Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.

Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. In the present study, we used 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detected transcription-dependent, replicated-strand bias, the expected footprint of transcription-replication collision (TRC), in large tandem duplications (TDs).

PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models.

Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination.

Male Survivors of Institutional Child Sexual Abuse: A Review.

Male child sexual abuse is over-represented in institutional settings. This realization has increasingly come into public focus in recent decades initially through lived experience, often with male survivors' stories told in the media and subsequently through court cases and government inquiries. Beginning at the turn of the century with the Irish Commission to Inquire into Child Abuse (1999-2009), numerous national and state inquiries into institutional child abuse followed around the world.

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2.

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses.

Promoting men-inclusive maternity services: exploring the expectations, experiences and needs of men as fathers.

Aim: This study aimed to explore the 'real time' expectations, experiences and needs of men who attend maternity services to inform the development of strategies to enhance men's inclusion.

Methods: A qualitative descriptive design was adopted for the study. Semi-structured face-to-face or telephone interviews were conducted with 48 men attending the Royal Brisbane and Women's Hospital before and after their partner gave birth.

Biomechanical Motion Changes in Adjacent and Noncontiguous Segments Following Single-Level Anterior Cervical Discectomy and Fusion: A Computed Tomography-Based 3D Motion Capture Study.

Background: Anterior cervical discectomy and fusion (ACDF) is known to elicit adverse biomechanical effects on immediately adjacent segments; however, its impact on the kinematics of the remaining nonadjacent cervical levels has not been understood. This study aimed to explore the biomechanical impact of ACDF on kinematics beyond the immediate fusion site. We hypothesized that compensatory motion following single-level ACDF is not predictably distributed to adjacent segments due to compensation from noncontiguous levels.

Intersections of Intimate Partner Violence and Natural Disasters: A Systematic Review of the Quantitative Evidence.

Natural disasters and extreme weather events are increasing in both intensity and frequency. Emerging evidence suggests that there is a relationship between intimate partner violence (IPV) and natural disasters. However, there is a scarcity of methodologically sound research in this area with no systematic review to date.

Large tandem duplications in cancer result from transcription and DNA replication collisions.

Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. Here, we use 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detect transcription-dependent replicated-strand bias, the expected footprint of transcription-replication collision (TRC), in large tandem duplications (TDs).

Novel approach to prenatal predictors of outcomes for fetuses with severe Ebstein anomaly.

Objective: Ebstein anomaly (EA) is a cardiac malformation with highly variable presentation and severity with limited perinatal management options. We present incorporation of fetal lung measurements into a multidisciplinary evaluation for counseling and predicting postnatal outcomes in patients with severe EA.

Methods: Five fetuses with severe fetal EA were reviewed.

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo.

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the role of Mac1 catalytic activity in viral replication, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site.

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication and pathogenesis .

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the therapeutic potential of Mac1 inhibition, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site.

Optimizing Referral Timing of Patients With Fontan Circulatory Failure for Heart Transplant.

Background: There are no criteria guiding the timing of heart transplant referral for Fontan patients, nor are there any characteristics of those deferred or declined listing reported. This study examines comprehensive transplant evaluations for Fontan patients of all ages, listing decisions, and outcomes to inform referral practices.

Methods: Retrospective review of 63 Fontan patients formally assessed by the advanced heart failure service and presented at Mayo Clinic transplant selection committee meetings (TSM) January 2006 to April 2021.

How Does Cross-Sectional Imaging Impact the Management of Patients With Single Ventricle After Bidirectional Cavopulmonary Connection?

Background: There is currently no consensus regarding the use of surveillance cross-sectional imaging in pediatric patients after bidirectional cavopulmonary connection (BDCPC). We sought to determine how computed tomography with angiography (CTA) and cardiac magnetic resonance (CMR) imaging impacted the clinical management of pediatric patients after BDCPC.

Methods: A single-center retrospective study including patients with single ventricle who had BDCPC between 2010 and 2019, and CTA/CMR studies obtained in these patients, at ≤5 years of age, and with Glenn physiology.

Myocardial Work in Echocardiography.

Myocardial work is an emerging tool in echocardiography that incorporates left ventricular afterload into global longitudinal strain analysis. Myocardial work correlates with myocardial oxygen consumption, and work efficiency can also be assessed. Myocardial work has been evaluated in a variety of clinical conditions to assess the added value of myocardial work compared to left ventricular ejection fraction and global longitudinal strain.

Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.

Unlabelled: Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer.

Bearing Witness as a Process for Responding to Trauma Survivors: A Review.

is a means for trauma survivors to give voice to lived experience. Bearing witness has been used in national and international commissions, inquiries, and tribunals to hear directly from survivors of abuse and trauma. This scoping review examines the documented research on the experience of survivors of trauma bearing witness.

RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction.

The Impact of Critical Life Points and Events for Survivors of Institutional Child Sexual Abuse: Understanding Trauma and the Role of Compensation in Recovery.

Although the impact of child sexual abuse (CSA) is well documented in the international literature, little is known about the critical points of recovery across the life course for survivors of institutional CSA. The aim of this study was to identify critical points, or events across the life course that may increase, or decrease, a survivor's vulnerability to the complex traumatization of institutional CSA (ICSA). The sample consisted of two hundred and forty-eight witness statements extracted from the 56 publicly available case studies presented to the Australian Royal Commission into Institutional Responses to Child Sexual Abuse during 2013-2016 (Commonwealth of Australia, 2017).

Technology-Facilitated Abuse Against Women From Culturally and Linguistically Diverse Backgrounds: A Scoping Review of the Literature.

Women from culturally and linguistically diverse (CALD) backgrounds are particularly vulnerable to domestic and family violence, including technology-facilitated abuse. Often CALD women depend on technology to connect with support networks in their home country. Technology-facilitated abuse can be devastating and isolating.

A Whole-Genome CRISPR Screen Identifies AHR Loss as a Mechanism of Resistance to a PARP7 Inhibitor.

Inhibitors directed toward PARP1 and PARP2 are approved agents for the treatment of BRCA1 and BRCA2-related cancers. Other members of the PARP family have also been implicated in cancer and are being assessed as therapeutic targets in cancer and other diseases. Recently, an inhibitor of PARP7 (RBN-2397) has reached early-stage human clinical trials.

Aorto-ventricular tunnel: Aortic regurgitation and noncompaction cardiomyopathy - Common late associations after repair.

Aorto-ventricular tunnels are rare, congenital extracardiac connections arising from the tubular ascending aorta, above the sinotubular junction, which communicate directly with the ventricular cavity. We present long-term follow-up in a series of five adults undergoing pediatric repair and describe the cardiovascular features and outcomes. Significant aortic regurgitation, ascending aortic aneurysm and left ventricular noncompaction were found to be highly prevalent, emphasizing the need for ongoing surveillance following repair of this anomaly.

Systemic Semilunar Valve Repair/Replacement With Fontan Circulation: The Mayo Clinic Experience.

There is a paucity of literature regarding systemic semilunar valve (SSLV) dysfunction in patients with Fontan circulation. We sought to describe our center's 47-year experience with systemic semilunar valve replacement or repair (SSLVR) in patients with Fontan circulation. The Mayo Clinic Fontan Database is a comprehensive institutional database that stores clinical information of 1176 patients from 1973 to 2021.

A protein interaction landscape of breast cancer.

Cancers have been associated with a diverse array of genomic alterations. To help mechanistically understand such alterations in breast-invasive carcinoma, we applied affinity purification–mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer (BC) proteins, with and without relevant mutations, across three human breast cell lines. These networks identify cancer-specific protein-protein interactions (PPIs), interconnected and enriched for common and rare cancer mutations, that are substantially rewired by the introduction of key BC mutations.

Cone Reconstruction for Ebstein Anomaly: Ventricular Remodeling and Preliminary Impact of Stem Cell Therapy.

Objective: To define the impact of tricuspid valve cone reconstruction (CR) on ventricular performance in Ebstein anomaly, both independently and after stem cell therapy.

Patients And Methods: The control group included 257 patients who had CR between June 2007 and December 2019. Ten subjects of a phase I stem cell therapy trial (May 2017 - March 2019) were compared with the controls to assess the echocardiographic impact on ventricular remodeling.