Citations

Alpha‐1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5‐methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early‐stage AATD and the ZZ genotype, genome‐wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver–impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome‐wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well‐known sex‐specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and affects millions worldwide. Due to the lack of effective systemic therapies for HCC, researchers have been investigating the use of locoregional tumor control with Yttrium-90 (Y90) radioembolization since the 1960s. Following the development of glass and resin Y90 microspheres in the early 1990s, Y90 radioembolization has been shown to be a safe and efficacious treatment for patients with HCC across Barcelona Clinic Liver Cancer (BCLC) stages. By demonstrating durable local control, good long term outcomes, and equivalent if not superior tumor responses and tolerability when compared to alternative therapies including transarterial chemoembolization (TACE) and sorafenib, Y90 radioembolization is being increasingly used in HCC treatment. More recently, investigations into variations in Y90 radioembolization technique including radiation segmentectomy and radiation lobectomy have further expanded its clinical utility. Here, we discuss the history and evolution of Y90 use in HCC. We outline key clinical trials that have established the safety and efficacy of Y90 radioembolization, and also summarize trials comparing its efficacy to existing HCC treatments. We conclude by reviewing the techniques of radiation segmentectomy and lobectomy, and by discussing dosimetry.

Lower extremity peripheral arterial disease (PAD) is a chronic, debilitating disease with a significant global burden. A number of diagnostic imaging techniques exist, including computed tomography angiography (CTA) and contrast-enhanced magnetic resonance angiography (CEMRA), to aid in PAD diagnosis and subsequent treatment planning. Due to concerns of renal toxicity or nephrogenic systemic fibrosis (NSF) for iodinated and gadolinium-based contrasts, respectively, a number of non-enhanced MRA (NEMRA) protocols are being increasingly used in PAD diagnosis. These techniques, including time of flight and phase contrast MRA, have previously demonstrated poor image quality, long acquisition times, and/or susceptibility to artifacts when compared to existing contrast-enhanced techniques. In recent years, Quiescent-Interval Single-Shot (QISS) MRA has been developed to overcome these limitations in NEMRA methods, with promising results. Here, we review the various screening and diagnostic tests currently used for PAD. The various NEMRA protocols are discussed, followed by a comprehensive review of the literature on QISS MRA to date. A particular emphasis is placed on QISS MRA feasibility studies and studies comparing the diagnostic accuracy and image quality of QISS MRA versus other diagnostic imaging techniques in PAD.

Abstract Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART ) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.