Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome.

We present one of the largest cohorts of TP53-pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76 y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337.

Evolution and Spatiotemporal Expression of and in Zebrafish.

Craniometaphyseal Dysplasia (CMD) is a rare skeletal disorder that can result from mutations in the gene. This gene encodes progressive anksylosis (ANK), which is responsible for transporting inorganic pyrophosphate (PPi) and ATP from the intracellular to the extracellular environment, where PPi inhibits bone mineralization. When ANK is dysfunctional, as in patients with CMD, the passage of PPi to the extracellular environment is reduced, leading to excess mineralization, particularly in bones of the skull.

Distinct genomic and immunologic tumor evolution in germline -driven breast cancers.

Pathogenic germline alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of with no recurrent oncogenic variants except (HER2) amplification.

SFRP1 decreases WNT-Mediated M2 macrophage marker expression in breast tissue.

The Wnt family of secreted proteins are involved in mammary gland development and tumorigenesis. It has recently been shown that Wnt ligands promote M2 macrophage polarization and so we sought to determine the effects of a Wnt signaling antagonist, Secreted Frizzled Related Protein 1 (SFRP1), on M2 marker expression. We measured a murine M2 marker (Arg1) in mice with a targeted deletion of Sfrp1 during different stages of mammary gland development including puberty, pregnancy, and lactation, as well as in response to obesity.

Empirical antimicrobial prescribing for pyelonephritis in patients discharged from 15 US Emergency Departments: an opportunity for improvement.

Background: Urinary tract infections (UTIs) are commonly treated in the emergency department (ED), and unfortunately, resistance to first-line agents is increasing.

Objectives: To characterize treatment of pyelonephritis in a nationally representative sample of ED patients and to identify patient- and treatment-specific factors associated with receiving initial inactive antibiotics.

Methods: We conducted a multicentre, observational cohort study utilizing the Emergency Medicine PHARMacotherapy Research NETwork (EMPHARM-NET), comprising 15 geographically diverse US EDs.

Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.

The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.

Benzophenone-3 exposure alters composition of tumor infiltrating immune cells and increases lung seeding of 4T1 breast cancer cells.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen.

Biallelic Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline Carriers.

Purpose: Breast and ovarian tumors in germline carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline carriers.

Methods: A clinically ascertained cohort of carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types.

"No matter what, we just work with the trauma…": Mental Health Therapists' Care of Diverse Sexual and Gender Identity Citizens in Cambodia.

The convergence of trauma symptomatology, mental health symptoms, family and social difficulties, and intersectionality of diverse sexual and gender minority (SGM) individual issues is complex, multi-faceted, and challenging for the individuals in Cambodia who suffer them and for the therapists in Cambodia who meet individuals in treatment. We documented and analyzed the perspectives of mental health therapists in the context of a randomized control trial (RCT) intervention within the Mekong Project in Cambodia. The research questions explored perceptions of therapists' care of mental health clients, therapist wellbeing, and experiences of navigating within a research environment in which SGM citizens with mental health concerns receive treatment.

Never in Mitosis Kinase 2 regulation of metabolism is required for neural differentiation.

Wnt and Hh are known signalling pathways involved in neural differentiation and recent work has shown the cell cycle regulator, Never in Mitosis Kinase 2 (Nek2) is able to regulate both pathways. Despite its known function in pathway regulation, few studies have explored Nek2 within embryonic development. The P19 embryonal carcinoma cell model was used to investigate Nek2 and neural differentiation through CRISPR knockout and overexpression studies.

Interindividual variation contributes to differential PCB 126 induced gene expression in primary breast epithelial cells and tissues.

PCB 126 is a pervasive, dioxin-like chemical pollutant which can activate the aryl hydrocarbon receptor (AhR). Despite being banned from the market, PCB 126 can be detected in breast milk to this day. The extent to which interindividual variation impacts the adverse responses to this chemical in the breast tissue remains unclear.

High prevalence of fluoroquinolone-resistant UTI among US emergency department patients diagnosed with urinary tract infection, 2018-2020.

Background: Uropathogen resistance, fluoroquinolone-resistance (FQR), and extended spectrum beta-lactamase (ESBL), has been observed to be emerging worldwide with prevalences above recommended thresholds for routine empirical treatment. The primary aim of our study was to determine the prevalence of FQR from a geographically diverse sample of United States emergency departments (EDs).

Methods: We conducted a multi-center, observational cohort study using a network of 15 geographically diverse US EDs.

Building Families Through Healthcare: Experiences of Lesbians Using Reproductive Services.

The use of assisted human reproduction (AHR) represents a meaningful and important life event for lesbians wishing to create biologically related families. Despite increasing numbers of lesbians utilizing AHR services, barriers to access persist. This qualitative study investigated the experiences of lesbians and their interactions with reproductive services in Ontario, Canada, where limited public funding is available for all AHR patients and where the lesbian, gay, bisexual, transgender, and queer (LGBTQ) community makes up to 30% of clientele.

Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis.

Unlabelled: G9a and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, yet the precise roles that these enzymes play cooperatively in cancer is unclear. We demonstrate here that frequent concurrent upregulation of both G9a and EZH2 occurs in several human tumors. These methyltransferases cooperatively repressed molecular pathways responsible for tumor cell death.

Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.

Background: Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa).

Objective: To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden.

Design, Setting, And Participants: A cross-sectional study of 2391 localized PrCa patients was carried out.

Staying InformED: Top emergency Medicine pharmacotherapy articles of 2020.

The year 2020 was not easy for Emergency Medicine (EM) clinicians with the burden of tackling a pandemic. A large focus, rightfully so, was placed on the evolving diagnosis and management of patients with COVID-19 and, as such, the ability of clinicians to remain up to date on key EM pharmacotherapy literature may have been compromised. This article reviews the most important EM pharmacotherapy publications indexed in 2020.

SARS-CoV-2 Seropositivity and Seroconversion in Patients Undergoing Active Cancer-Directed Therapy.

Purpose: Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. We aimed to gauge the effectiveness of these measures at the University of Pennsylvania.

Methods: We conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between May 21, 2020, and October 8, 2020.

G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma.

Purpose: G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether , a G9a target gene, can predict treatment response.

Incidence of thromboembolic events following administration of four-factor prothrombin complex concentrate (4F-PCC) for oral anticoagulation reversal.

Introduction: Prothrombin complex concentrates (4F-PCC) for anticoagulation reversal pose a risk of thromboembolism although data are limited. This study aims to quantify thromboembolic events (TE) and describe associations.

Materials And Methods: Retrospective, two-center, study of patients receiving 4F-PCC between September 2013 and December 2017 for warfarin or direct oral anticoagulant (DOAC) reversal.

Key articles and guidelines for the emergency medicine clinical pharmacist: 2011-2018 update.

Purpose: To summarize recently published research reports and practice guidelines on emergency medicine (EM)-related pharmacotherapy.

Summary: Our author group was composed of 14 EM pharmacists, who used a systematic process to determine main sections and topics for the update as well as pertinent literature for inclusion. Main sections and topics were determined using a modified Delphi method, author and peer reviewer groups were formed, and articles were selected based on a comprehensive literature review and several criteria for each author-reviewer pair.