Custody: Kids, Counsel and the Constitution

Fifty years ago, the United States Supreme Court in In re Gault held that children have the constitutional right to traditional counsel in cases where their physical liberty interests are at stake. As a result, children are provided counsel during the adjudication phase of delinquency proceedings in order to ensure protection of their rights. Gault did not, however, extend the automatic right to traditional counsel to other contexts in which children most frequently appear in court: family law cases. This Article explores whether a child’s right to traditional counsel should be extended to children in the private custody context. The article reviews cases that have explicitly expanded children’s rights since Gault, both children’s cases expanding their rights in various contexts and adults’ cases with implications for children in the family context. In addition, it reviews current inconsistencies in practice, rules and standards related to children’s attorneys. It concludes that children’s constitutional rights require traditional client-directed advocacy by attorneys in custody matters, and recommends a role of counsel that protects constitutional rights while ensuring consistent and ethical advocacy by children’s attorneys

Juvenile Pariahs

Under federal and some state laws, juveniles who have been adjudicated delinquent for sex offenses can be required to register on sex offender registries for extended periods or life. In some jurisdictions, lifetime sex offender registration, community notification, and other sex offender restrictions are mandatory.This Article explores whether mandatory lifetime sex offender registration, community notification and other sex offender restrictions violate the Eighth Amendment’s guarantee against cruel and unusual punishment as applied to juveniles. Citing Roper v. Simmons and Graham v. Florida, the United States Supreme Court recently held in Miller v. Alabama that assigning mandatory life-without-parole prison sentences to juveniles violates the Eighth Amendment because a judge must be allowed to consider mitigating circumstances—including a juvenile’s lack of maturity, vulnerability to negative influences, and capacity for change—before imposing a lifetime penalty. With Miller, and before that Graham, the Court extended the definition of the “most severe” punishments to include permanent non-capital punishments applied to juveniles. This reasoning should be applied to mandatory lifetime sex offender registration and related restrictions as applied to juveniles because they are similarly punitive and permanent penalties

Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis