Citations

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.MethodThe graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.ResultEntorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).ConclusionWhile there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.

AbstractBackgroundConsistent failure of clinical trials for Alzheimer Disease (AD) emphasizes the necessity to identify novel therapeutic targets for this debilitating condition. We recently identified the mitochondrial complex I (MCI) as a small molecule druggable therapeutic target for AD.MethodUsing rational design and extensive structure‐activity relationship studies, we developed novel classes of partial MCI inhibitors with high selectivity, specificity, safety, and drug‐like properties. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro assays, including surface plasmon resonance (SPR), competitive and direct binding, proteomics and pull down experiments. Using these techniques, we developed new lead compound C458 that was interrogated in in vivo efficacy studies in APP/PS1 mice.ResultWe demonstrated that the new lead C458 directly binds to MCI. A single dose administration of C458 to mice or treatment of primary mouse neurons activates AMPK‐a, Akt, autophagy, Sirtuins 1 and 3, and upregulates PGC‐1a leading to enhanced mitochondrial biogenesis. C458 has excellent oral bioavailability, blood–brain‐barrier penetrance, and was remarkably clean in the 250 kinase and CEREP 44 safety panels. Chronic administration of C458 (25 mg/kg/day in drinking water ad lib) to APP/PS1 mice for 6 months starting at pre‐symptomatic stage did not cause detectable side effects, and resulted in cognitive protection, improved long‐term potentiation, and decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in glucose uptake and utilization in the brain detected with a translational in vivo biomarker FDG‐PET, as well as an enhancement of ATP production measured in vivo using 31P NMR.ConclusionMechanistic studies confirmed that C458 treatment triggered mitochondrial stress response augmenting mitochondrial biogenesis, anti‐oxidant signaling, and cellular energetics that ultimately restored energy brain homeostasis, leading to cognitive protection in a mouse model of AD. Our studies demonstrate that modulation of MCI activity using novel specific MCI inhibitors improves bioenergetics in the brain and averts cognitive decline representing novel therapeutic approach for AD.

AbstractBackgroundGenetic risk in common variants have been identified for Progressive Supranuclear Palsy (PSP), but common variants only account for a portion of disease heritability. A proportion of the remaining disease heritability is likely contributed by rare variants identifiable via sequencing. Leveraging whole‐genome sequencing of 1719 PSP cases and 2940 controls from the Alzheimer’s Disease Sequencing Project, we detected single nucleotide variants (SNVs), insertion/deletions (INDELs), and copy number variants (CNVs). Note that all samples are non‐Hispanic whites with identity by descent (IBD) >0.25, and no outlier is >6 standard deviation in the principal component analysis. We conducted association analysis for variants, genes and gene sets to identify rare genetic risk for PSP.MethodAfter quality control (variants and genotypes notated PASS by the calling algorithms), we detected 85,228,234 rare SNVs/INDELs and 163,987 rare CNVs (minor allele frequency (MAF) < 1%). For rare SNVs/INDELs, the Sequence Kernel Association Test Optimized was performed to identify rare genetic PSP risk from protein truncating variants (PTV) and damaging missense variants (MAF<0.01%) in both protein coding genes and gene sets that were previously associated with PSP based on protein co‐expression networks. For rare CNVs, a permutation‐based association test implemented in Plink was performed to identify CNVs associated with PSP.ResultCombining protein truncating variants (PTV) and damaging missense variants, we identified one genome‐wide significant gene, FBXO38 (FDR = 0.0003, OR = 1.78). We also found enrichment of PTVs and damaging missense variants in genes comprising the C2 module, a neuronal module previously identified in post mortem PSP brain (FDR = 0.0016). For CNV analysis, there were 17 significant deletions and 2 significant duplications that were associated with PSP (Padjust < 0.05). The deletion (18:58488230‐58488489) in ALPK2, which has been identified as an Alzheimer’s Disease risk gene, was the only CNV that conferred a higher‐risk for PSP. Particularly, one deletion (17:46009357‐46009595) was in linkage disequilibrium with MAPT H2 haplotype which has been associated various neurodegenerative diseases including PSP.ConclusionWe identified several new genes and a protein co‐expression network in which risk variants were associated with PSP. These genes and pathways provide potential candidate drug targets for future investigation.

Abstract The COVID‐19 pandemic and its accompanying infection control measures introduced sudden and significant disruptions to the lives of children and adolescents around the world. Given the potential for negative impacts on the mental health of youths as a result of these changes, we conducted a systematic review and meta‐analysis to examine the prevalence of depressive symptoms, anxiety symptoms, and sleep disturbances in children and adolescents during the pandemic. We searched major literature databases for relevant cross‐sectional or longitudinal studies that included primary and secondary school students or children and adolescents ≤18 years of age. Prevalence values were extracted, logit‐transformed, and pooled. Based on 191 included studies with 1,389,447 children and adolescents, we found the pooled prevalence of depressive symptoms, anxiety symptoms, and sleep disturbances to be 31%, 31%, and 42%, respectively. Age, grade levels, education levels, gender, geographical regions, and electronics use were correlated with the prevalence of mental health symptoms. The prevalence of mental health symptoms also increased with time, although signs of recovery and stabilization were also observed. Overall, the results from this review demonstrate the need for increased mental health research, monitoring, and intervention for children and adolescents during the current and future pandemics.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

AbstractBackground and ObjectivesSerum tumor markers are widely used for diagnosis, prognosis, treatment response, and surveillance. Our study evaluated cancer embryonic antigen (CEA) in patients with appendiceal adenocarcinoma.MethodsThe National Cancer Database was reviewed (2004–2011) for patients with surgical treatment for appendiceal adenocarcinoma. Patients were stratified into two groups: normal and elevated CEA. Multivariable adjusted Cox proportional hazards regression analyses were used to determine the independent effect of CEA on survival.ResultsOur study consisted of 2867 patients, 54.0% having elevated CEA. Patients with elevated CEA were more likely to have Stage IV disease, be female, and African American; all p < 0.001. Three‐year overall survival (OS) was significantly higher with normal CEA (75.5% vs. 62.8%, p < 0.001). On multivariable analysis, elevated CEA was associated with worse survival (hazard ratio 1.49, 95% confidence interval 1.23–1.80). Patients with elevated CEA had improved 3‐year OS with neo‐adjuvant compared to adjuvant chemotherapy (p = 0.004), while those with normal CEA showed no difference.ConclusionsIn patients with surgically treated appendiceal adenocarcinoma, preoperative elevation in CEA independently predicts decreased 3‐year survival and correlates with improved OS with neo‐adjuvant therapy. CEA levels should be considered in clinical decision‐making regarding neo‐adjuvant therapy in patients with appendiceal adenocarcinoma.

Abstract Measuring prebiotic activities of foods on human microbiome and providing dietary guidelines on one’s health status are an emerging research topic. However, it is difficult to directly compare different foods using the prebiotic index (PI) proposed in 2003 to determine their prebiotic activities. This ambiguity can be resolved with the gut microbiome health index (GMHI), newly built in 2020, using a consortium of 50 microbial species associated with human health. As a translational application of this index, we used this formula to predict the PI of five commercial prebiotics, fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS), inulin (IN), and 2`-fucosyllactose (2FL), using in vitro human fecal fermentation. To calculate the GMHI-based PI values, microbial community changes were analyzed at the species level using shotgun sequencing during the fermentation of the prebiotics. As a result, the five compounds exerted a prebiotic effect, increasing the abundance of health-prevalent species, such as Bifidobacterium adolescentis and decreasing health-scarce species. In this context, the GMHI of prebiotics increased after 24 h, but that of the control group without carbon sources decreased. GMHI was highest in the order of IN (0.48 ± 0.06), FOS (0.47 ± 0.03), XOS (0.33 ± 0.02), GOS (0.26 ± 0.02), and 2FL (0.16 ± 0.06), which more accurately reflects the prebiotic effect than PI. Additionally, GMHI stratified the prebiotics more effectively than ecological metrics analyses, such as Shannon diversity, species richness, species evenness, and the inverse Simpson diversity index. This study demonstrates that GMHI-based PI can be used to measure prebiotic activities of several bifidogenic oligosaccharides and perhaps predict the health-beneficial effects of diets after collecting substantial amounts of population-scale meta-datasets.

AbstractObjectivesThe objective of this article is to review options for regional pedicled reconstruction for large head and neck defects in a salvage setting.MethodsRelevant regional pedicled flaps were identified and reviewed. Expert opinion and supporting literature were used to summarize and describe the available options.ResultsSpecific regional pedicled flap options are presented including the pectoralis major flap, deltopectoral flap, supraclavicular flap, submental flap, latissimus flap, and trapezius flap.ConclusionsRegional pedicled flaps are useful options in a salvage setting even for large defects and should be in the armamentarium of any reconstructive head and neck surgeon. Each flap option carries specific characteristics and considerations.