Aldrich, J. | Search bioRxiv

bioRxiv2025

Spinal cord injury in rats disrupts thermoregulation and suppresses stress-induced hyperthermia

Spinal cord injury (SCI) in humans can robustly dysregulate healthy autonomic nervous system function, including thermoregulation. Despite this, the relationship between SCI and autonomic dysfunction remains incompletely understood and is often overlooked in rodent models that emphasize locomotor recovery. One notable autonomic output in rodents is stress-induced hyperthermia, which is a transient core temperature increase caused by an acute stressor. Here, we tested whether SCI in rats dysregulates stress-induced hyperthermia. To assess SCI-induced thermoregulatory dysfunction, we continuously monitored core temperature in male and female rats using implantable telemetry devices before and after a T8 contusion SCI (or sham surgery including laminectomy). Prior to surgery, stress—in response to handling and cage changes— resulted in transient hyperthermia that peaked ∼1°C higher than baseline and lasted 60-90 minutes. Sham-operated rats retained typical stress-induced hyperthermia beginning immediately after surgery. In contrast, SCI transiently abolished stress-induced hyperthermia in both sexes, indicating a profound disruption in autonomic regulation acutely after injury. Within 3-4 weeks after SCI, the stress-induced hyperthermic response gradually returned and reached pre-injury levels by week seven. Therefore, thoracic SCI in rats abolishes stress-induced hyperthermia, which gradually recovers over time post-injury. Overall, this study underscores the impact of incomplete SCI on autonomic function and highlights the need for future research focused on autonomic outcomes.HighlightsHandling and care procedures elicit stress-induced hyperthermia in ratsStress-induced hyperthermia was abolished in rats after spinal cord injuryStress-induced hyperthermia gradually returned over the subsequent weeksBy 7 weeks, the hyperthermic response had returned to pre-injury levels

neuroscience↗

bioRxiv2017

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine melanoma by integrated comparative genomic analysis

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.\n\nAUTHOR SUMMARYMelanoma, an aggressive cancer arising from transformed melanocytes, commonly occurs in pet dogs. Unlike human melanoma, which most often occurs in sun-exposed cutaneous skin, canine melanoma typically arises in sun-shielded oral mucosa. Clinical features of canine melanoma resemble those of human melanoma, particularly the less common sun-shielded human subtypes. However, whereas the genomic basis of diverse human melanoma subtypes is well understood, canine melanoma genomics remain poorly defined. Similarly, although diverse new treatments for human melanoma based on a biologic disease understanding have recently shown dramatic improvements in outcomes for these patients, treatments for canine melanoma are limited and outcomes remain universally poor. Detailing the genomic basis of canine melanoma thus provides untapped potential for improving the lives of pet dogs while also helping to establish canine melanoma as a comparative model system for informing human melanoma biology and treatment. In order to better define the genomic landscape of canine melanoma, we performed multi-platform characterization of 37 tumors. Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 as well mutational patterns that share important similarities with human melanoma subtypes. We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma. These data will guide additional biologic and therapeutic studies in canine melanoma while framing the utility of comparative studies of canine and human cancers more broadly.

cancer biology↗