Minimally Invasive Surgery in Neonates with Congenital Anomalies: Experience from the NSQIP-P

Background: Congenital diaphragmatic hernias (CDH) and tracheoesophageal fistulas (TEF) are managed with minimally invasive surgery (MIS) or open surgery. Little is known about the patient populations and outcomes for those treated by each approach. Hypothesis/Specific Aims: We expect that there will be fewer complications, better outcomes, and longer operative times for the MIS group versus the open group. Methods: National Surgical Quality Improvement Program-Pediatric Participant Use Files (NSQIP-P PUFs) from 2012-2015 were used to identify neonates (up to 30 days old) who underwent CDH and TEF repair. The patient characteristics, post-operative complications, and 30-day mortality were analyzed using multivariable logistic regression to determine morbidity associated with each. Data/Results: We identified 1,142 neonates who underwent CDH (n=577) and TEF (n=565) repair. Neonates who underwent open repair were sicker than those who underwent MIS and had slightly worse select outcomes. Median operative time was longer for both CDH and TEF with the MIS approach. However, multivariable logistic regression analysis adjusting for patient comorbidities showed that open versus MIS surgical approach was not associated with increased morbidity. Discussion: Neonates who underwent MIS repair had fewer co-morbidities and better outcomes. This surgical approach was not associated with any adverse 30-day outcomes in the multivariable models. This suggests that MIS repair of CDH and TEF can be safely performed in a subset of patients, but further research is needed to understand whether surgical approach affects the incidence of longer-term complications such as CDH recurrence or esophageal stricture

Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C‐MYC depletion

The down‐regulation of dominant oncogenes, including C‐MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC‐depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase (TS) and ribonucleotide reductase (RR) and subsequent depletion of deoxyribonucleoside triphosphate pools. Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC‐depletion. Reciprocally, overexpression of TS and RR in melanoma cells or addition of deoxyribonucleosides to culture media substantially inhibited DNA damage and senescence‐associated phenotypes caused by C‐MYC depletion. Our data demonstrate the essential role of TS and RR in C‐MYC‐dependent suppression of senescence in melanoma cells.Keywords: ribonucleotide reductase, oncogene‐induced senescence, dNTP, myc, melanoma, thymidylate synthas

Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Alexander disease (AxD) is a devastating leukodystrophy caused by gain-of-function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report, we introduce a rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with about 14% dying of unknown cause between 6 and 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long-lasting suppression, reverses GFAP pathology, and, depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. In this report, we characterize an improved animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease, and use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease

High resolution IgH repertoire analysis reveals fetal liver as the likely origin of life-long, innate B lymphopoiesis in humans

The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM+ B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM+ B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime