.0001) and less likely to have chemoradiation (aRR = 0.78; p < 0.0001) or go untreated (aRR = 0.90; p < 0.0001). Socioeconomic factors (race, education, income, and insurance status) affected the likelihood of receiving chemotherapy and surgery. Median overall survival (OS) was significantly improved for patients treated with chemotherapy and particularly in those patients who went on to receive RT or undergo surgical resection. OS was also longer for patients treated at high-volume academic centers. Patients insured by Medicaid, Medicare, or those without insurance had worse OS. CONCLUSIONS:Despite improvement over time, many patients go untreated. Clinical factors were influential, but the impact of vulnerable social standing suggests persistent inequity in access to care.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

INTRODUCTION/UNASSIGNED:This study examined the potential interplay between motor development and intervention in support of action understanding. METHODS/UNASSIGNED:Eighty nine-month-old infants completed a tool-use training session and goal imitation paradigm that assessed action understanding in counterbalanced order. A metric of motor development was obtained using the Early Motor Questionnaire. RESULTS/UNASSIGNED:Results indicated that training improved action understanding, particularly for those infants who started out with lower means-end skills. Results further indicated that infants who did not receive any training experience in the lab beforehand, drew on their existing means-end skills. DISCUSSION/UNASSIGNED:These results emphasize independent contributions of training and motor development on action understanding and shed light on the interaction between training and individual motor readiness in facilitating action understanding in infancy.