Citations

ObjectiveRecent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites.InterpretationOur data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often measured by Thal phase and Braak stage, respectively. Frequently, Aβ also deposits in the brain vasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. Assessment of these and related endophenotypes can reveal biological insights into the phenotypic variability in AD. We hypothesize that, amongst AD patients, severity of neuropathology and brain levels of AD‐related proteins are influenced by variation in DNA methylation (DNAm), the identification of which may uncover biological pathways for AD pathogenesis. To test this, we performed epigenome‐wide association studies (EWAS) using DNAm from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathology measures (Braak, Thal, and CAA) and brain levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from autopsy‐confirmed AD cases available through the Mayo Clinic Brain Bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Bisulfite converted reads were sequenced on the Illumina High Seq4000 and quality filtered. Neuropathology scoring was performed by an experienced neuropathologist. TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Individual CpG methylation ratios were tested for association with each neuropathological and biochemical measure using the R package CpGassoc.ResultsWe identified multiple epigenome‐wide significant CpGs unique to each AD‐related measure. Comparisons between the TCX and CER revealed region specific CpG associations. The effects of sex, age at death, APOE genotype, and presence of genetic variants for each significant CpG association were also identified.ConclusionsAlthough all neuropathological and biochemical measures tested reflect core AD pathologies, our results demonstrate unique associations of epigenetic factors with these individual phenotypes, suggesting that their variability may be governed by distinct epigenetic processes. Discovery of DNAm changes that underlie specific neuropathological or biochemical outcomes can enhance our understanding of AD pathophysiology and may lead to the identification of novel gene or pathway targets for the different facets of this complex condition.

Abstract Mixed lineage leukemia 1 (MLL1), a histone H3 lysine 4 (H3K4) methyltransferase, exerts its enzymatic activity by interacting with menin and other proteins. It is unclear whether inhibition of the MLL1‐menin interaction influences epithelial‐mesenchymal transition (EMT), renal fibroblast activation, and renal fibrosis. In this study, we investigated the effect of disrupting MLL1‐menin interaction on those events and mechanisms involved in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), in cultured mouse proximal tubular cells and renal interstitial fibroblasts. Injury to the kidney increased the expression of MLL1 and menin and H3K4 monomethylation (H3K4me1); MLL1 and menin were expressed in renal epithelial cells and renal interstitial fibroblasts. Inhibition of the MLL1‐menin interaction by MI‐503 administration or siRNA‐mediated silencing of MLL1 attenuated UUO‐induced renal fibrosis, and reduced expression of α‐smooth muscle actin (α‐SMA) and fibronectin. These treatments also inhibited UUO‐induced expression of transcription factors Snail and Twist and transforming growth factor β1 (TGF‐β1) while expression of E‐cadherin was preserved. Moreover, treatment with MI‐503 and transfection with either MLL siRNA or menin siRNA inhibited TGF‐β1‐induced upregulation of α‐SMA, fibronectin and Snail, phosphorylation of Smad3 and AKT, and downregulation of E‐cadherin in cultured renal epithelial cells. Finally, MI‐503 was effective in abrogating serum or TGFβ1‐induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1‐menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation.

Background and objectives: Primary percutaneous coronary intervention (PCI)-related outcomes in acute myocardial infarction (AMI) have improved over time, but there are limited data on the length of stay (LOS) in relation to in-hospital mortality. Materials and Methods: A retrospective cohort of adult AMI admissions was identified from the National Inpatient Sample (2000–2017) and stratified into short (≤3 days) and long (>3 days) LOS. Outcomes of interest included temporal trends in LOS and associated in-hospital mortality, further sub-stratified based on demographics and comorbidities. Results: A total 11,622,528 admissions with AMI were identified, with a median LOS of 3 (interquartile range [IQR] 2–6) days with 49.9% short and 47.3% long LOS, respectively. In 2017, compared to 2000, temporal trends in LOS declined in all AMI, with marginal increases in LOS >3 days and decreases for ≤3 days (median 2 [IQR 1–3]) vs. long LOS (median 6 [IQR 5–9]). Patients with long LOS had lower rates of coronary angiography and PCI, but higher rates of non-cardiac organ support (respiratory and renal) and use of coronary artery bypass grafting. Unadjusted in-hospital mortality declined over time. Short LOS had comparable mortality to long LOS (51.3% vs. 48.6%) (p = 0.13); however, adjusted in-hospital mortality was higher in LOS >3 days when compared to LOS ≤ 3 days (adjusted OR 3.00, 95% CI 2.98–3.02, p < 0.001), with higher hospitalization (p < 0.001) when compared to long LOS. Conclusions: Median LOS in AMI, particularly in STEMI, has declined over the last two decades with a consistent trend in subgroup analysis. Longer LOS is associated with higher in-hospital mortality, higher hospitalization costs, and less frequent discharges to home compared to those with shorter LOS.

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19 . Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

PurposeTo improve calibrationless parallel imaging using pre‐learned subspaces of coil sensitivity functions.Theory and MethodsA subspace‐based joint sensitivity estimation and image reconstruction method was developed for improved parallel imaging with no calibration data. Specifically, we proposed to use a probabilistic subspace model to capture prior information of the coil sensitivity functions from previous scans acquired using the same receiver system. Both the subspace basis and coefficient distributions were learned from a small set of training data. The learned subspace model was then incorporated into the regularized reconstruction formalism that includes a sparsity prior. The nonlinear optimization problem was solved using alternating minimization algorithm. Public fastMRI brain dataset was retrospectively undersampled by different schemes for performance evaluation of the proposed method.ResultsWith no calibration data, the proposed method consistently produced the most accurate coil sensitivity estimation and highest quality image reconstructions at all acceleration factors tested in comparison with state‐of‐the‐art methods including JSENSE, DeepSENSE, P‐LORAKS, and Sparse BLIP. Our results are comparable to or even better than those from SparseSENSE, which used calibration data for sensitivity estimation. The work also demonstrated that the probabilistic subspace model learned from T2w data can be generalized to aiding the reconstruction of FLAIR data acquired from the same receiver system.ConclusionA subspace‐based method named JSENSE‐Pro has been proposed for accelerated parallel imaging without the acquisition of companion calibration data. The method is expected to further enhance the practical utility of parallel imaging, especially in applications where calibration data acquisition is not desirable or limited.

PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.