Citations

AbstractBackgroundPathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers.MethodALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD.ResultFive treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect.ConclusionPlatform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure.

Abstract During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block‐face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase‐quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3 , Chchd6 , and Mitofilin . We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age‐related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age‐related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue‐dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.

Purpose of review To describe the relationship between three pandemics: hypertension, obesity, and heart failure. From pathophysiology to treatment, understanding how these disease entities are linked can lead to breakthroughs in their prevention and treatment. The relevance of this review lies in its discussion of novel pharmacological and surgical treatment strategies for obesity and hypertension, and their role in the prevention and treatment of heart failure. Recent findings Novel medications such as GLP-1 agonists have demonstrated sustained weight loss in patients with obesity, and concurrent improvements in their cardiometabolic profile, and possibly also reductions in hypertension-related comorbidities including heart failure. Surgical therapies including laparoscopic bariatric surgery represent an important treatment strategy in obese patients, and recent studies describe their use even in patients with advanced heart failure, including those with ventricular assist devices. Summary These developments have deep implications on our efforts to understand, mitigate, and ultimately prevent the three pandemics, and offer promising improvements to quality of life, survival, and the cost burden of these diseases.

Abstract Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusions: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.

AbstractBackgroundClinical trials are underway to treat familial frontotemporal lobar degeneration (f‐FTLD). This is a rare disease, and a limited number of mutation carriers have been identified; thus, efficient trial design is critical. Multimodal, latent disease progression models (DPM) can estimate time to symptom onset and define the temporal ordering of biomarker changes. DPMs can also be leveraged to select endpoints and potentially supplement analyses by integrating historical data. Recent draft FDA guidance for gene therapy trials in neurological disease supports these novel approaches to clinical trials.MethodParticipants included 1,049 members of families affected by f‐FTLD, due to mutations in GRN, MAPT, or C9orf72 genes, who were enrolled in ALLFTD or GENFI. A Bayesian repeated measures model incorporated multimodal data to estimate disease progression, conditional on latent disease age (proximity to symptom onset), in 677 mutations carriers (GRN (n=233), MAPT (n=151) and C9orf72 (n=293)). Family members without pathogenic mutations were used as the reference group. Mean follow‐up was 1.1 (SD=1.1) years. Jointly modeled longitudinal variables included neuropsychological scores, CDR®+NACC‐FTLD Box Score, MRI volumes of brain regions affected by f‐FTLD, and plasma levels of neurofilament light chain (NfL).ResultDisease progression curves were similar across ALLFTD and GENFI cohorts. Plasma NfL elevations occurred earliest, up to 10 years before symptom onset, and NfL was the most powerful endpoint in the asymptomatic stage. MRI abnormalities occurred next, closer to symptom onset. The earliest MRI changes relative to symptom onset were observed in C9orf72+. GRN mutation carriers showed the most rapid acceleration in all biomarkers, and this acceleration occurred in close proximity to symptom onset. Neuropsychological measures and CDR®+NACC‐FTLD Box Score were among the most promising endpoints in the symptomatic stage. Trial simulations indicated that using latent disease age as an enrollment criterion would allow some asymptomatic mutation carriers to be enrolled without sacrificing power.ConclusionSimilarity in disease progression across ALLFTD and GENFI participants suggests these models will apply to international trials. Model‐derived estimates of disease progression curves indicate that endpoint selection should be specific to disease stage and mutation, and DPMs would facilitate greater participant enrollment.

ABSTRACT Background Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. Methods Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. Results From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76–100%) versus those enrolling patients with and without kidney involvement (56%, 45–66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. Conclusions In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

Abstract Background: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. Methods: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. Results: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10–6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. Conclusions: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. Impact: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

Introduction: To report a case of a Hispanic girl with late-onset Retinoblastoma (Rb) who was misdiagnosed as a pars planitis prior to referral. Nearly 95% of all Rb cases are detected before age 5, and this patient was 8 years-old. Methods: Case report of a late-onset Retinoblastoma with anterior chamber (AC) involvement plus the presence of an Ahmed valve. The patient had a history of a couple of months of topical therapy comprising medication for glaucoma, systemic steroids, and a filtration surgery (Ahmed valve), after that a biopsy was performed prior to referral. Upon arrival at our clinic, we performed an examination under anesthesia (EUA) and a B-scan ultrasound (US). Results: Unilateral Retinoblastoma with an Ahmed valve in an AC filled with Rb seeds was diagnosed with the EUA and US in the left eye. An orbital exenteration with map biopsies of the left orbital cavity was performed with confirmation by histopathology of a poorly differentiated endophytic retinoblastoma with Bruch’s membrane invasion. Follow-up sessions were then arranged as well as subsequent systemic chemotherapy cycles. Conclusion: Given the rare incidence of retinoblastoma in children older than 5 years old, it can be easily mistaken for other differential diagnoses and treated with filtration surgeries that could put the patient’s life at risk. In this report, late-onset Rb diagnosis is highlighted as a differential diagnosis in children and adults with atypical uveitis, which required a multidisciplinary approach.