Citations

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase ( erm ) genes.

AbstractBackgroundGene expression changes have been identified in post‐mortem brain tissue of AD cases when compared with controls, implicating various genes and pathways. Such findings provide important insights into molecular dysregulation associated with this disease and nominate therapeutic targets. Here we investigate brain gene and co‐expression network changes in a cohort of AD cases to identify associations with degree of AD neuropathology including Braak stage (Tau), Thal phase (Amyloid beta) and brain tissue levels of five AD‐related proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodGene expression measures were collected from temporal cortex (TCX) tissue of 477 AD cases, available through the Mayo Clinic Brain Bank, using RNA sequencing (Illumina TruSeq mRNA) performed on the HiSeq4000. Following quality control 456 cases remained for analysis. Braak and Thal were provided by an experienced neuropathologist and TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Weighted gene coexpression network analysis (WGCNA) R package was used to build co‐expression networks. Genes and networks were tested for association with neuropathology and AD‐related protein levels, adjusting for relevant covariates.ResultA total of 57,353 genes were profiled, of which 19,044 were reliably expressed above background levels and formed 20 co‐expression modules. 36 genes were associated with Braak stage, 10 with Thal phase and up to 9,000 with the AD‐related protein fractions. Brain levels of pTau had the greatest number of associations, with an overrepresentation of genes involved in synaptic signalling and immune response gene ontology biological processes. 16 of the coexpression modules associated with at least one trait after Bonferroni correction for number of tests.ConclusionWe have identified a number of genes and networks associated with different aspects of AD neuropathology and associated proteins, further lending support to the involvement of synaptic and immune biology in AD. However it is not clear whether observed changes cause disease or are a consequence of the neurodegenerative process. Comparison of these findings across different proteins and fractions is expected to reveal common and distinct vulnerabilities associated with amyloid and tau, and different stages of protein aggregation.

Introduction: Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Methods and Results: Through a meta-analysis of 8 GWAS (1917 cases, 9292 controls of European ancestry), we identified 17 risk loci, including 12 new. Functional annotations pointed at enrichment in enhancer marks of arteries, specifically smooth muscle cells, and strong candidate genes, such as tissue factor gene ( F3 ) on Chr1 near rs1146473 (OR=1.32, P=5.8 х10 -9 ). F3 is novel for SCAD or any cardiovascular disease. The risk allele correlated with F3 lower expression in arteries, supporting a mechanism consistent with hematoma formation. Bayesian gene regulatory networks constructed from expression and genetics data indicated the extracellular matrix organization in arteries as the biological function where most prioritized genes clustered (e.g. COL4A1/A2, HTRA1, and TIMP3 ). Overall, we report substantial polygenicity for SCAD (LDSC: h 2 SNP = 0.71 ± 0.11) and shared genetics with several neurovascular diseases (e.g intracranial aneurysm). Intriguingly, for 6 loci, colocalization analyses showed that SCAD and CAD are likely to share the same causal variants but involve opposite risk alleles (e.g COL4A1/A2 ). In addition, a negative genetic correlation was found between SCAD and CAD (rg=-0.12; P=3.7х10 -3 ), including after conditioning on BP (mt-COJO: rg CAD/SBP =-0.19, P=4.6х10 -6 ). Mendelian randomization analyses indicated higher BP to associate with increased risk for SCAD (beta IVW-SBP =0.05, P=7.6х10 -6 , beta IVW-DBP =0.10, P=1.9х10 -6 ) and CAD (beta IVW-SBP =0.04, P=8.6х10 -49 ; DBP: beta IVW-DBP =0.06, P=1.6х10 -44 ) but not BMI, lipids, or type 2 diabetes, which we confirmed as genetic risk factors for CAD Conclusions: Our results set the stage for future investigation of novel biological pathways relevant to both SCAD and CAD and potential therapeutic and preventive strategies specifically targeting this ischemic disease predominantly affecting women.

AbstractThe coronavirus disease 2019 (COVID‐19) pandemic created unprecedented challenges for anesthesiologists both at work and home. This study examined whether the pandemic affected academic productivity and career satisfaction among anesthesiologists practicing in the United States during the early stages of the pandemic and whether these effects differed by gender. A survey was emailed to 25,473 members of the American Society of Anesthesiologists to learn about their experiences during the beginning of the pandemic. The survey directed respondents to rate their change in academic productivity, clinical care hours, scholarly and leadership opportunities, income, childcare duties, and household responsibilities during the first 5 months of the pandemic (March 1–July 31, 2020). The primary variable was gender, academic productivity was the primary outcome, and data were analyzed by multivariable proportional odds logistic regression models and correlations. Female anesthesiologists reported lower academic productivity and career satisfaction relative to male anesthesiologists during the study period. Career satisfaction positively correlated with academic productivity. Compared to male anesthesiologists, female anesthesiologists also had more household responsibilities before and during the pandemic. Being a female parent reduced academic productivity relative to that reported by nonparents of either gender. In conclusion, the early months of the COVID‐19 pandemic had a greater adverse professional impact on female anesthesiologists than on their male counterparts. Efforts to support and retain female anesthesiologists, particularly those early in their careers and those with children, are essential for the specialty to maintain its workforce and promote gender equity in promotion and leadership.

AbstractAlthough pathogenic variants in PSEN1 leading to autosomal‐dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non‐carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre‐symptomatic and symptomatic phases of disease as compared to CY, using both cross‐sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ‐secretase and the generation of toxic β‐amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.

TPS11584 Background: Uterine leiomyosarcoma (uLMS) is an aggressive sarcoma subtype with frequent metastatic relapse. Advanced uLMS is treated with gemcitabine/docetaxel or anthracycline-based regimens. After failure of initial chemotherapy, remaining options provide limited benefit (trabectedin: objective response rate (ORR) 11%, median progression-free survival (mPFS) 4.0 months (mo); pazopanib: ORR 11%, mPFS 3.0 mo; dacarbazine: ORR 9%, mPFS 1.5 mo). 18-23% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. HR-deficient cancers are unable to effectively repair double-stranded DNA breaks and may be sensitive to poly ADP-ribose polymerase (PARP) inhibitor-based strategies. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, markedly suppressed proliferation of uLMS models. Among 22 uLMS patients with median 3 prior lines, O+T demonstrated mPFS 6.9 mo and ORR 27% (Ingham M. et al. ASCO 2021: #11506). In correlative analysis, alterations in HR genes including PALB2 and RAD51B or absence of RAD51 foci formation by a functional assay were observed in patients with prolonged PFS (Bose S. et al. ASCO 2022: #11509). Based on these results, we designed a randomized phase 2/3 study to further evaluate O+T in advanced, pretreated uLMS. Methods: Alliance for Clinical Trials in Oncology A092104 is a randomized, open-label phase 2/3 clinical trial of O+T versus investigator’s choice in advanced uLMS. Eligible patients have ECOG performance status ≤2, progression on ≥ 2 prior treatment lines and measurable disease. Patients are randomized 1:1 to receive T 75 mg/m2 orally daily + O 200 mg orally twice daily on days 1-7 in 21-day cycles (Arm 1) or investigator’s choice of trabectedin 1.5 mg/m2 over 24 hours every 21 days or pazopanib 400-600 mg orally daily (Arm 2). For phase 2, the primary endpoint is PFS. The design evaluates for an improvement in PFS from 4 mo to 8 mo, requires 70 patients, and yields 90% power and 1-sided alpha 0.10. If phase 2 is positive, phase 3 will enroll. For phase 3, the primary endpoint is overall survival (OS). The design evaluates for an improvement in OS from 13 mo to 23 mo, requires 165 patients (including 70 from phase 2) and yields 90% power with 1-sided alpha 0.025. Secondary endpoints include ORR, duration of response, safety and patient-reported outcomes. Archival tissue will be collected and evaluated with a RAD51 foci formation assay. Genomic sequencing results will be obtained where available. The study opened to accrual in 1/2023. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT05633381 .

11503 Background: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes. Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO). Results: 21 eligible pts [median age 66 yrs (32-92), 10 female] received ≥1 dose of C+N. Primary disease sites: 12 cutaneous (scalp/face), 1 liver, 2 breast, 6 other. All pts received prior taxanes (11/21 = 52% as adjuvant therapy) and 5/21 (24%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 21 pts achieved OR (11 partial response, 2 complete), for ORR 62% (95%CI: 38-82%). Responses were seen in pts with primary cutaneous disease 7/12 (58%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.3-NR), and OS 20.5 mo (14.4-NR). Off treatment reasons include: progressive disease (14), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension was the only possibly treatment related AE (TRAE) occurring in ³10%. No G 4/5 TRAE were reported. Conclusions: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org . U10CA180868; U10CA180888. NCT04339738. Clinical trial information: NCT04339738 .