👤 Johanna Calderon

Dichlorodiphenyltrichloroethane (DDT), a persistent organochlorine pesticide, continues to be used for malaria control under the Stockholm Convention. We investigated associations between exposure to DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) and midlife cognitive function and brain structure among primarily Mexican-born Latina women in an agricultural community in California, USA. In the CHAMACOS Maternal Cognition Study, a prospective cohort study, we assessed global and domain-specific cognitive performance in 472 women. A subset of 95 women underwent T1-weighted brain MRI to measure cortical thickness. We evaluated associations between serum p,p'-DDT and p,p'-DDE concentrations-measured 12 years earlier-and cognitive Z scores and cortical thickness using linear regression. Bayesian hierarchical models accounted for co-exposure to other organochlorine pesticides. Apolipoprotein E (APOE) genotype was assessed as a potential modifier. Higher p,p'-DDT and p,p'-DDE concentrations were significantly associated with lower executive function scores (p,p'-DDT β=-0·10 [95% CI -0·18 to -0·02]; p,p'-DDE β=-0·09 [-0·19 to 0·00]; SDs per ten-fold increase in serum concentration). No associations were observed with other cognitive domains. Results were robust to adjustment for APOE genotype and organochlorine co-exposures. No effect modification by APOE ε4 status was found. Both exposures were associated with greater frontal lobe cortical thickness, particularly in the medial orbitofrontal and pars orbitalis regions. p,p'-DDT and p,p'-DDE exposure was associated with reduced executive function more than a decade later, and with altered frontal brain structure. These findings suggest potential long-term neurodevelopmental effects of legacy organochlorine exposure and warrant further investigation. US National Institutes of Health and US Environmental Protection Agency. Show less

Children with complex congenital heart disease (CCHD) are at high risk for early neurodevelopmental delays across all domains. Neuromotor delay often emerges first and may impact broader development. Identifying early biomarkers of motor function could capture a critical window for intervention. We assessed the prognostic value of neuron-specific enolase (NSE) and S100B in predicting 4-month motor outcomes in newborns undergoing cardiac surgery with cardiopulmonary bypass (CPB). Between December 2021 and October 2024, we conducted a prospective, single-centre study including term neonates with (CCHD) who required cardiac surgery within the first two months of life. NSE and S100B levels were measured at five perioperative time points. Blinded Alberta Infant Motor Scale (AIMS) assessment at four months evaluated motor outcomes. Of 35 newborns, 27 completed follow-up. Preoperative NSE levels were significantly higher in infants with AIMS scores below the 10th percentile (32.7 vs. 20.9 ng/mL, p = 0.044) and negatively correlated with AIMS percentiles (ρ = -0.617, p = 0.006. There was no significant association between motor outcomes, MRI findings or S100B levels. Higher preoperative NSE levels predict poor early motor outcomes in CCHD and may be a marker for early risk stratification and intervention. Neuron-specific enolase (NSE) may serve as an early biomarker of neuromotor development in newborns with complex congenital heart disease (CCHD). Elevated preoperative NSE levels were associated with poorer motor outcomes at four months. NSE may serve as an additional biomarker within a multimodal risk stratification strategy, complementing clinical, imaging, and electrophysiological assessments to refine prognostic evaluation. These findings highlight the prognostic value of perioperative biomarkers for predicting early motor outcomes and support earlier identification of at-risk newborns, enabling targeted neurodevelopmental interventions. This work adds new evidence to limited literature on biological predictors of motor development after neonatal cardiac surgery. Show less

Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07 cells displayed a unique dependency on class III PI3K (PIK3C3). Unexpectedly, 4T07 cells exhibited higher mechanistic target of rapamycin complex 1 (mTORC1) activity than 4T1 cells due to lysosome-dependent signaling occurring at the cell periphery. Pharmacologic inhibition of PIK3C3 suppressed this phenotype in the 4T1-4T07 models as well as in human breast cancer cell lines and a breast cancer patient-derived xenograft. Furthermore, inhibiting PIK3C3 selectively reduced metastasis burden in the 4T07 model and eliminated dormant cells in a HER2-dependent murine breast cancer dormancy model. These findings suggest that PIK3C3-peripheral lysosomal signaling to mTORC1 may represent a targetable axis for preventing dormant cancer cell-initiated metastasis in patients with breast cancer. Dormancy-prone breast cancer cells depend on the class III PI3K to mediate peripheral lysosomal positioning and mTORC1 hyperactivity, which can be targeted to blunt breast cancer metastasis. Show less

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1. We reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis. Show less

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC. Show less

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Show less