Valdes, J. A. | Search bioRxiv

bioRxiv2026

Immunizing small cell lung cancer mice with isoaspartylated Elavl4 after chemotherapy mimics improved survival of anti-ELAVL4 antibody-positive small cell lung cancer patients

Introduction: Small cell lung cancer (SCLC) patients have an ~8% 5-year survival; new therapies are urgently needed. Approximately 15% of SCLC patients have naturally-occurring low-titer antibodies against neuronal ELAVL proteins, associated with improved response to therapy and significantly improved survival. We previously determined that the anti-ELAVL4 response is triggered by isoaspartylation in the unstructured ELAVL4 N-terminal region. Methods: We used a Tp53fl/fl;Rb1fl/fl inducible SCLC mouse model to test whether 1) immunization with isoaspartylated Elavl4 (isoAsp-Elavl4) prior to SCLC induction improves survival in the absence of any other treatment, and 2) immunization with isoAsp-Elavl4 following completion of 3 rounds of cisplatin+etoposide therapy improves survival. Immunizations contained incomplete Freund's adjuvant with either a recombinant N-terminal fragment of Elavl4 (amino acids 1-117), incubated under isoaspartyl-inducing conditions, or phosphate-buffered saline (used as the negative control, since Elavl4 spontaneously isoaspartylates). Mice were monitored by blinded assessors until euthanasia was indicated. Results: IsoAsp-Elavl4-immunized animals all became immune responsive, and spontaneous anti-isoAsp-Elavl4 antibodies were observed in 7% of the control animals. Kaplan-Meier analyses revealed that pre-SCLC immunization with isoAsp-ELAVL4 in the absence of other treatments did not affect survival. In contrast, immunization of SCLC mice following chemotherapy significantly improved survival. Conclusions: An anti-isoAsp-ELAVL4 response can be actively induced in mice and significantly increases SCLC survival when given following chemotherapy. This indicates that the anti-isoAsp-ELAVL4 immune response can be leveraged to develop new therapies for SCLC patients.

cancer biology↗

bioRxiv2022

Neural systems underlying RDoC social constructs: An activation likelihood estimation meta-analysis

Neuroscientists have sought to identify the underlying neural systems supporting social processing that allow interaction and communication, forming social relationships, and navigating the social world. Through the use of NIMHs Research Domain Criteria (RDoC) framework, we evaluated consensus among studies that examined brain activity during social tasks to elucidate regions comprising the "social brain". We examined convergence across tasks corresponding to the four RDoC social constructs, including Affiliation and Attachment, Social Communication, Perception and Understanding of Self, and Perception and Understanding of Others. We performed a series of coordinate-based meta-analyses using the activation likelihood estimate (ALE) method. Meta-analysis was performed on whole-brain coordinates reported from 864 fMRI contrasts using the NiMARE Python package, revealing convergence in medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, temporoparietal junction, bilateral insula, amygdala, fusiform gyrus, precuneus, and thalamus. Additionally, four separate RDoC-based meta-analyses revealed differential convergence associated with the four social constructs. These outcomes highlight the neural support underlying these social constructs and inform future research on alterations among neurotypical and atypical populations.

neuroscience↗