The transforming growth factor-beta (TGF-β) signaling pathway is a vital regulator of cell proliferation, differentiation, apoptosis, and extracellular matrix production. It functions through canonical SMAD-mediated processes and noncanonical pathways involving MAPK cascades, PI3K/AKT, Rho-like GTPases, and NF-κB signaling. This intricate signaling system is finely tuned by interactions between canonical and noncanonical pathways and plays key roles in both physiologic and pathologic conditions including tissue homeostasis, fibrosis, and cancer progression. TGF-β signaling is known to have paradoxical actions. Under normal physiologic conditions, TGF-β signaling promotes cell quiescence and apoptosis, acting as a tumor suppressor. In contrast, in pathological states such as inflammation and cancer, it triggers processes that facilitate cancer progression and tissue remodeling, thus promoting tumor development and fibrosis. Here, we detail the role that TGF-β plays in cancer and fibrosis and highlight the potential for future theranostics targeting this pathway.

Traumatic brain injury (TBI) is a serious condition in which trauma to the head causes damage to the brain, leading to a disruption in brain function. This is a significant health issue worldwide, with around 69 million people suffering from TBI each year. Immediately following the trauma, damage occurs in the acute phase of injury that leads to the primary outcomes of the TBI. In the hours-to-days that follow, secondary damage can also occur, leading to chronic outcomes. TBIs can range in severity from mild to severe, and can be complicated by the fact that some individuals sustain multiple TBIs, a risk factor for worse long-term outcomes. Although our knowledge about the pathophysiology of TBI has increased in recent years, unfortunately this has not been translated into effective clinical therapies. The U.S. Food and Drug Administration has yet to approve any drugs for the treatment of TBI; current clinical treatment guidelines merely offer supportive care. Outcomes between individuals greatly vary, which makes the treatment for TBI so challenging. A blow of similar force can have only mild, primary outcomes in one individual and yet cause severe, chronic outcomes in another. One of the reasons that have been proposed for this differential response to TBI is the underlying genetic differences across the population. Due to this, many researchers have begun to investigate the possibility of using precision medicine techniques to address TBI treatment. In this review, we will discuss the research detailing the identification of genetic risk factors for worse outcomes after TBI, and the work investigating personalized treatments for these higher-risk individuals. We highlight the need for further research into the identification of higher-risk individuals and the development of personalized therapies for TBI.

After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E (APOE) are known to increase risk for developing Alzheimer’s disease, however there is controversy from human and rodent studies as to whether ApoE4 is a risk factor for worse outcomes after brain trauma. To resolve these conflicting studies we have explored the effect of the human APOE4 gene in a reproducible mouse model that mimics common human injuries. We have investigated cellular and behavioral outcomes in genetically engineered human APOE targeted replacement (TR) mice following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. Relative to injured APOE3 TR mice, injured APOE4 TR mice had more inflammation, neurodegeneration, apoptosis, p-tau, and activated microglia and less total brain-derived neurotrophic factor (BDNF) in the cortex and/or hippocampus at 1 and/or 21 days post-injury. We utilized a novel personalized approach to treating APOE4 susceptible mice by administering Bryostatin-1, which improved cellular as well as motor and cognitive behavior outcomes at 1 DPI in the APOE4 injured mice. This study demonstrates that APOE4 is a risk factor for poor outcomes after rmTBI and highlights how personalized therapeutics can be a powerful treatment option.

Clinicians have long noticed that some Traumatic Brain Injury (TBI) patients have worse symptoms and take a longer time to recover than others, for reasons unexplained by known factors. Identifying what makes some individuals more susceptible is critical to understanding the underlying mechanisms through which TBI causes deleterious effects. We have sought to determine the effect of a single nucleotide polymorphism (SNP) in Brain-derived neurotrophic factor (BDNF) at amino acid 66 (rs6265) on recovery after TBI. There is controversy from human studies as to whether the BDNF Val66Val or Val66Met allele is the risk factor for worse outcomes after brain trauma. We therefore investigated cellular and behavioral outcomes in genetically engineered mice following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. We found that relative to injured Val66Val carriers, injured Val66Met carriers had a larger inflammation volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post-injury (DPI). We therefore concluded that the Val66Met genetic polymorphism is a risk factor for poor outcomes after rmTBI. In order to determine the mechanism for these differences, we investigated levels of the apoptotic-inducing pro BDNF and survival-inducing mature BDNF isoforms and found that Met carriers had less total BDNF in the cortex and a higher pro/mature ratio of BDNF in the hippocampus. We then developed a personalized approach to treating genetically susceptible individuals by overexpressing wildtype BDNF in injured Val66Met mice using an AAV-BDNF virus. This intervention improved cellular, motor, and cognitive behavior outcomes at 21 DPI and increased levels of mature BDNF and phosphorylation of mature BDNF’s receptor trkB. This study lays the groundwork for further investigation into the genetics that play a role in the extent of injury after rmTBI and highlights how personalized therapeutics may be targeted for recovery in susceptible individuals.

This review examines the role of positron emission tomography (PET) imaging tracers in advancing our understanding of traumatic brain injury (TBI) induced neurodegeneration and the therapeutic targets they help to identify. It focuses on tracers used to evaluate post-TBI alterations in metabolism, amyloid, tau, neuroinflammation, and neurotransmitter systems. These molecular imaging tools provide critical insights into pathophysiological processes such as disrupted glucose metabolism, amyloid deposition, tau accumulation, chronic neuroinflammatory responses, and neurotransmitter dysregulation. The review also explores how these tracers, as imaging biomarkers, may guide future therapeutic strategies. Finally, it discusses the challenges and opportunities associated with integrating PET imaging into TBI diagnosis, longitudinal monitoring, and treatment planning.

Cancer-associated fibroblasts (CAFs) are an abundant and diverse cell population within tumor microenvironments of solid tumors. Multiple subtypes of CAFs, defined by molecular and functional markers, have been described in the literature. CAFs contribute to tumor progression by remodeling the extracellular matrix, promoting immune evasion, and supporting angiogenesis and metastasis. Fibroblast activation protein (FAP) is a transmembrane serine protease minimally expressed in normal adult tissues but significantly upregulated in certain subtypes of CAFs across many solid tumors. High levels of FAP have been associated with poor prognosis in various cancers. FAP has increasingly emerged as a promising target for both imaging and therapy. Multiple FAP-targeting strategies, such as small molecules, monoclonal antibodies, drug conjugates, and radiolabeled ligands, are currently being investigated in preclinical and early clinical settings. This review provides a clinically focused overview of CAFs in the tumor microenvironment, highlighting key fibroblast markers, their associations with prognosis across various tumor types, and their utility in radiologic imaging and targeted therapy. We also discuss the potential of non-FAP fibroblast targeting molecules and the clinical rationale for more selective, subtype-specific strategies. By examining fibroblast biology through a radiologist’s lens, we aim to explore the evolving role of stromal targeting in imaging and the treatment of solid tumors.