No abstract

Isocitrate dehydrogenase 1 (IDH1) is a key metabolic enzyme for maintaining cytosolic levels of α-ketoglutarate (AKG) and preserving the redox environment of the cytosol. Wild-type (WT) IDH1 converts isocitrate to AKG; however, mutant IDH1-R132H that is recurrent in human cancers catalyzes the neomorphic production of the oncometabolite d -2-hydroxyglutrate (D-2HG) from AKG. Recent work suggests that production of l -2-hydroxyglutarte in cancer cells can be regulated by environmental changes, including hypoxia and intracellular pH (pHi). However, it is unknown whether and how pHi affects the activity of IDH1-R132H. Here, we show that in cells IDH1-R132H can produce D-2HG in a pH-dependent manner with increased production at lower pHi. We also identify a molecular mechanism by which this pH sensitivity is achieved. We show that pH-dependent production of D-2HG is mediated by pH-dependent heterodimer formation between IDH1-WT and IDH1-R132H. In contrast, neither IDH1-WT nor IDH1-R132H homodimer formation is affected by pH. Our results demonstrate that robust production of D-2HG by IDH1-R132H relies on the coincidence of (1) the ability to form heterodimers with IDH1-WT and (2) low pHi or highly abundant AKG substrate. These data suggest cancer-associated IDH1-R132H may be sensitive to physiological or microenvironmental cues that lower pH, such as hypoxia or metabolic reprogramming. This work reveals new molecular considerations for targeted therapeutics and suggests potential synergistic effects of using catalytic IDH1 inhibitors targeting D-2HG production in combination with drugs targeting the tumor microenvironment.

Objective To determine if secondary alveolar bone grafting (SABG) timing in patients with cleft lip and palate (CLP) influences the future need for additional maxillary advancement procedures, particularly Le Fort I osteotomy with rigid external distraction (RED). Design Retrospective cohort study. Groups were separated by SABG timing: early mixed dentition (ages 68 years) or late mixed dentition (ages 9-11 years). The criterion for RED was negative overjet ≥8 mm, and sufficient dental development for RED. Setting Single tertiary care institution. Patients Patients with CLP that underwent SABG from 2010 to 2015. Exclusion criteria included syndromic conditions, SABG surgery at age >12 years, current age <12 years, and <2 years follow-up. 104 patients were included. Main outcome measures The number of RED candidates and treated patients. Results There was no statistical difference in the number of RED candidates ( P  =  .0718) nor treated patients ( P  =  .2716) based on SABG timing; stratification by laterality was also insignificant. Early SABG is associated with higher odds of being a RED candidate (pooled, unilateral, bilateral) and treated patient (pooled and unilateral); however, there were no statistically significant associations between SABG timing and the number of RED candidates and treated patients as determined by logistic regression models. Conclusion There is no statistically significant association between SABG timing and the odds of being a RED candidate or treated patient. Future prospective studies are recommended to assess the relationship between SABG timing and maxillary growth in patients with CLP.