Selective Aurora A-TPX2 Interaction Inhibitors Have Efficacy as Targeted Antimitotic Agents.

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI).

Patient Experience of Women With Dense Breasts Undergoing Screening Contrast-Enhanced Mammography.

Objective: We investigated patient experience with screening contrast-enhanced mammography (CEM) to determine whether a general population of women with dense breasts would accept CEM in a screening setting.

Methods: In this institutional review board-approved prospective study, patients with heterogeneous and extremely dense breasts on their mammogram were invited to undergo screening CEM and complete pre-CEM and post-CEM surveys. On the pre-CEM survey, patients were asked about their attitudes regarding supplemental screening in general.

Designing a Collaborative Breast Radiology Training Program to Tackle Tanzania's Breast Cancer Crisis.

Breast cancer incidence and mortality continue to increase in Africa. In Tanzania, breast cancer is the second leading cause of cancer death for women, and breast cancer incidence and mortality are projected to increase by 80% by 2030. Education gaps among health care workers, delayed presentation, limited screening, and low health literacy all pose significant challenges to providing optimal breast cancer care.

The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K).

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders as they are key components in regulating cell signalling pathways. In an effort to make probe molecules available for further exploring these targets, we have previously reported PI5P4Kα-selective and PI5P4Kγ-selective ligands. Herein we report the rational design of PI5P4Kα/γ dual inhibitors, using knowledge gained during the development of selective inhibitors for these proteins.

Subspecialty Breast Imaging Education in Tanzania; Clinical, Infrastructure, and Logistical Paradigms for Best Practices in the Low- and Middle-Income Settings.

We present subspecialty radiologist training for breast imaging at an Academic center in Dar Es Salaam, Tanzania. The training incorporates remote, in-person, asynchronous and synchronous teaching methods and multidisciplinary conferences. We use a team of US academic faculty under the auspices of the Radiological Society of North America Global Learning centers paradigm.

The Identification of Potent, Selective, and Brain Penetrant PI5P4Kγ Inhibitors as In Vivo-Ready Tool Molecules.

Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets in diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited in potency or isoform selectivity, which has hampered further investigation of biology and drug development. Herein we describe the virtual screening workflow which identified a series of thienylpyrimidines as PI5P4Kγ-selective inhibitors, as well as the medicinal chemistry optimization of this chemotype, to provide potent and selective tool molecules for further use.

Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.

Background And Purpose: Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown.

Experimental Approach: To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry.

A pilot multi-institutional study to evaluate the accuracy of a supine MRI based guidance system, the Breast Cancer Locator™, in patients with palpable breast cancer.

Background: Evaluate whether the Breast Cancer Locator™ (BCL), a novel guidance system based on supine MRI images, can be safely and effectively deployed by several surgeons at multiple sites.

Methods: Patients with palpable breast cancer underwent supine MRI at their local institution. A three dimensional (3D) digital image of the tumor in the breast was derived from supine MRI images and used to generate 1) an interactive 3D virtual image of the tumor in the breast (Visualizer) and 2) a plastic bra-like form that allowed the surgeon to place a central wire and bracketing wires in the breast (BCL).

Persistent post-galactogram intraductal iodinated contrast detected on contrast-enhanced mammography (CEM) in a patient with nipple discharge.

Nipple discharge is a common complaint among adult women and is often evaluated by galactography. Contrast-enhanced mammography (CEM) is an emerging breast imaging modality that is useful in the evaluation of patients with nipple discharge who have a negative galactogram, especially if they are not good candidates for contrast-enhanced MRI. Here we present a case of a 37-year-old female who was 22 weeks pregnant and presented with suspicious nipple discharge.

Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 ().

Increasing Applicant Engagement During the 2020-2021 Virtual Residency Interview Cycle and Beyond: The Dartmouth-Hitchcock Radiology Residency Video Project.

Rationale And Objectives: To explore the effectiveness of the video medium and YouTube platform in conveying residency program and community information to prospective applicants during the 2020-2021 virtual residency interview cycle. To garner insights on the virtual-only residency interview experience and our video-centered approach through survey data collected from interviewing candidates for potential implementation in future application cycles.

Materials And Methods: 13 custom content videos were produced highlighting our radiology residency program and uploaded onto a newly created YouTube channel and the institutional website during the late summer through fall of the 2020-2021 residency interview cycle.

Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain.

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1.

Tumor suppressor function of Gata2 in acute promyelocytic leukemia.

Most patients with acute promyelocytic leukemia (APL) can be cured with combined all-trans retinoic acid (ATRA) and arsenic trioxide therapy, which induces the destruction of PML-RARA, the initiating fusion protein for this disease. However, the underlying mechanisms by which PML-RARA initiates and maintains APL cells are still not clear. Therefore, we identified genes that are dysregulated by PML-RARA in mouse and human APL cells and prioritized GATA2 for functional studies because it is highly expressed in preleukemic cells expressing PML-RARA, its high expression persists in transformed APL cells, and spontaneous somatic mutations of GATA2 occur during APL progression in mice and humans.

Is Apixaban Safe and Effective for Venous Thromboembolism Prophylaxis After Primary Total Hip and Total Knee Arthroplasties?

Background: Venous thromboembolism (VTE) is a serious complication of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Apixaban is approved for VTE prophylaxis. This study seeks to ascertain the risk of VTE and bleeding complications in patients undergoing primary THA and TKA receiving apixaban for postoperative VTE prophylaxis for one of the following indications: high risk for VTE, previously on apixaban, and contraindication to the use of aspirin.

is elevated in neuromyelitis optica spectrum disorder in India and shares sequence similarity with AQP4.

Objective: To understand the role of gut microbiome in influencing the pathogenesis of neuromyelitis optica spectrum disorders (NMOSDs) among patients of south Indian origin.

Methods: In this case-control study, stool and blood samples were collected from 39 patients with NMOSD, including 17 with aquaporin 4 IgG antibodies (AQP4+) and 36 matched controls. 16S ribosomal RNA (rRNA) sequencing was used to investigate the gut microbiome.

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system.

Identification of TNFAIP3 as relapse biomarker and potential therapeutic target for MOG antibody associated diseases.

MOG-antibody associated disease (MOG-AAD) is a recently recognized demyelinating disorder predominantly affecting children but also occurs in adults, with a relapsing course in approximately 50% of patients. We evaluated peripheral blood mononuclear cells from MOG-AAD patients by flow cytometry and found a strong antigen specific central memory cell (CMC) response with increased Th1 and Th17 cells at the time of a relapse. Transcriptomic analysis of CMCs by three independent sequencing platforms revealed TNFAIP3 as a relapse biomarker, whose expression was down regulated at a relapse compared to remission in MOG-AAD patients.

The shape of breast cancer.

Purpose: Little is known about the three-dimensional shape of breast cancer. Implicit to approaches that localize the center of the tumor for breast-conserving surgery (BCS) of non-palpable cancers is the assumption that breast cancers are spherical about a central point, which may not be accurate.

Methods: Pre-operative supine breast MRI images were obtained of 83 breast cancer patients undergoing partial mastectomy using supine MRI-guided resection techniques.

Breast Imaging and Image-guided Intervention in Tanzania: Initial Experience.

Breast imaging capacity in Tanzania is currently very limited. In a country of almost 60 million people, mammographic units are exceedingly rare. The few existing units are compromised by lack of maintenance and quality control and extremely limited technologist training.

Quantitative Proteomics Reveals a Role for SERINE/ARGININE-Rich 45 in Regulating RNA Metabolism and Modulating Transcriptional Suppression the ASAP Complex in .

Pre-mRNA alternative splicing is a conserved mechanism for eukaryotic cells to leverage existing genetic resources to create a diverse pool of protein products. It is regulated in coordination with other events in RNA metabolism such as transcription, polyadenylation, RNA transport, and nonsense-mediated decay protein networks. SERINE/ARGININE-RICH 45 (SR45) is thought to be a neutral splicing regulator.

A Randomized Prospective Trial of Supine MRI-Guided Versus Wire-Localized Lumpectomy for Breast Cancer.

Background: Wire-localized excision of non-palpable breast cancer is imprecise, resulting in positive margins 15-35% of the time.

Methods: Women with a confirmed diagnosis of non-palpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) were randomized to a new technique using preoperative supine magnetic resonance imaging (MRI) with intraoperative optical scanning and tracking (MRI group) or wire-localized (WL group) partial mastectomy. The main outcome measure was the positive margin rate.

Assessing Resident Performance in Screening Mammography: Development of a Quantitative Algorithm.

Rationale And Objectives: This study aims to provide objective performance data and feedback, including examination volumes, recall rates, and concordance with faculty interpretations, for residents performing independent interpretation of screening mammography examinations.

Method And Materials: Residents (r) and faculty (f) interpret screening mammograms separately and identify non-callbacks (NCBs) and callbacks (CBs). Residents review all discordant results.

A Patient-Specific 3D-Printed Form Accurately Transfers Supine MRI-Derived Tumor Localization Information to Guide Breast-Conserving Surgery.

Background: Wire-localized excision of nonpalpable breast cancer is imprecise, resulting in positive margins 25-30% of the time.

Methods: Patients underwent preoperative supine magnetic resonance imaging (MRI). A radiologist outlined the tumor edges on consecutive images, creating a three-dimensional (3D) view of its location.

Isoxazole-Derived Amino Acids are Bromodomain-Binding Acetyl-Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3.

A range of isoxazole-containing amino acids was synthesized that displaced acetyl-lysine-containing peptides from the BAZ2A, BRD4(1), and BRD9 bromodomains. Three of these amino acids were incorporated into a histone H4-mimicking peptide and their affinity for BRD4(1) was assessed. Affinities of the isoxazole-containing peptides are comparable to those of a hyperacetylated histone H4-mimicking cognate peptide, and demonstrated a dependence on the position at which the unnatural residue was incorporated.