Citations

AbstractBackgroundThe histopathological diagnosis of MF is challenging, and there is significant overlap with benign inflammatory processes. Clinical features may be relevant in the assessment of skin biopsies.MethodsWe provided photomicrographs to board‐certified dermatopathologists and one hematopathologist with and without accompanying clinical photographs and assessed accuracy and confidence in diagnosing MF.ResultsWe found that access to clinical photographs improved diagnostic accuracy in both MF and non‐MF (distractors); the degree of improvement was significantly higher in the non‐MF/distractor category. Across all categories, diagnostic confidence level was higher when clinical images were available.ConclusionThese findings suggest that clinical images are useful in making an accurate diagnosis of MF, and may be particularly helpful in ruling it out when an inflammatory disorder is clinically suspected.

AbstractBackgroundWe have previously demonstrated that partial reduction of mitochondrial complex I (MCI) activity using small molecules is efficacious in decreasing levels of amyloid beta (Aβ), phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial axonal trafficking, levels of BDNF and synaptic proteins in pre‐symptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype compared to their untreated littermates.MethodIn the current study, we tested whether treatment with MCI inhibitors could halt the disease progression when treatment was administered to symptomatic APP/PS1 mice.ResultTreatment improved glucose tolerance, prevented body weight loss, and ameliorated systemic inflammation. Treatment improved glucose uptake in the brain measured using FDG‐PET imaging. Electrophysiological recording in hippocampus indicated that synaptic activity and LTP were restored in treated APP/PS1 mice. Data gathered using 3D electron microscopy reconstruction of dendrites in CA1 region of hippocampus showed that treatment increased the population of mature dendritic spines in APP/PS1 mice, which correlates with restored synaptic activity and improved glucose uptake and utilization in the brain. Immunohistochemical analysis showed that treated APP/PS1 mice had reduced brain level of Aβ plaques, markers of inflammation and reduced degeneration of TH+ neurons in locus coeruleus. The RNA‐seq gene function enrichment analysis showed that pathways down‐regulated by treatment with MCI inhibitors in APP/PS1 mice included the ones involved in oxidative stress and immune system response. Moreover, RNA‐seq data analysis depicted a cluster of genes involved in dendritic morphology, axonal guidance and neuronal development, which expression were reverted by treatment in APP/PS1 mice to the level observed in NTG mice. Western blot analysis in cortico‐hippocampal brain region of APP/PS1 mice confirmed that treatment increased signaling molecules involved in IGF‐1/insulin pathway, mitochondrial biogenesis, oxidative stress protection, autophagy and synaptic function.ConclusionOverall, our data suggest that long‐term treatment with MCI inhibitors is safe and efficacious in restoring cognitive function and preventing degeneration in symptomatic APP/PS1 mice. Therefore, partial MCI inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.

AbstractBackgroundAlzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amyloid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We developed small molecules partial mitochondrial complex I (MCI) inhibitors and demonstrated that their application prevents the development of cognitive and behavior phenotype, improves LTP, reduces oxidative stress and inflammation, and restores glucose uptake and utilization in the brain in mouse models of familial AD. Efficacy could be monitored in vivo using translational biomarkers FDG‐PET, 31P NMR and blood biomarkers.MethodWe conducted extensive structure‐activity relationship (SAR) studies to characterize novel classes of compounds partial MCI inhibitors including a new lead compound C458. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro and cellular assays including SPR, competitive and direct binding, proteomics and pull down experiments.ResultWe demonstrated that the lead C458 directly binds and competes with the FMN for binding to complex I. In primary neurons and mouse brain tissue, single dose administration of C458 activates AMPK‐a, autophagy, Sirtuins 1 and 3, and upregulate PGC‐1a leading to enhanced mitochondrial biogenesis. In vivo, chronic administration of C458 had no detectable toxicity at therapeutic doses. C458 has excellent oral bioavailability and blood–brain‐barrier penetration. C458 was remarkably clean in 250 kinase panel. Finally, in pre‐symptomatic APP/PS1 mice, treatment with C458 resulted in cognitive protection and improved long‐term potentiation after 6 months of chronic oral administration (25 mg/kg/day), decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in metabolic rates and glucose brain uptake and utilization detected with translational FDG‐PET imaging as well as an enhancement of ATP production in the brain measured in vivo with 31P NMR.ConclusionMechanistic studies demonstrate that MCI inhibitors induce protective stress response increasing mitochondrial biogenesis and turnover, augmenting cellular energetics and the protection against oxidative stress, and engage other mechanisms that intersect with the pathways involved in longevity and health extension. Our studies demonstrate that modulation of MCI activity using novel FMN MCI inhibitors improves bioenergetics in the brain and averts cognitive decline in Alzheimer’s Disease representing novel therapeutic approach.

Background: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. Methods: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. Results: No significant differences in ΔSAQ angina frequency scores ( P =0.53) or Duke Activity Status Index ( P =0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores ( P =0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO 2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 ( P =0.02). Conclusions: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02147067.

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.

Abstract To assess the impact of the pandemic on the field, we performed an international web-based survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents from April 24 through May 17. Of 582 respondents, 258 (45%) were in the US, and 314 (55%) were international. 80.4% were affiliated with academic institutions. 94% respondents reported changes in clinical practice; 95% reported conversion to telemedicine for at least some appointments. However, almost 10% practitioners felt the need to see patients in person specifically because of billing concerns and perceived institutional pressure. Over 50% believed neuro-oncology patients were at increased risk of contracting COVID-19. 67% practitioners suspended enrollment for at least one clinical trial: 53% suspended phase II and 62% suspended phase III trial enrollment. 71% clinicians feared for their or their families’ safety, specifically because of their clinical duties. 20% percent said they did not have enough PPE to work safely; about the same percentage were unhappy with their institutions’ response to the pandemic. 43% believed the pandemic would negatively affect their academic career, and 52% fellowship program directors were worried about losing funding for their training programs. While 69% respondents reported increased stress, 44% were offered no psychosocial support. 37% had their salary reduced. 36% researchers had to temporarily close their laboratories. In contrast, the pandemic created positive changes in perceived patient and family satisfaction, quality of communication, and use of technology to deliver care and interactions with other practitioners. CONCLUSIONS: The pandemic has altered standard treatment schedules and limited investigational treatment options for patients. In some cases, clinicians felt institutional pressure to continue conducting billable in-person visits when telemedicine visits would have sufficed. A lack of institutional support created anxiety among clinicians and researchers. We make specific recommendations to guide clinical and scientific infrastructure moving forward.

AbstractAlthough the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.

Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5–18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

I. Executive Summary Background The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS.

Background and Aims Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5‐year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary‐to‐secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary‐to‐secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine‐learning model, PSC‐BA profile score (concordance statistic [C‐statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C‐statistic, 0.86). Conclusions Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.