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AbstractBackground and purposeLower left atrial (LA) function is associated with higher dementia risk and may be mechanistically linked through vascular brain injury, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities study, we assessed the cross‐sectional association between LA function and brain magnetic resonance imaging (MRI) markers of vascular brain injury.MethodsWe included 1488 participants who were free of prevalent dementia, stroke, or atrial fibrillation and who underwent a two‐dimensional echocardiogram and brain MRI in 2011–2013 (mean [± standard deviation] age 76 [± 5] years, 60% female, 27% Black). LA function measures (reservoir, conduit, contractile strain) were assessed in quartiles. Brain MRI measures included cerebral microbleeds, brain infarcts, and white matter hyperintensity (WMH) volume. Logistic regression was used for dichotomous outcomes. Linear regression was used for WMH volume.ResultsOverall, 343 (23%) and 344 participants (23%) had ≥1 cerebral microbleed or brain infarct. After multivariable adjustments, the lowest LA reservoir and conduit strain quartiles (vs. highest quartile) were associated with higher odds of the presence of ≥1 cerebral microbleed (odds ratios [95% confidence intervals] 1.78 [1.42–2.22] and 1.52 [1.22–1.90]). Compared to the highest quartile, participants in the lowest LA conduit strain quartile had 1.51 (95% confidence interval 1.22–1.88) times higher odds of having ≥1 brain infarct. Lower LA contractile strain was associated with lower odds of brain infarcts. No association with WMH volume was noted.ConclusionsWe found that LA reservoir and conduit strain were associated with cerebral microbleeds and brain infarcts. Lower LA function may be linked to dementia risk via vascular brain injury. Prospective studies are needed to confirm these findings.

Knowledge of the adaptation of the soft tissue to mechanical factors and biomolecules would be essential to better understand the mechanism of tendon injury and to improve the outcome of tendon repair. The responses to these factors could be different for the distinct types of cells in the tendon: cells from the tendon sheath, fibroblasts from the epitenon surface, or fibroblasts from the internal endotenon. In this study, we examined the mechanical and histological characteristics of the rate of contraction of the collagen gel seeded with epitenon and endotenon fibroblasts. The rate of contraction and the mechanical property of the contracted construct depend on the gel concentration and also the treatment of TGF-β 1 .

Rosai–Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic neoplasm. Although the disease classically presents as massive painless lymphadenopathy in young adults, RDD can also involve the central nervous system in some patients. CNS lesions, can cause headaches, neurologic deficits, and even neurologic deficits. The imaging appearance of CNS RDD typically mimics that of meningiomas: well-circumscribed dural-based lesions that often have dural tails. However, some imaging clues also exist that might help a radiologist recognize RDD, even before histopathologic confirmation. This radiology-pathology report of a patient with CNS RDD highlights the most pertinent clinical, imaging, and pathologic features of CNS RDD, and discusses what the neuroradiologist needs to know about the disease.

Purpose of review The purpose of this article is to provide a review of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), with a focus on what renders optic neuritis “atypical” in these two conditions. Clinical features, diagnostic criteria, and epidemiology are outlined. Acute treatments for optic neuritis, as well as immunotherapy for NMOSD and MOGAD are discussed. Recent findings Updates in NMOSD and MOGAD are highlighted, with an emphasis on novel work including the new 2023 MOGAD diagnostic criteria, our evolving understanding on the epidemiology of these conditions, and recently FDA-approved NMOSD treatments. Pipeline therapies are also discussed. Summary A thorough history and examination, supported by ancillary testing, continues to be the mainstay of optic neuritis diagnosis. Stratifying typical versus atypical optic neuritis is paramount. Within the atypical category, NMOSD and MOGAD are important considerations. Clues can point towards these diagnoses and guide steps for treatment, which is increasingly becoming targeted to individual diseases, as the pathophysiology is different for these disorders.

ABSTRACTIntroduction/AimsThe degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.MethodsData from the NEURO‐TTRansform trial on patients with ATTRv‐PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor‐based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL‐Diabetic Neuropathy (Norfolk QoL‐DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.ResultsMeaningful improvement in mNIS+7 was estimated as −4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL‐DN were −12.8 to −4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were −2.4 to −1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was −40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.DiscussionEplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors. Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395. Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively. Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors. Trial registration number NCT03889275

Abstract T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection. Thus, by expressing a broad range of SELF epitopes against which minimal functional T cell reactivities exist because of thymic deletion, AIRE acts as a master controller of SELFNESS, effectively cloaking the tumor from T cell attack. Moreover, we describe a completely novel immunotherapy in which engineered changes in AIRE expression in tumor cells alters their profile of SELFNESS, exposing both AIRE-modified, and parental unmodified, tumor cells to T cell attack. Consistent with our studies, patient RNAseq shows expression of AIRE predicts response to immune therapies with a strong correlation between AIRE expression and markers of TCR signaling. Therefore, by re-setting the immunological SELFNESS of cancer cells, this novel AIRE-mediated immunotherapy 1). converts a highly tolerized T cell compartment into a heteroclitic tumor-reactive T cell population; 2) confers de novo sensitivity to immune checkpoint blockade upon non-immunogenic tumors; 3). completely removes the need to identify potentially immunogenic tumor-associated antigens as targets for generation of de novo CD8+ and helper CD4+ T cell responses; and 4) leads to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors.

Background: D-flow’s impact on metabolic reprogramming, particularly glycolysis, needs reevaluation due to its conflicting role in atherosclerosis. We show that d-flow reduces LATS1/2 expression, leading to both EC proliferation and senescence. However, the exact molecular mechanisms remain elusive. Methods: We utilized EC-specific Lats1 +/- /Lats2 -/- knockout (LATS1/2-EKO) mice in a partial left carotid ligation (PLCL) model under hypercholesterolemia with AAV-PCSK9 injection to mimic d-flow. Anti-CD38 antibody (Ab68) and IgG2a control were administered intraperitoneally every 5 days at a dose of 5 mg/kg starting one day before PLCL. Plaque characterization was performed using imaging mass cytometry and sequential immunofluorescence (COMET TM ), integrating spatial metabolite data from Bruker timsTOF Flex Mass Spectrometer, and spatial single-cell metabolite data via the Visiopharm platform. Results: EC LATS1/2 depletion induced a unique atherothrombosis lesion with induced EC proliferation and senescence-associated secretory phenotype (SASP). Utilizing spatial single-cell metabolomics, we cataloged 134 distinct metabolites within the ECs. Subsequent overrepresentation analysis revealed that pathways related to glutamate and the citric acid cycle were enhanced in LATS1/2-EKO mice. Specifically, CD38-dependent downregulation of the pyruvate dehydrogenase (PDH) substrate lipoamide decreased PDH enzymatic activity, linking to CD38 to senescence induction. This inhibition led to a metabolic shift towards YAP-dependent glutaminolysis, and upregulated the citric acid cycle. The use of a glutaminase 1 inhibitor (CB-839) significantly curtailed senescence-associated stemness (SAS), underscoring the pivotal role of CD38 in driving glutaminolysis that contributes to d-flow-induced SAS. Moreover, the application of Ab68 but not IgG2a control decreased atherothrombosis formation following PLCL in LATS1/2-EKO mice. However, the effectiveness of Ab68 in attenuating atherosclerosis in wild-type mice was less pronounced. Conclusions: In the presence of d-flow, upregulated CD38, resulting from reduced LATS1/2 expression, triggers EC responses characterized by increased glutaminolysis and the emergence of an EC SAS phenotype. These processes play a crucial role in a unique form of atherothrombosis. Additionally, CD38’s impact on reducing PDH activity, along with YAP and CD38-mediated enhancement of glutaminolysis, constitutes critical pathways for inducing EC SAS by d-flow.