Machine learning reveals genetic modifiers of the immune microenvironment of cancer.

Heritability in the immune tumor microenvironment (iTME) has been widely observed yet remains largely uncharacterized. Here, we developed a machine learning approach to map iTME modifiers within loci from genome-wide association studies (GWASs) for breast cancer (BrCa) incidence. A random forest model was trained on a positive set of immune-oncology (I-O) targets, and then used to assign I-O target probability scores to 1,362 candidate genes in linkage disequilibrium with 155 BrCa GWAS loci.

Cardiac Magnetic Resonance for Early Detection of Radiation Therapy-Induced Cardiotoxicity in a Small Animal Model.

Background: Over half of all cancer patients receive radiation therapy (RT). However, radiation exposure to the heart can cause cardiotoxicity. Nevertheless, there is a paucity of data on RT-induced cardiac damage, with limited understanding of safe regional RT doses, early detection, prevention and management.

Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells.

During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found activation of NK cells during infection-augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent on the transcriptional coactivator PGC-1α. Using an -based conditional knockout mouse, we found that PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios.

Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells.

Natural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as (which includes , and ) in NK cell-mediated proinflammatory responses.

Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.

Purpose: Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer.

Experimental Design: Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer.

Identification of a Rat Mammary Tumor Risk Locus That Is Syntenic with the Commonly Amplified 8q12.1 and 8q22.1 Regions in Human Breast Cancer Patients.

Breast cancer risk is 31% heritable, yet the majority of the underlying risk factors remain poorly defined. Here, we used F2-linkage analysis in a rat mammary tumor model to identify a novel 11.2 Mb modifier locus of tumor incidence and burden on rat chromosome 5 (chr5: 15.

mTORC1 and mTORC2 differentially promote natural killer cell development.

Natural killer (NK) cells are innate lymphoid cells that are essential for innate and adaptive immunity. Mechanistic target of rapamycin (mTOR) is critical for NK cell development; however, the independent roles of mTORC1 or mTORC2 in regulating this process remain unknown. -mediated deletion of or in mice results in altered homeostatic NK cellularity and impaired development at distinct stages.

Transplantation of human amnion prevents recurring adhesions and ameliorates fibrosis in a rat model of sciatic nerve scarring.

Unlabelled: Peripheral nerve fibrosis and painful adhesions are common, recurring pathological sequelae following injury. In this study, vital human amnion (hAM), an increasingly interesting biomaterial for regenerative medicine, was investigated as a novel therapy. hAM was first analyzed in vitro regarding its anti-adhesive characteristics.

Human amniotic membrane as newly identified source of amniotic fluid pulmonary surfactant.

Pulmonary surfactant (PS) reduces surface tension at the air-liquid interface in the alveolar epithelium of the lung, which is required for breathing and for the pulmonary maturity of the developing foetus. However, the origin of PS had never been thoroughly investigated, although it was assumed to be secreted from the foetal developing lung. Human amniotic membrane (hAM), particularly its epithelial cell layer, composes the amniotic sac enclosing the amniotic fluid.

Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer.

Purpose: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function.

Methods: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer.

A novel experimental rat model of peripheral nerve scarring that reliably mimics post-surgical complications and recurring adhesions.

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. These features can reoccur following external neurolysis, currently the most common surgical treatment for peripheral nerve scarring, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients.

SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis.

Background: Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myocardial infarction (MI), but its role in post-MI inflammation and fibrosis is completely unknown.

Methods And Results: Using an experimental model of MI (left anterior descending artery occlusion/reperfusion injury) in wild-type and Sh2b3 knockout rats (Sh2b3(em2Mcwi)), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression.

CXM: a new tool for mapping breast cancer risk in the tumor microenvironment.

The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment.

Accelerating cine-MR imaging in mouse hearts using compressed sensing.

Purpose: To combine global cardiac function imaging with compressed sensing (CS) in order to reduce scan time and to validate this technique in normal mouse hearts and in a murine model of chronic myocardial infarction.

Materials And Methods: To determine the maximally achievable acceleration factor, fully acquired cine data, obtained in sham and chronically infarcted (MI) mouse hearts were 2-4-fold undersampled retrospectively, followed by CS reconstruction and blinded image segmentation. Subsequently, dedicated CS sampling schemes were implemented at a preclinical 9.

High-density rat radiation hybrid maps containing over 24,000 SSLPs, genes, and ESTs provide a direct link to the rat genome sequence.

The laboratory rat is a major model organism for systems biology. To complement the cornucopia of physiological and pharmacological data generated in the rat, a large genomic toolset has been developed, culminating in the release of the rat draft genome sequence. The rat draft sequence used a variety of assembly packages, as well as data from the Radiation Hybrid (RH) map of the rat as part of their validation.