The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.

Several therapeutic agents have been approved for treating multiple myeloma, a cancer of bone marrow-resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. In this study, we present an integrated functional genomic analysis of tumor samples from patients multiple myeloma that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes.

Genomic Classification and Individualized Prognosis in Multiple Myeloma.

Purpose: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.

Methods: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data.

Results: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications.

CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.

Unlabelled: Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in multiple myeloma that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-multiple myeloma activity, including against primary multiple myeloma patient specimens.

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma.

Background: Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis.

Methods: Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes.

Harmonizing the preclinical Alzheimer cognitive composite for multicohort studies.

Objectives: Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC.

Method: We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts ( = 2,712).

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

Background: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline.

Objectives: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.

Racial and ethnic differences in clonal hematopoiesis, tumor markers, and outcomes of patients with multiple myeloma.

Multiple myeloma (MM) incidence, mortality, and survival vary by race and ethnicity, but the causes of differences remain unclear. We investigated demographic, clinical, and molecular features of diverse MM patients to elucidate mechanisms driving clinical disparities. This study included 495 MM patients (self-reported Hispanic, n = 45; non-Hispanic Black, n = 52; non-Hispanic White, n = 398).

Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.

Background And Objectives: Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive vs independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury.

Plasma cell dependence on histone/protein deacetylase 11 reveals a therapeutic target in multiple myeloma.

The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM.

In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline.

Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer’s disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer’s Coordinating Center cases providing three different LC measures (pigmentation, tangle density, and neuronal density), Braak staging, β-amyloid, and longitudinal cognitive measures.

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer's disease: A cross-sectional study.

Introduction: Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD).

Methods: Two hundred eleven participants (105 presenilin-1 [] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging.

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma.

Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge.

DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden.

Objective: DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population.

NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.

Aims: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness.

Main Methods: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence.

Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer's disease.

Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aβ), in clinically-normal older adults.

Inferior temporal tau is associated with accelerated prospective cortical thinning in clinically normal older adults.

Neurofibrillary tau tangles are a hallmark pathology of Alzheimer's disease (AD) and are more closely associated with AD-related cortical atrophy and symptom severity than amyloid-beta (Aβ). However, studies regarding the effect of tau on longitudinal cortical thinning, particularly in healthy aging and preclinical AD, have been limited in number due to the relatively recent introduction of in vivo PET tracers for imaging tau pathology. Here, we investigate [18F]-flortaucipir (FTP, a marker of paired helical filament tau) PET as a predictor of atrophy in healthy aging and preclinical AD.

Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults.

Importance: In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease.

Objective: To examine whether physical activity moderates the association of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk.

Design, Setting, And Participants: This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene.

SVachra: a tool to identify genomic structural variation in mate pair sequencing data containing inward and outward facing reads.

Background: Characterization of genomic structural variation (SV) is essential to expanding the research and clinical applications of genome sequencing. Reliance upon short DNA fragment paired end sequencing has yielded a wealth of single nucleotide variants and internal sequencing read insertions-deletions, at the cost of limited SV detection. Multi-kilobase DNA fragment mate pair sequencing has supplemented the void in SV detection, but introduced new analytic challenges requiring SV detection tools specifically designed for mate pair sequencing data.

Therapy-related Acute Leukemia With Mixed Phenotype and Novel t(1: 6)(q25;p23) After Treatment for High-risk Neuroblastoma.

Neuroblastoma is the most common extracranial malignancy of childhood. Patients with high-risk disease receive multimodal treatment including chemotherapy combinations containing alkylating agents and topoisomerase inhibitors with potential for inducing therapy-related malignancy later in life. Most commonly, cytogenetic changes of pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia involve chromosome 5 or 7.

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss.

Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma.

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor.

Non-malignant respiratory epithelial cells preferentially proliferate from resected non-small cell lung cancer specimens cultured under conditionally reprogrammed conditions.

The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung.