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Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research.

BackgroundPancreatic cancer is projected to become the second leading cause of cancer death in the United States by 2030. Screening of high-risk individuals (HRI’s) using endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI), specifically magnetic resonance cholangiopancreatography (MRCP), saves lives and reduces morbidity and mortality. Screening can detect surgically resectable lesions, which is key to survival since most lesions present as unresectable or metastatic. The specific aims of this project were to address the quality improvement process to track adherence of the patients who participate in the high-risk pancreatic cancer clinic at UMass Memorial Healthcare.MethodsPatients deemed to be high risk according to the Cancer of the Pancreas Screening (CAPS) Consortium Guidelines included having at least one first-degree relative with a diagnosis of pancreatic cancer, a genetic mutation that places them at higher risk for pancreatic cancer, or both are the cohort. The data was collected via EMR using REDCap, a secure web application to analyze high-risk patients’ adherence with yearly screening. The method utilized a quality improvement project design.ResultsResults demonstrated a majority of participants were female, 53% had a first-degree relative with pancreatic cancer, a majority of participants did not carry a genetic mutation while the highest mutation finding included 16 participants (14.4%) with a BRCA 2 gene mutation. A majority of participants, 64.9% (n=72) were non-compliant with screening while 35% (n=39) had yearly screening. Participants who were non-adherent with screening endorsed multiple factors for non-adherence including not believing surveillance was necessary, not qualifying for screening at the time of initial appointment, not receiving reminder phone calls for clinic appointments and surveillance imaging, other health concerns, high insurance deductibles, the COVID pandemic, and high anxiety.ConclusionsMitigation of the reasons for non-adherence is a crucial practice implication. Patient education regarding the importance of long-term yearly screening and teaching patients self-efficacy behaviors may improve screening adherence. Prospectively analyzing compliance will reduce missed care opportunities. Health care policies must be amended to require insurance companies to cover the screening of HRI’s.

Abstract To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion—even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as “aging” by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

Gain-of-function mutations in STimulator of INterferon Genes (STING) cause STING-Associated Vasculopathy with Onset in Infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, non-healing ulcers. Mice expressing the most common SAVI-associated variant STING (VM) recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low dose of ultraviolet B (UVB) irradiation, which induces only transient skin inflammation in wild-type (WT) mice, causes severe and progressive skin injury in VM mice. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with WT bone marrow, demonstrating that STING expression in non-hematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis identified endothelial cells expressing STING as the primary driver of the cutaneous phenotype. Flow cytometry and bulk RNA sequencing showed that VM mice exhibited reduced early skin infiltration of macrophages and dendritic cells after UVB exposure. These findings establish a critical link between endothelial STING activation, impaired recruitment of skin myeloid cells, and defective resolution of acute inflammation, offering new insights into the pathogenesis of SAVI-associated skin disease.

Gain-of-function mutations in STimulator of INterferon Genes (STING) cause STING-Associated Vasculopathy with Onset in Infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, non-healing ulcers. Mice expressing the most common SAVI-associated variant STINGV154M (VM) recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low dose of ultraviolet B (UVB) irradiation, which induces only transient skin inflammation in wild-type (WT) mice, causes severe and progressive skin injury in VM mice. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with WT bone marrow, demonstrating that STINGV154M expression in non-hematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis identified endothelial cells expressing STINGV154M as the primary driver of the cutaneous phenotype. Flow cytometry and bulk RNA sequencing showed that VM mice exhibited reduced early skin infiltration of macrophages and dendritic cells after UVB exposure. These findings establish a critical link between endothelial STING activation, impaired recruitment of skin myeloid cells, and defective resolution of acute inflammation, offering new insights into the pathogenesis of SAVI-associated skin disease.