Citations

Background: Little is known about the relationship between carotid plaque formation and cognitive function in a middle-aged population. Hypothesis: We hypothesize that there will be an association between carotid atherosclerotic burden and cognitive function in middle-aged adults. Aim: The purpose of the present study is to examine the relationship between carotid artery (CA) plaque and cognitive function in middle-aged white and black men and women from the Bogalusa Heart Study (BHS) cohort. Methods: We included a total of 1,107 BHS participants with echocardiography and carotid ultrasound performed between 2013 and 2016. Cognitive function was quantified in a global cognitive score (GCS) comprised of the z standardized sum of 7 neuropsychiatric tests. CA plaque was defined by carotid intima media thickness ≥1.5mm in any segment of the CA including right and left common artery (RCC/LCC), bulbs (RCB/LCB) as well as right and left internal carotid artery (RIC/LIC). We compared demographic, clinical, and echocardiographic characteristics in participants with or without CA plaque and used linear regression analysis for the association between CA and GCS adjusted for age, sex, race and education. Results: Among all, 373 (33.7%) of participants had one or more CA plaque. The most common locations of CA plaque formation differed according to laterality, with 230 (61.7%), 189 (50.7%), 108 (29.0%), 92 (24.7%), 83 (22.3%), 10 (2.7%) participants having plaque in the RCB, LCB, LCA, RIC, LIC, and RCA, respectively. Participants with CA plaque were likely to be older (49.9 vs. 47.2 years), male (52 vs.38.9%), white (70.2 vs.63.4%,), have larger left ventricular (LV) end-diastolic volume (97.4 vs.94 ml) and LV mass index (83.4 vs.76.3 g/m 2 , all p -value<0.01), but similar LV ejection fraction (60.1 vs.60.0%) as compared to those without CA plaque. Moreover, CA is associated with poorer cognitive function (GCS, standardized β coefficient=-0.07; p =0.02) adjusted for age, sex, and race. However, the association was attenuated after adjusting for education. Conclusion: CA plaque was highly prevalent and inversely associated with cognitive function. The association was attenuated by education emphasizing the importance of social determinants in cognitive health.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Introduction: Patients requiring postcardiotomy veno-arterial extracorporeal membrane oxygenation (V-A-ECMO) have a high risk of early mortality. In this analysis, we evaluated whether any interinstitutional difference exists in the results of postcardiotomy V-A-ECMO. Methods: Studies on postcardiotomy V-A-ECMO were identified through a systematic review for individual patient data (IPD) meta-analysis. Analysis of interinstitutional results was performed using direct standardization, estimation of observed/expected in-hospital mortality ratio and propensity score matching. Results: Systematic review of the literature yielded 31 studies. Data from 10 studies on 1269 patients treated at 25 hospitals were available for the present analysis. In-hospital mortality was 66.7%. The relative risk of in-hospital mortality was significantly higher in six hospitals. Observed versus expected in-hospital mortality ratio showed that four hospitals were outliers with significantly increased mortality rates, and one hospital had significantly lower in-hospital mortality rate. Participating hospitals were classified as underperforming and overperforming hospitals if their observed/expected in-hospital mortality was higher or lower than 1.0, respectively. Among 395 propensity score matched pairs, the overperforming hospitals had significantly lower in-hospital mortality (60.3% vs 71.4%, p = 0.001) than underperforming hospitals. Low annual volume of postcardiotomy V-A-ECMO tended to be predictive of poor outcome only when adjusted for patients’ risk profile. Conclusions: In-hospital mortality after postcardiotomy V-A-ECMO differed significantly between participating hospitals. These findings suggest that in many centers there is room for improvement of the results of postcardiotomy V-A-ECMO.

Abstract Background Alcohol use disorder (AUD) has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. Methods We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), and the NF-κB p65 and IKK-α/β signaling pathways in modulating neuroinflammation and amyloid beta (Aβ) deposition. We assessed apolipoprotein E (ApoE) in the mouse brain using IHC and ELISA in response to moderate ethanol exposure (MEE). First, to confirm the intracerebral distribution of ApoE, we co-stained with GFAP, a marker for astrocytes that biosynthesize ApoE. We sought to investigate whether the ethanol-induced upregulation of LRP1 could potentially inhibit the activity of IL-1β and TNF-α induced IKK-α/β towards NF-κB p65, resulting in a reduction of pro-inflammatory cytokines. To evaluate the actual Aβ load in the brains of APP/PS1 mice, we performed with a specific antibody Aβ (Thioflavin S) on both air- and ethanol-exposed groups, subsequently analyzing Aβ levels. We also measured glucose uptake activity using 18F-FDG in APP/PS1 mice. Finally, we investigated whether MEE induced cognitive and memory changes using the Y maze, noble objective recognition (NOR) test, and Morris water maze (MWM). Results Our findings demonstrate that MEE reduced astrocytic glial fibrillary acidic protein (GFAP) and ApoE levels in the cortex and hippocampus in presymptomatic APP/PS1 mice. Interestingly, increased LRP1 protein expression is accompanied by dampening the IKK-α/β-NF-κB p65 pathway, resulting in decreased IL-1β and TNF-α levels in male mice. Notably, female mice show reduced anti-inflammatory cytokines, IL-4, and IL-10 levels without altering IL-1β and TNF-α concentrations. In both males and females, Aβ plaques, a hallmark of AD, were reduced in the cortex and hippocampus of ethanol-exposed presymptomatic APP/PS1 mice. Consistently, MEE increased fluorodeoxyglucose (FDG)-positron emission tomography (PET)-based brain activities and normalized cognitive and memory deficits in the APP/PS1 mice. Conclusions Our findings suggest that MEE may benefit AD pathology via modulating LRP1 expression, potentially reducing neuroinflammation and attenuating Aβ deposition. Our study implies that reduced astrocyte derived ApoE and LDL cholesterol levels are critical for attenuating AD pathology.

Abstract Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would thus be warranted, and in this report, we have established such a classifier. Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated and reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by g-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent data sets. Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2) and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions: The 20-gene transcriptional signature has the potential to better stratify patients and to evaluate the response of future Notch-based therapies for breast cancer. Citation Format: Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A. Leon-Ferre, Antonino B. D’Assoro, James N. Ingle, Matthew P. Goetz, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl. Identification of a Notch transcriptomic signature for breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B013.

The primary mediator of transforming growth factor β (TGFβ) responses are the Smad proteins. Here, we identify sorting nexin 9 (SNX9) as being required for Smad3 (but not Smad2) nuclear translocation and cell stimulation. SNX9 principally interacts with phosphorylated (p) Smad3 and promotes more rapid nuclear delivery from that observed independent of ligand. Although SNX9 does not bind Imp7, Impb, Nup153 or Nup214, it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates recruitment of pSmad3/SNX9 to the nuclear pore, heterodimerization of Imp8 with Impb, and nuclear translocation of pSmad3, but not SNX9. The demonstration that Smad3 is regulated in a distinct manner from Smad2 provides the opportunity to develop intervention strategies to enhance or dampen specific aspects of the cellular response to TGFβ. Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.

Transforming growth factor‐β (TGFβ) is the prototype of a family of secreted polypeptide growth factors with key roles in cellular growth and differentiation. The primary mediators of TGFβ action are the Smad proteins, specifically Smad2 and Smad3. Upon receptor activation these 55–60 kDa proteins are phosphorylated (p) by the type I TGFβ receptor and undergo nuclear translocation to function as co‐modulators of gene expression. While the specific roles of Smad2 and Smad3 are being actively investigated, recent findings have shown that while Smad3 is clearly pro‐fibrotic/pro‐carcinogenic, Smad2 can induce anti‐fibrotic/anti‐carcinogenic responses. Thus, approaches designed to target more downstream TGFβ receptor signaling components may provide equivalent efficacy and greater specificity. To that end, as we previously determined that sorting nexin 9 (SNX9) plays an integral role in the nuclear import of pSmad3 (but not pSmad2), we have extended those findings and identified the functional element in SNX9 critical for pSmad3 binding. Furthermore, we show that a TAT‐fusion encompassing this region can act in a dominant manner to block SNX9/pSmad3 binding, pSmad3 nuclear translocation, and subsequent pro‐fibrotic responses dependent upon pSmad3 both in vitro and in vivo . Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.

Alterations in cellular metabolism are known to play critical roles in a variety of normal as well as pathological processes, including (but not limited to) cancer, hepatic steatosis, and cell differentiation. While TGFβ is routinely considered a pleotropic cytokine due to its ability to impact numerous diseases and biological phenotypes, the role of metabolism in profibrotic TGFβ signaling is relatively unexplored/unknown. Fatty Acid Synthase (FASN) is the primary anabolic enzyme responsible for the de novo synthesis of fatty acids. Renewed interest in FASN has been sparked by the recognition of the critical inter‐relation of metabolic dysregulation and tumor progression with the findings that (i) FASN levels are significantly increased in numerous human tumors including breast, prostate, colorectal, and ovarian; and (ii) the efficacy of ErbB receptor inhibitors is enhanced by inhibiting FASN activity. In the current study we show that FASN expression is regulated by TGFβ in multiple murine and human fibroblasts, required for profibrotic TGFβ signaling, and, most importantly, treatment with C75 ((trans‐4‐carboxy‐5‐octyl‐3‐methylenebutyrolactone, a novel cerulenin‐derived semi‐synthetic FASN inhibitor) abrogates pathologic and physiologic changes in a murine model of lung fibrosis. Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.

Abstract Background To nurture a new online community for health behavior change, a fruitful strategy is to recruit “seed users” to create content and encourage participation. Purpose This study evaluated the impact of support from seed users in an online community for smoking cessation among people living with HIV/AIDS and explored the linguistic characteristics of their interactions. Methods These secondary analyses examined data from a randomized trial of a smoking cessation intervention for HIV+ smokers delivered via an online health community (OHC). The analytic sample comprised n = 188 participants randomized to the intervention arm who participated in the community. Independent variables were OHC interactions categorized by participant interlocutor type (study participant, seed user) and interaction type (active, passive). The primary outcome was biochemically verified 7-day abstinence from cigarettes measured 3 months post-randomization; 30-day abstinence was examined for robustness. Results Logistic regression models showed that participants’ interactions with seed users were a positive predictor of abstinence but interactions with other study participants were not. Specifically, the odds of abstinence increased as the number of posts received from seed users increased. Exploratory linguistic analyses revealed that seed users wrote longer comments which included more frequent use of “we” and “you” pronouns and that study participants users used more first-person singular pronouns (“I”). Conclusions Seeding a community at its inception and nurturing its growth through seed users may be a scalable way to foster behavior change among OHC members. These findings have implications for the design and management of an OHC capable of promoting smoking cessation.