Citations

AbstractThe Endosomal Sorting Complexes Required for Transport (ESCRTs) drive membrane remodeling in a variety of cellular processes that include the formation of endosomal intralumenal vesicles (ILVs) during multivesicular body (MVB) biogenesis. During MVB sorting, ESCRTs recognize ubiquitin (Ub) attached to membrane protein cargo and execute ILV formation by controlling the activities of ESCRT‐III polymers regulated by the AAA‐ATPase Vps4. Exactly how these events are coordinated to ensure proper cargo loading into ILVs remains unclear. Here we discuss recent work documenting the ability of Bro1, an ESCRT‐associated Ub‐binding protein, to coordinate ESCRT‐III and Vps4‐dependent ILV biogenesis with upstream events such as cargo recognition.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)–expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti–PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti–PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti–PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Abstract Objective To compare the artificial intelligence‐enabled electrocardiogram (AI‐ECG) atrial fibrillation (AF) prediction model output in patients with migraine with aura (MwA) and migraine without aura (MwoA). Background MwA is associated with an approximately twofold risk of ischemic stroke. Longitudinal cohort studies showed that patients with MwA have a higher incidence of developing AF compared to those with MwoA. The Mayo Clinic Cardiology team developed an AI‐ECG algorithm that calculates the probability of concurrent paroxysmal or impending AF in ECGs with normal sinus rhythm (NSR). Methods Adult patients with an MwA or MwoA diagnosis and at least one NSR ECG within the past 20 years at Mayo Clinic were identified. Patients with an ECG‐confirmed diagnosis of AF were excluded. For each patient, the ECG with the highest AF prediction model output was used as the index ECG. Comparisons between MwA and MwoA were conducted in the overall group (including men and women of all ages), women only, and men only in each age range (18 to <35, 35 to <55, 55 to <75, ≥75 years), and adjusted for age, sex, and six common vascular comorbidities that increase risk for AF. Results The final analysis of our cross‐sectional study included 40,002 patients (17,840 with MwA, 22,162 with MwoA). The mean (SD) age at the index ECG was 48.2 (16.0) years for MwA and 45.9 (15.0) years for MwoA ( p < 0.001). The AF prediction model output was significantly higher in the MwA group compared to MwoA (mean [SD] 7.3% [15.0%] vs. 5.6% [12.4%], mean difference [95% CI] 1.7% [1.5%, 2.0%], p < 0.001). After adjusting for vascular comorbidities, the difference between MwA and MwoA remained significant in the overall group (least square means of difference [95% CI] 0.7% [0.4%, 0.9%], p < 0.001), 18 to <35 (0.4% [0.1%, 0.7%], p = 0.022), and 35 to <55 (0.5% [0.2%, 0.8%], p < 0.001), women of all ages (0.6% [0.3%, 0.8%], p < 0.001), men of all ages (1.0% [0.4%, 1.6%], p = 0.002), women 35 to <55 (0.6% [0.3%, 0.9%], p < 0.001), and men 18 to <35 (1.2% [0.3%, 2.1%], p = 0.008). Conclusions Utilizing a novel AI‐ECG algorithm on a large group of patients, we demonstrated that patients with MwA have a significantly higher AF prediction model output, implying a higher probability of concurrent paroxysmal or impending AF, compared to MwoA in both women and men. Our results suggest that MwA is an independent risk factor for AF, especially in patients <55 years old, and that AF‐mediated cardioembolism may play a role in the migraine–stroke association for some patients.

Abstract BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.

AbstractSeizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4‐NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune‐associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4‐NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)‐like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM‐like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4‐NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most‐updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4‐NMOSD/MOGAD. Treatment cautions including drug‐drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.

Background Persons who accumulate chronic conditions at a rate faster than their peers may experience accelerated aging and poor health outcomes, including functional limitations. Methods Adults aged ≥40 years who resided in Olmsted County, Minnesota on 1 January 2006 were identified. The prevalence of 21 chronic conditions was ascertained, and age-specific quartiles of the number of chronic conditions was estimated within 4 age groups: 40–54, 55–64, 65–74, and ≥75 years. Difficulty with nine patient-reported functional limitations (including basic and instrumental activities of daily living and mobility activities) were ascertained through 31 October 2018. Cox regression was used to model associations of chronic condition quartiles with new-onset functional limitations considered separately. We estimated absolute risk differences and hazard ratios stratified by age group, and adjusted for sex, race, ethnicity, marital status, education, and the residual effect of age. Results Among 39,624 persons (44.5% men, 93.2% white), the most common reported new functional limitations were difficulty with climbing stairs, walking, and housekeeping. For all functional limitations, the absolute risk differences were largest among the oldest age group (≥75 years). Approximately twofold increased hazard ratios were observed among those in the highest vs. lowest quartile for the three oldest age groups, and approximately threefold or higher hazard ratios were observed for persons aged 40-54 years. Conclusion Persons with increased accumulation of chronic conditions experience increased risks of developing functional limitations compared to their peers. These findings underscore the importance of assessing health status and of employing interventions to prevent and effectively manage multi-morbidity at all ages.

Abstract Introduction End‐of‐life care differs by serious illness diagnosis. Cancer and dementia are serious illnesses that have been associated with less intensive end‐of‐life health care use. It is not known how health care utilization varies in the presence of >1 serious illness. Methods We used the Rochester Epidemiology Project to identify persons living in a midwestern area who died on July 1, 2017–June 30, 2018 at age ≥65 years, and were seriously ill. We examined the number of emergency department (ED), hospital, and intensive care unit (ICU) stays in the last 6 months and the last 30 days of life. We used Poisson regression to determine the incidence rate ratio for ED, hospital, and ICU stay in the last 6 months and 30 days of life by number of serious illness diagnoses. For cancer and dementia, we examined the effect of an additional serious illness. Results We included a population of 1372 adults who were, on average, 84 years, 52% female, and 96% white. Approximately 41% had multiple serious illnesses. Compared to older adults with 1 serious illness diagnosis, rates of hospitalization, and ICU stay for adults with 2 or ≥3 serious illness diagnoses were at least 1.5 times higher in the last 6 months and the last 30 days of life. Rates of ED visits were significantly higher for older adults with 2 or ≥3 serious illness diagnoses in the last 6 months of life, but only higher for those with ≥3 versus 1 serious illness diagnosis in the last 30 days of life. For both cancer and dementia, rates of ED visits, hospitalization and ICU stay were lower for the condition alone than when an additional serious illness diagnosis was present. Conclusion Having multiple serious illnesses increases the risk of health care utilization at the end of life.

Lay Summary Herein, we evaluated the humoral immunogenicity of a third coronavirus disease 2019 messenger RNA vaccine dose in patients with inflammatory bowel diseases. All patients displayed a humoral immune response, and median antibody concentrations were higher after the third dose than after completion of the 2-dose series.