Biology subjects

Bassett, R.

Publications and source records attributed to Bassett, R..

4 recordsLinked to original sources

bioRxiv2025

2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice

2-Methoxyestradiol (2ME2, Panzem) is an endogenous metabolite that is well-tolerated in phase I/II clinical trials for variety of tumors. The plasma levels of 2ME2 may increase up to 1,000-fold during pregnancy and correlate temporally with the remission of rheumatoid arthritis (RA) and multiple sclerosis (MS) symptoms. The anti-inflammatory properties of 2ME2 were recently established in the mouse model of MS, and the mechanism of action is the ability of 2ME2 to inhibit lymphocyte proliferation, cytokine production and T cell polarization. Herein, we have demonstrated that 2ME2 treatment can significantly reduce the mortality and morbidity associated with graft-versus-host disease (GVHD). There is a lower number of donor-derived CD4+ and CD8+ T cells in the peripheral lymph node and Peyers patches of 2ME2-treated mice compared to control recipients. Moreover, 2ME2 exposure can significantly decrease the production of IFN-{gamma} and IL-2 in donor-derived CD4+ T cells and serum in GVHD mice. However, 2ME2 treatment has no effect on the differentiation of CD8+ effector T cells in vivo and their cytolytic activity remains intact. Furthermore, 2ME2 therapy is effective in preventing GVHD while preserving graft-versus leukemia (GVL) activity in mice. Our findings indicate that 2ME2 could be a novel and effective treatment for GVHD patients.

immunology↗

bioRxiv2025

Activating RET Mutations Promotes Osteoblastic Bone Metastases in Medullary Thyroid Cancer

Development of bone metastases increases mortality in patients with medullary thyroid cancer (MTC), with [~]50% survival at 5 years after diagnosis, but the underlying mechanisms are unknown. We show that patient-derived MTC cells (RETC634W mutant TT cells and RETM918T mutant MZCRC1 cells) promote an osteoblastic phenotype due to reduced bone resorption. Mechanistically, activated RET increases the expression of osteoprotegerin (OPG), an inhibitor of bone resorption, leading to decreased osteoclast differentiation. Furthermore, RET knockdown or pharmacological RET inhibition attenuates tumor burden and osteoblastic lesions in MTC-bearing femurs. Circulating levels of OPG were increased in the plasma of MTC patients who developed bone metastases and this was associated with poor overall survival. Patients who were treated with multi-kinase inhibitors have lower circulating levels of OPG. These novel findings identify a link between the RET signaling pathway and abnormal osteoblastic bone formation and suggest OPG as a potential biomarker of MTC bone metastases. HighlightsO_LIPatient-derived MTC cells promote osteoblastic lesions in a mouse model. C_LIO_LIActivating the RET mutation promotes osteoprotegerin. C_LIO_LIBlocking RET kinase activity inhibits tumor growth and the osteoblastic lesion phenotype. C_LIO_LIHigh levels of circulating osteoprotegerin are associated with poor overall survival. C_LI

cancer biology↗

bioRxiv2025

Multi-modal screening for synergistic neuroprotection of extremely preterm brain injury

Preterm brain injury affects both white and grey matter, including altered cortical development and gyrification, with associated neurodevelopmental sequelae such as cerebral palsy and learning deficits. The preterm brain also displays regionally heterogeneous responses to both injury and treatment, supporting the need for drug combinations to provide global neuroprotection. We developed an extremely preterm-equivalent organotypic whole hemisphere (OWH) slice culture injury model using the gyrencephalic ferret brain to probe treatment mechanisms of promising therapeutic agents and their combination. Regional and global responses to injury and treatment were assessed by cell death quantification, machine learning-augmented morphological microglia assessments, and digital transcriptomics. Using two promising therapeutic agents, azithromycin (Az) and erythropoietin (Epo), we show minimal neuroprotection by either therapy alone, but evidence of synergistic neuroprotection by Az*Epo both globally and regionally. This effect of Az*Epo involved emergent augmentation of transcriptomic responses to injury related to neurogenesis and neuroplasticity and downregulation of transcripts involved in cytokine production, inflammation, and cell death. This study supports the use of the ferret OWH slice culture model to provide a powerful high-throughput platform to examine combinations of therapeutics for extremely preterm brain injury.

neuroscience↗

bioRxiv2019

Simplified Molecular Classification of Lung Adenocarcinomas Based on EGFR, KRAS, and TP53 Mutations

IntroductionGene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.\n\nMethodsMutational status of EGFR, KRAS, and TP53 was used to define six mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.\n\nResultsThe proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with comutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.\n\nConclusionsThe mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into six subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

cancer biology↗