LIG1 is a synthetic lethal target in BRCA1 mutant cancers.

Synthetic lethality approaches in BRCA1/2-mutated cancers have focused on poly(ADP-ribose) polymerase (PARP) inhibitors, which are subject to high rates of innate or acquired resistance in patients. Here, we used CRISPR/Cas9-based screening to identify DNA Ligase I (LIG1) as a novel target for synthetic lethality in BRCA1-mutated cancers. Publicly available data supported LIG1 hyperdependence of BRCA1-mutant cells across a variety of breast and ovarian cancer cell lines.

Insights into the flexibility of the domain-linking loop in actinobacterial coproheme decarboxylase through structures and molecular dynamics simulations.

Prokaryotic heme biosynthesis in Gram-positive bacteria follows the coproporphyrin-dependent heme biosynthesis pathway. The last step in this pathway is catalyzed by the enzyme coproheme decarboxylase, which oxidatively transforms two propionate groups into vinyl groups yielding heme b. The catalytic reaction cycle of coproheme decarboxylases exhibits four different states: the apo-form, the substrate (coproheme)-bound form, a transient three-propionate intermediate form (monovinyl, monopropionate deuteroheme; MMD), and the product (heme b)-bound form.

Cryo-EM SPR structures of Salmonella typhimurium ArnC; the key enzyme in lipid-A modification conferring polymyxin resistance.

Polymyxins are last-resort antimicrobial peptides administered clinically against multi-drug resistant bacteria, specifically in the case of Gram-negative species. However, an increasing number of these pathogens employ a defense strategy that involves a relay of enzymes encoded by the pmrE (ugd) loci and the arnBCDTEF operon. The pathway modifies the lipid-A component of the outer membrane (OM) lipopolysaccharide (LPS) by adding a 4-amino-4-deoxy-l-arabinose (L-Ara4N) headgroup, which renders polymyxins ineffective.

Metabolic profiles of cutaneous lupus have abnormalities in the nicotinamide adenine dinucleotide pathway.

Objective: Metabolic reprogramming plays a critical role in modulating the innate and adaptive immune response, but its role in cutaneous autoimmune diseases, such as cutaneous lupus erythematosus (CLE), is less well studied. An improved understanding of the metabolic pathways dysregulated in CLE may lead to novel treatment options, biomarkers and insights into disease pathogenesis. The objective was to compare metabolomic profiles in the skin and sera of CLE and control patients using liquid chromatography-mass spectrometry (LC-MS).

An Updated Systematic Review and Network Meta-Analysis of First-Line Triplet vs. Doublet Therapies for Metastatic Hormone-Sensitive Prostate Cancer.

: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies.

Association of an HIV-Prediction Model with Uptake of Pre-Exposure Prophylaxis (PrEP).

Background: Global efforts aimed at ending human immunodeficiency virus (HIV) incidence have adapted and evolved since the turn of the century. The utilization of machine learning incorporated into an electronic health record (EHR) can be refined into prediction models that identify when an individual is at greater HIV infection risk. This can create a novel and innovative approach to identifying patients eligible for preventative therapy.

Romosozumab Improves Tissue Thickness-Adjusted Trabecular Bone Score in Women With Osteoporosis and Diabetes.

Context: Trabecular bone score (TBS), a gray-level texture index derived from lumbar spine (LS) dual-energy x-ray absorptiometry (DXA) scans, is decreased in patients with diabetes and is associated with increased fracture risk, independent of areal bone mineral density (aBMD), but potentially influenced by abdominal fat tissue.

Objective: Evaluate effect of romosozumab (210 mg monthly) for 12 months followed by alendronate (70 mg weekly) for 24 months vs alendronate alone (70 mg weekly) for 36 months on LS aBMD and TBS in women with type 2 diabetes (T2D) enrolled in the ARCH study.

Methods: This post hoc analysis included women from ARCH who had T2D at baseline and LS DXA scans at baseline and ≥1 postbaseline visit (romosozumab-to-alendronate, n = 165; alendronate-to-alendronate, n = 195).

A Generalized Bayesian Stochastic Block Model for Microbiome Community Detection.

Advances in next-generation sequencing technology have enabled the high-throughput profiling of metagenomes and accelerated microbiome studies. Recently, there has been a rise in quantitative studies that aim to decipher the microbiome co-occurrence network and its underlying community structure based on metagenomic sequence data. Uncovering the complex microbiome community structure is essential to understanding the role of the microbiome in disease progression and susceptibility.

Concussion and the Autonomic, Immune, and Endocrine Systems: An Introduction to the Field and a Treatment Framework for Persisting Symptoms.

A significant proportion of patients who sustain a concussion/mild traumatic brain injury endorse persisting, lingering symptoms. The symptoms associated with concussion are nonspecific, and many other medical conditions present with similar symptoms. Medical conditions that overlap symptomatically with concussion include anxiety, depression, insomnia, chronic pain, chronic fatigue, fibromyalgia, and cervical strain injuries.

Interaction Between Malat1 and miR-499-5p Regulates Meis1 Expression and Function with a Net Impact on Cell Proliferation.

Meis1 is a transcription factor involved in numerous functions including development and proliferation and has been previously shown to harness cell cycle progression. In this study, we used in silico analysis to predict that miR-499-5p targets Meis1 and that Malat1 sponges miR-499-5p. For the first time, we demonstrated that the overexpression of miR-499-5p led to the downregulation of Meis1 mRNA and protein in C166 cells by directly binding to its 3'UTR.

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118.

Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118.

Bone-Induced Her2 Promotes Secondary Metastasis in HR+/Her2- Breast Cancer.

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases.

Closing the Gap: The Need for Fertility Intervention for Young Adult Cancer Survivors.

The current study identified the fertility-related needs of young adult (YA; ages 19-39) survivors. Participants ( = 94) completed the Adolescent and Young Adult Survivorship Psycho-Oncology Screening Tool-a screening tool developed to assess cancer-related concerns of YAs in survivorship. Approximately one-third of survivors endorsed fertility-related concerns.

Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial.

Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3-5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study.

The Human Urinary Microbiome and Its Potential Role in Urinary Tract Infections.

After identifying a urinary microbiota, new insights have emerged into how urinary tract infections (UTIs) develop and recur in women. This review explores factors influencing the urinary microbiome, and its role in UTI susceptibility and recurrence. Age, menopausal status, estrogen, and prior UTIs can impact the urinary microbiome significantly, with estrogen promoting predominance of beneficial Lactobacillus species in women.

Creating a collaborative culture of learning within a network of community mental health early psychosis programs in Texas.

Learning Health Systems (LHSs) promise meaningful health care improvement through the ongoing use of data, including the lived experience of diverse constituents, such as people participating in and providing services. Most LHSs operate within a specific healthcare system, typically hospital-based, under a common electronic health record (EHR) and management structure. The Early Psychosis Intervention Network in Texas (EPINET-TX) is a novel case study of a developing LHS across 16 independent community mental health clinics operating state-funded coordinated specialty care (CSC) programs for early psychosis.

Collagen turnover during cervical remodeling involves both intracellular and extracellular collagen degradation pathways.

Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown.

Development, review, and activation of thoracic oncology investigator-initiated trials.

Background: Investigator-initiated trials (IITs) may address important biological and clinical questions that may not be prioritized by pharmaceutical sponsors. However, little is known about the process by which IIT proposals are evaluated and activated.

Methods: We performed a retrospective study of IIT concepts submitted through the Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC), which comprises 13 institutions in the U.

Detection of Elder Abuse Through Emergency Care Technicians Screening Tool Revision for Home-Based Primary Care (DETECT-RPC): a cluster randomised controlled trial study protocol.

Introduction: The annual prevalence of elder mistreatment (EM) in cognitively intact older adults is estimated to be 11%, yet the annual prevalence in older adults with Alzheimer's disease and related dementias (AD/ADRD) is estimated to be as high as 75%. Associated with a decrease in quality of life and increase in risk of mortality, EM represents a significant public health burden. Home-based primary care (HBPC) providers are uniquely positioned to address the critical need for robust EM screening and reporting, especially among individuals with AD/ADRD.

The Dose-Dependent Effect of Obesity on Adverse Maternal and Neonatal Outcomes in a Hispanic Population.

Objective: To evaluate the frequency of adverse maternal and neonatal outcomes associated with maternal obesity in a Hispanic population. We hypothesized that obesity confers a dose-dependent risk associated with these outcomes.

Study Design: This was a retrospective cohort study of singleton pregnancies delivered between 24 and 42 weeks gestation at an urban county hospital between 2013 and 2021.

Intracellular Retention of Estradiol is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells.

Elevated blood levels of estrogens are associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating blood hormone levels and intracellular hormone concentrations are not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal.

Protocol for the three-dimensional analysis of rodent skeletal muscle.

Confocal imaging is a powerful tool capable of analyzing cellular spatial data within a given tissue. Here, we present a protocol for preparing optically cleared extensor digitorum longus (EDL) skeletal muscle samples suitable for confocal imaging/computational analysis. We describe steps for sample preparation (including perfusion fixation and tissue clearing of muscle samples), image acquisition, and computational analysis, with sample segmentation/3D rendering outlined.

Analysis of healthcare utilization before the diagnosis of radiologically isolated syndrome.

Background: Previous studies have shown that people with multiple sclerosis (MS) had frequent healthcare visits up to 10 years before being diagnosed but with no information from magnetic resonance imaging (MRI) scans of the connection with the radiologically isolated syndrome (RIS).

Objective: To analyze healthcare use 3 years before the RIS diagnosis.

Methods: We examined healthcare usage before the first scan in RIS cases from 2010 to 2019.