Citations

Abstract Trigeminal neuralgia (TN) is characterized by excruciating facial pain usually caused by neurovascular compression of the trigeminal nerve roots. TN can be treated medically or invasively. Microvascular decompression is the procedure of choice and usually results in complete symptom relief. During surgical decompression, Teflon can be placed between the offending vessel and the nerve root entry zone. In some cases, chronic Teflon-related inflammation can cause recurrent TN, which might lead to additional surgical intervention. We present imaging and histopathological correlation of a patient presenting with intractable recurrent TN approximately 2 years after microvascular decompression with Teflon implant.

ABSTRACTBackgroundPreventive strategies for cytomegalovirus (CMV) in the posttransplant period have changed the pattern of CMV infections, now more commonly manifesting as late‐onset occurrences known as post‐prophylaxis delayed‐onset CMV disease (PPDOC). We conducted a survey to investigate provider practices in managing PPDOC.MethodsA web‐based provider survey on the management of PPDOC was developed using Research Electronic Data Capture (REDCap). It was distributed to the online forums of the American Society of Transplantation communities of practice (COP) for Infectious Diseases (IDCOP), Kidney and Pancreas (KPCOP), Liver and Intestinal (LICOP), and Thoracic and Critical Care (TCCOP). The survey was posted twice within a span of a month.ResultsFifty‐six respondents, comprising 50 (89%) transplant physicians and 6 (11%) transplant pharmacists, from 46 distinct transplant centers, completed the survey. Universal antiviral prophylaxis (UAP) was the predominant preventive approach for both high‐risk (85%) and moderate‐risk (85%) transplant recipients. Out of 56, 51 respondents completed the questions regarding management of PPDOC. Regular surveillance with nucleic acid amplification tests (NAAT) (88%) was the most commonly used approach in high‐risk recipients, while symptom monitoring (73%) was the most common strategy in moderate‐risk recipients. Immunologic monitoring was used only by a few respondents who found it moderately useful in high‐risk recipients.ConclusionManagement of PPDOC was highly variable among providers and strategies differed based on patient risk profile. These findings could help shape future studies and guidelines to harmonize CMV management.

Abstract Background Glioblastoma is the most aggressive malignant brain tumor with poor survival due to its invasive nature driven by cell migration, with unclear linkage to transcriptomic information. The aim of this study was to develop a physics-based framework connecting to transcriptomics to predict patient-specific glioblastoma cell migration. Methods and Results We applied a physics-based motor-clutch model, a cell migration simulator (CMS), to parameterize the migration of glioblastoma cells and define physical biomarkers on a patient-by-patient basis. We reduced the 11-dimensional parameter space of the CMS into 3 principal physical parameters that govern cell migration: motor number—describing myosin II activity, clutch number—describing adhesion level, and F-actin polymerization rate. Experimentally, we found that glioblastoma patient-derived (xenograft) cell lines across mesenchymal (MES), proneural, and classical subtypes and 2 institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3 kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. By contrast, with the CMS parameterization, we found that glioblastoma cells consistently had balanced motor/clutch ratios to enable effective migration and that MES cells had higher actin polymerization rates resulting in higher motility. The CMS also predicted differential sensitivity to cytoskeletal drugs between patients. Finally, we identified 18 genes that correlated with the physical parameters, suggesting transcriptomic data alone could potentially predict the mechanics and speed of glioblastoma cell migration. Conclusions We describe a general physics-based framework for parameterizing individual glioblastoma patients and connecting to clinical transcriptomic data that can potentially be used to develop patient-specific anti-migratory therapeutic strategies.

Abstract Background Transforming growth factor beta (TGFβ) and its receptors (TGFβRs) are widely expressed by most human and murine cells and are implicated in several physiological and pathological conditions. In the context of atherosclerosis, TGFβ has been identified as a pleiotropic molecule involved in both pro- and anti-atherogenic processes, with its effects varying depending on the cell type it signals through. Purpose Given that myeloid cells play a major role in atherogenesis, we sought out to unravel the involvement of myeloid TGFβ signaling in atherosclerosis. Methods Aortic leukocytes from ApoE-/- mice fed a Western diet (WD) for 20 weeks were subjected to CITE-Seq analysis to assess the expression profile of Tgfβ and Tgfβrs. To investigate the effect of myeloid Tgfβ signaling on atherosclerosis, LysMCre+Tgfβr1flox/floxTgfβr2flox/floxmT/mGflox/floxApoE-/- (M-Tgfβr1/2dkoApoE-/-) mice and their LysMCre- littermates (ApoE-/-) were fed a WD for 6 weeks. Leukocyte phenotyping was assessed by flow cytometry (FC) and qPCR. Atherosclerotic plaque size in the aortic root was assessed by immunohistochemistry. Results CITE-Seq revealed that aortic ApoE-/- leukocytes highly expressed Tgfb1, whereas Tgfb2 and Tgfb3 were very lowly expressed. Tgfbr1 was mainly expressed in myeloid cells with macrophages and neutrophils showing the highest expression. Tgfbr2 was primarily expressed in T and B cells, while still showing a high level of expression in macrophages. Importantly, Tgfbr3 was not expressed in myeloid cells. Thus, to study the effect of myeloid Tgfβ signaling on atherosclerosis and to mitigate the potential for aberrant signaling that might arise from deleting only one receptor, we generated ApoE-/- mice with myeloid lineage tracing mT/mG alleles and combined deletion of Tgfbr1 and Tgfbr2 in myeloid cells using the LysMCre model. FC analysis of eGFP+ cells, i.e., cells where LysMCre is active, revealed a ~60-80% Tgfbr1/2 deletion efficiency in bone marrow-derived macrophages (BMDM) and in blood, splenic and BM CD11b+ cells, which was accompanied by decreased Smad2/3 signaling. M-Tgfβr1/2dkoApoE-/- mice showed a ~35% increase in blood and splenic CD11b+ cells and a ~25% increase in splenic macrophages compared to ApoE-/- controls, while BM CD11b+ cells were not affected. Tgfbr1/2-deficient BMDMs had increased Il-6, Il-1b and CD38 expression compared to controls, suggesting that Tgfbr1/2-deficient macrophages have acquired a pro-inflammatory phenotype. Interestingly, M-Tgfβr1/2dkoApoE-/- mice had ~30% fewer blood and splenic T cells compared to controls, which was explained by decreased naïve CD4+ and CD8+ T cells. M-Tgfβr1/2dkoApoE-/- mice had a ~50% increase in atherosclerotic plaque burden compared to ApoE-/- controls. Conclusion Our data suggest that impaired myeloid Tgfβ signaling leads to a pro-atherogenic environment in ApoE-/- mice. These effects may be mediated by an altered crosstalk between T cells and Tgfβr1/2-deficient macrophages.

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). Whether the incidence of AF has changed over time and if contributing risk factors are present remains to be defined. Methods Leveraging the Mayo Electronic Medical Record, we extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. From this cohort, we identified those who had a diagnosis of AF at any point. We then defined the endpoint of interest as the first episode of new or recurrent AF during or after CAR T-cell infusion. Fine and Gray subdistribution hazard modeling was used to calculate the association of patient characteristics to the endpoint of interest. Variables with P<0.20 in univariate modeling were chosen for the multivariate model. Significance was defined as P<0.05. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022. Of this cohort, 27 (8.2%) patients had a pre-existing diagnosis of AF, of which 6 had recurrence of AF after CAR T (22.2%), while 21 (77.8%) did not. Of the 301 patients without a prior history of AF, 8 (2.7%) patients developed new-onset AF after CAR T. The majority of the 14 new or recurrent AF events (4.3% overall incidence) occurred within 30 days of receiving CAR T (N=10, 71.4%), the remainder after 180 days (Figure 1). No trend in declining incidence over time was noted. Prior AF, neurotoxicity, and inflammation (cytokine release syndrome and macrophage activating syndrome-like (MAS-L)) were strongly associated with the risk of developing new or recurrent AF (Table 1). Only presence of MAS-L remained an independent predictor in the multivariate model (HR 15.4, 95% CI 3.9-61.2, P<0.001). Conclusion AF is mainly seen early following CAR T-cell therapy, and mainly in association with severe inflammatory responses. Early and aggressive treatment of CRS and MAS-L may be recommendable for patients undergoing CAR-T therapy, especially for those with a prior history of AF.

Abstract Background/Introduction MANP is a novel atrial natriuretic peptide (ANP) analog bioengineered as a particulate guanylyl cyclase A receptor (GC-A) activator with superior receptor binding, resistance to neprilysin degradation, natriuretic, aldosterone suppressing and blood pressure (BP) lowering properties than native ANP. MANP is now under clinical development for resistant hypertension (RH). The rationale for its design was the fundamental role of the ANP/GC-A system in BP homeostasis through which GC-A activation with MANP leads to BP reduction through renal, vascular, and hormonal mechanisms mediated by the second messenger cGMP. Purpose We investigated the safety, tolerability, cGMP activation and BP reductions of MANP compared to placebo in subjects with RH. Methods We performed a double-blind, placebo controlled randomized trial in 36 RH patients comprised of approximately 50% non-African Americans (NAA) and 50% AA. MANP was administered in 6 cohorts receiving ascending subcutaneous (SQ) doses of MANP once daily from 3 ug/kg to a maximal dose of 7 ug/kg or placebo for 5 days and then followed for 21 days after dosing. Endpoints included safety, cGMP activation and changes in systolic BP (SBP), aldosterone (Aldo) levels and glomerular filtration rate (GFR). Results MANP was safe and well tolerated. One patient in the 7 ug/kg cohort was discontinued due to symptomatic hypotension. Compared to baseline, plasma cGMP increased in all MANP groups on Day 1 and Day 5 with no change in the placebo group. The maximal SBP reduction in the MANP group on Days 1 (D1) and 5 (D5) was -17.5 (D1) and -16 mmHg (D5) with 3 ug/kg (lowest dose) and -39.5 (D1) and -36.3 mmHg (D5) with 7 ug/kg (highest dose); Changes in the Placebo group were -6.3 (D1) and -16.7 mmHg (D5). Notably, the SBP reductions in AA were greater than NAA in the 4 and 7 ug/kg cohorts. After the 1-hour timepoint on both the first and fifth days, Aldo and percentage of Aldo reduction generally remained suppressed compared to baseline. Twenty-one days after MANP dosing, SBP remained lower in three groups receiving SQ MANP (4, 4.5 and 7 ug/kg) compared to placebo in association with a preservation of GFR. There were no reported drug related serious adverse events. Conclusions This clinical trial demonstrates that once a day SQ administration of MANP in RH subjects activates cGMP, without attenuation over 5 days, and reduces SBP and preserves GFR. At higher doses of MANP, SBP reductions were greater in AA compared to NAA. MANP also demonstrated Aldo inhibiting actions compared to placebo. Importantly, MANP was overall safe and well-tolerated. Our findings support the continued clinical development of MANP as a novel GC-A activating peptide for the treatment of RH.